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Yang J, Duan Y, Wu Q, Ma Y, Tan S, Zhang Y, Zhang J, Liu X. Insights into modifiable risk factors of migraine: a Mendelian randomization analysis. Neurol Res 2025:1-20. [PMID: 40366766 DOI: 10.1080/01616412.2025.2504717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Accepted: 05/05/2025] [Indexed: 05/16/2025]
Abstract
OBJECTIVES Increasing epidemiological evidence has reported that various factors are associated with migraine risk and subtypes. Nevertheless, definitive conclusions regarding whether the putative modifiable risk factors are causally related to the pathogenesis of migraine have not been drawn. METHODS Using single-nucleotide polymorphisms as instrumental variables, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of 38 modifiable factors, including dietary nutrients, lifestyle factors, cardiometabolic diseases, and associated traits, as well as reproductive characteristics and sex hormones, on the risk of migraine, migraine with aura (MA), and migraine without aura (MO). Subsequently, meta-analyses were performed to combine causal estimates from two independent genome-wide association studies. RESULTS In the combined findings with multiple test correction, genetically predicted higher alcohol intake frequency (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.12-1.40), lifetime smoking index (OR: 1.24; 95% CI: 1.08-1.42), insomnia (OR: 1.20; 95% CI: 1.17-1.24), long sleep duration (OR: 1.26; 95% CI: 1.07-1.50), and hypertension (OR: 1.76; 95% CI: 1.47-2.11) were causally linked to migraine incidence. Subgroup analyses revealed higher carbohydrate and sugar intake, alcohol consumption frequency, lifetime smoking index, insomnia, and hypertension causally increased susceptibility to MA, while later age at first birth (AFB) had a protective effect on MA risk. Meanwhile, the MR findings revealed a detrimental association between alcohol intake frequency, insomnia, hypertension, and early AFB and MO incidence. DISCUSSION Overall, our study demonstrated various causal risk factors for migraine and its subtypes risk, providing insights into its pathogenesis and potential prevention strategies. Further research is needed to validate these findings and explore their clinical implications and underlying mechanisms.
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Affiliation(s)
- Junyi Yang
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, Liaoning, China
| | - Yuanjie Duan
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, Liaoning, China
| | - Qian Wu
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, Liaoning, China
| | - Yumei Ma
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, Liaoning, China
| | - Shutong Tan
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, Liaoning, China
| | - Yue Zhang
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, Liaoning, China
| | - Jian Zhang
- Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
- Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the People's Republic of China, China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Medical Cell Biology, Ministry of Education of the People's Republic of China, China Medical University, Shenyang, Liaoning, China
| | - Xu Liu
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
- Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, Liaoning, China
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Liu L, Cheng Y, Yan S, Zhou J. Exploring the Links Between Micronutrients and Cardiac Traits: Roles of Vitamins A1, B9, and D. J Gene Med 2025; 27:e70022. [PMID: 40405315 DOI: 10.1002/jgm.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 04/29/2025] [Accepted: 05/08/2025] [Indexed: 05/24/2025] Open
Abstract
OBJECTIVE Micronutrients, such as vitamins and minerals, are essential for cardiac health, but their effects on cardiac structure and function remain unclear. This study aimed to investigate the causal impact of micronutrients on cardiac traits through Mendelian randomization (MR). METHODS A two-sample MR approach was employed to assess the causal effects between 14 micronutrients and 98 cardiac traits from various consortia and cohorts. Inverse variance-weighted (IVW) MR analyses were conducted, alongside a range of sensitivity analyses to confirm robustness. Both exposure and outcome populations were of European descent. RESULTS Significant associations were found for Vitamins A1, B9, and D with various cardiac traits. Vitamin D was linked to reduced left ventricular end-diastolic myocardial wall thickness (IVW β: -0.16; 95% CI: -0.29 to -0.03; p = 0.01) and increased regional longitudinal and radial strains of the left ventricle (IVW β: 0.19; p = 0.03; IVW β: 0.17; p = 0.04). Vitamin A1 was associated with reduced left ventricular mass (IVW β: -10.23; p = 0.03; IVW β: -13.72; p = 0.007), both with and without body surface area and blood pressure adjustments. Vitamin B9 was associated with reductions in left ventricular mass (IVW β: -0.09; p = 0.04), myocardial wall thickness (IVW β: -0.13; p = 0.04), and ascending aorta maximum area (IVW β: -0.19; p = 0.01). No significant heterogeneity or horizontal pleiotropy was observed. CONCLUSIONS Vitamins A1, B9, and D exhibit beneficial effects on cardiac structure and function, offering potential targets for nutritional intervention in at-risk populations.
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Affiliation(s)
- Lingwei Liu
- Department of Nuclear Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yongxi Cheng
- Department of Cardiology, Shangrao Municipal Hospital, Shangrao, Jiangxi, China
| | - Shujun Yan
- Department of Obstetrics and Gynecology Medicine, Zhoukou Maternal and Child Health Hospital, Zhoukou, Henan, China
| | - Jian Zhou
- Department of Cardiovascular Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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Yuan S, Long C, Zhang X, Yuan M, Li J, Wu H. Causal Effects of Circulating Micronutrients on Cognitive Function: Evidence From a Mendelian Randomization Study. Brain Behav 2025; 15:e70488. [PMID: 40259845 PMCID: PMC12012310 DOI: 10.1002/brb3.70488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/05/2025] [Accepted: 03/31/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND Cognitive impairment is a growing concern worldwide, driven by an aging population. Emerging evidence suggests that micronutrients may play critical roles in maintaining cognitive health and preventing neurodegeneration. However, the causal relationships between specific micronutrients and cognitive function remain unclear. METHODS This study employed a two-sample Mendelian randomization (MR) approach to investigate the causal effects of 16 circulating micronutrients on cognitive function. Genetic variants associated with micronutrient levels were used as instrumental variables (IVs), and cognitive outcomes, including reaction time, cognitive performance, prospective memory, and fluid intelligence, were assessed using publicly available genome-wide association study (GWAS) datasets. Sensitivity analyses were conducted to evaluate heterogeneity, pleiotropy, and robustness of the findings. RESULTS MR analysis revealed potential positive effects of β-carotene and phosphorus on reaction time, reflecting faster cognitive responses. Vitamin E was positively associated with cognitive performance, while vitamin B6 had a negative effect. Selenium was positively correlated with fluid intelligence, whereas elevated vitamin A1 levels were associated with reduced fluid intelligence. No significant associations were observed for other micronutrients across the cognitive domains assessed. CONCLUSION This study highlights the roles of specific micronutrients, like β-carotene, phosphorus, selenium, and vitamin E, in cognitive health, while excessive vitamin A1 and B6 may be harmful, warranting further investigation.
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Affiliation(s)
- Sen‐fu Yuan
- Department of PathologyThe First People's Hospital of YibinYibinChina
| | - Chang‐hai Long
- Department of PathologyThe First People's Hospital of YibinYibinChina
| | - Xu Zhang
- Department of PathologyThe First People's Hospital of YibinYibinChina
| | - Mi Yuan
- Department of PathologyThe First People's Hospital of YibinYibinChina
| | - Jun Li
- Department of PathologyThe First People's Hospital of YibinYibinChina
| | - He‐gang Wu
- Department of PathologyThe First People's Hospital of YibinYibinChina
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Li C, Deng J, Huang W, Chen W, Wei L, Ran G, Liu L, Li Z, Liu M, Huang D, Liu S, Zeng X, Wang L. Effects of micronutrients on neurodevelopmental disorders through the mediation of brain structure and function: A two-step Mendelian randomization analysis. AUTISM : THE INTERNATIONAL JOURNAL OF RESEARCH AND PRACTICE 2025:13623613251326702. [PMID: 40145617 DOI: 10.1177/13623613251326702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
The physiological functions of micronutrients in neurodevelopment are well documented, but their protective effects on neurodevelopmental disorders remain controversial. We assessed the associations between micronutrients and three main neurodevelopmental disorders, that is, autism spectrum disorder (18,381 cases), attention-deficit/hyperactivity disorder (38,691 cases), and Tourette's syndrome (4,819 cases), using two-sample Mendelian randomization analyses. In addition, we estimated the mediation role of brain imaging-derived phenotypes (n = 33,224) in these associations. Each 1 SD (0.08 mmol/L) increase in serum magnesium concentration was associated with a 16% reduced risk of autism spectrum disorder (odds ratio 0.84, 95% confidence interval 0.72-0.98). Each 1 SD (65 μmol/L) increase in blood erythrocyte zinc concentration was associated with an 8% reduced risk of attention-deficit/hyperactivity disorder (0.92, 0.86-0.98). Each 1 SD (173 pmol/L) increase in serum vitamin B12 concentration was associated with a 19% reduced risk of Tourette's syndrome (0.81, 0.68-0.97). These effects were partly mediated by alterations in multiple brain imaging-derived phenotypes, with mediated proportions ranging from 5.84% to 32.66%. Our results suggested that interventions targeting micronutrient deficiencies could be a practical and effective strategy for preventing neurodevelopmental disorders, especially in populations at high risk of malnutrition.Lay abstractIncreasing evidence highlights the critical role of micronutrients in neurodevelopment. However, the causal relationship between micronutrients and neurodevelopmental disorders remains unclear. Using genetic variants associated with micronutrient levels and neurodevelopmental disorders, our study revealed the protective effects of magnesium on autism spectrum disorders, zinc on attention-deficit/hyperactivity disorder, and vitamin B12 on Tourette's syndrome. These protective effects were partially mediated through alterations in brain structure, function, and connectivity. Our findings emphasize the importance of adequate micronutrient intake for healthy neurodevelopment and may support the development of intervention strategies aimed at preventing neurodevelopmental disorders by addressing micronutrient deficiencies.
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Affiliation(s)
| | | | | | | | | | | | - Lili Liu
- Guangxi Medical University, China
| | | | | | | | - Shun Liu
- Guangxi Medical University, China
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Zhang Y, Xia H, Yang S, Yu W, Liu M, Li D. Dietary factors and the risk of gastric and colorectal cancers: A Mendelian randomization study. Medicine (Baltimore) 2025; 104:e41610. [PMID: 39960923 PMCID: PMC11835071 DOI: 10.1097/md.0000000000041610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 01/31/2025] [Indexed: 02/20/2025] Open
Abstract
Dietary factors can significantly affect the development of gastric and colorectal cancers; however, observational findings on the impact of micronutrients and macronutrients on the risk of gastric and colorectal cancers are inconsistent. It is crucial to clarify these relationships to create nutritional recommendations for cancer prevention. A two-sample Mendelian randomization investigation was performed to examine the impact of circulating levels of 15 micronutrients (such as vitamin A, folate, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc), along with adjusted relative macronutrient intake (including protein, carbohydrate, sugar, and fat), on the risk of gastric and colorectal cancers. Genetically predicted relative protein intake is significantly associated with the risk of colorectal cancer (odds ratio [OR] 95% confidence interval [CI] = 0.41 [0.24, 0.69]; P = .0007). Evidence suggests that genetically predicted macronutrients, such as carbohydrate (OR 95% CI = 1.88 [1.13, 3.14]; P = .0154), and micronutrients, such as vitamin C (OR 95% CI = 0.81 [0.69-0.94]; P = .008) and vitamin B12 (OR 95% CI = 1.16 [1.04, 1.28]; P = .006), may also influence the risk of colorectal cancer. Evidence suggests that intake of sugar (OR 95% CI = 0.47 [0.24, 0.90]; P = .02), and vitamin C (OR 95% CI = 0.78 [0.62, 0.99]; P = .04) may influence the risk of gastric cancer. However, no significant associations were observed between other nutrients and gastrointestinal malignancy. Taken together, these findings suggest that the intake of protein, carbohydrate, sugar, vitamin C, and vitamin B12 may influence the risk of gastric and colorectal cancers. However, further in-depth studies are needed to confirm this.
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Affiliation(s)
- Yunda Zhang
- Department of General Surgery, DongGuan SongShan Lake Tungwah Hospital, DongGuan, China
| | - Haiqun Xia
- Department of Radiation Oncology, DongGuan SongShan Lake Tungwah Hospital, DongGuan, China
| | | | - Weixuan Yu
- Department of General Surgery, DongGuan SongShan Lake Tungwah Hospital, DongGuan, China
| | - Ming Liu
- Department of General Surgery, DongGuan SongShan Lake Tungwah Hospital, DongGuan, China
| | - Dongwei Li
- Department of General Surgery, DongGuan SongShan Lake Tungwah Hospital, DongGuan, China
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Zhang R, Luo L, Zhang L, Lin X, Wu C, Jiang F, Wang J. Genetically Supported Causality Between Micronutrients and Sleep Behaviors: A Two-Sample Mendelian Randomization Study. Brain Behav 2025; 15:e70237. [PMID: 39910798 PMCID: PMC11799067 DOI: 10.1002/brb3.70237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 08/28/2024] [Accepted: 12/14/2024] [Indexed: 02/07/2025] Open
Abstract
BACKGROUND Sleep behaviors, defined by the total duration of sleep and chronotype, significantly influence overall health. Compromised sleep quality, which is often manifested through reduced sleep duration and the prevalence of insomnia, has been found to be associated with micronutrient deficiencies. Nonetheless, the existence of a causal relationship between micronutrient levels and sleep behaviors remains to be established. METHODS A two-sample Mendelian randomization (MR) analysis, utilizing data from genome-wide association studies (GWAS), was employed to examine the associations between 15 micronutrients (copper; calcium; carotene; folate; iron; magnesium; potassium; selenium; vitamins A, B12, B6, C, D, and E; and zinc) and various sleep behaviors, including short and long sleep durations, insomnia, and chronotype. Furthermore, multivariable MR (MVMR) analysis was performed to address potential confounding due to the interrelationships among micronutrients and to discern potential causal relationships. RESULTS The MR analysis identified a causal association between folate levels and chronotype (odds ratio [OR] = 1.09; 95% confidence interval [CI]: 1.01-1.17; p = 0.02), indicating a tendency toward morningness. Conversely, vitamin B6 (OR = 0.91; 95% CI: 0.86-0.96; p = 1.05 × 10-3) and vitamin D (OR = 0.94; 95% CI: 0.88-1.00; p = 0.03) showed inverse associations with chronotype, indicative of a preference for eveningness. MVMR analysis confirmed the positive association between folate (OR = 1.286, 95% CI = 1.124-1.472, p < 0.001) and chronotype and a negative association with vitamin B6 (OR = 0.750, 95% CI = 0.648-0.868, p < 0.001). No causal relationships were established between micronutrient levels and either sleep duration or insomnia. CONCLUSIONS Elevated folate levels correlate with morning-type preferences ("morning birds"), while higher concentrations of vitamin B6 are associated with evening-type preferences ("evening owls").
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Affiliation(s)
- Ruijie Zhang
- Department of NeonatologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Liyan Luo
- Department of NeonatologyDali Bai Autonomous Prefecture Maternal and Child Health Care HospitalDaliChina
| | - Lu Zhang
- Department of NeonatologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Xinao Lin
- Department of NeonatologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Chuyan Wu
- Department of Rehabilitation MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Feng Jiang
- Department of NeonatologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Jimei Wang
- Department of NeonatologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
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Zeng X, Wu Z, Pan Y, Ma Y, Chen Y, Zhao Z. Effects of micronutrients and macronutrients on risk of allergic disease in the European population: a Mendelian randomization study. FOOD AGR IMMUNOL 2024; 35. [DOI: 10.1080/09540105.2024.2442369] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/10/2024] [Indexed: 01/21/2025] Open
Affiliation(s)
- Xiangyue Zeng
- Department of Gastrointestinal Surgery, the Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
| | - Zhimin Wu
- Department of Otorhinolaryngology, Guiyang maternal and child health care hospital, the maternal and child health care hospital of Guizhou Medical University, Guiyang, People’s Republic of China
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China
| | - Yipeng Pan
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yifei Ma
- Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China
| | - Yi Chen
- Department of Breast and Thyroid Surgery, the Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
| | - Zeliang Zhao
- Department of Gastrointestinal Surgery, the Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
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Kashyap S, Gowda P, Pasanna RM, Sivadas A, Sachdev HS, Kurpad AV, Devi S. The Oral Bioavailability of Vitamin B 12 at Different Doses in Healthy Indian Adults. Nutrients 2024; 16:4157. [PMID: 39683551 PMCID: PMC11643782 DOI: 10.3390/nu16234157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/04/2024] [Accepted: 11/06/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND/OBJECTIVES The bioavailability of crystalline vitamin B12 (B12) through active absorption is reported to have a maximum capacity of 1.5-2.5 µg per dose. A small passive bioavailability has also been suggested at high doses. The present study aimed to determine the dose-dependency of active B12 absorption and to quantify its passive absorption at higher doses. METHODS The dose-dependency of crystalline B12 bioavailability was determined in nine healthy adults, using oral [13C]-cyanocobalamin, in a cross-over design at doses of 2.5, 5, and 10 µg. The dose order was randomised, with a washout of one month. Literature data from was added to the present study data in a meta-analysis of the relation between B12 bioavailability and dose, to evaluate its pattern at different doses. RESULTS Bioavailability, as a function of dose, was significantly different between 2.5, 5, and 10 µg doses of [13C]-cyanocobalamin at 50.9 ± 32.5%, 26.7 ± 22.3%, 15.4 ± 13.6%, respectively, (p < 0.01), while the absolute bioavailability trended upward, at 1.16 ± 0.74 µg, 1.22 ± 1.02 µg, and 1.39 ± 1.23 µg (p = 0.46). The meta-analysis showed two distinct phases of bioavailability. Up to a dose of 2.6 µg, there was a significant steep positive correlation, with a slope (bioavailability) of 43%/µg suggesting an active process with a maximum of 1.2 µg. At higher doses, the slope was 1%/µg, not significantly different from zero, possibly a passive process. CONCLUSIONS The active bioavailability of crystalline B12 is not dose-dependent, saturating at ~1.2 µg.
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Affiliation(s)
- Sindhu Kashyap
- Division of Nutrition, St. John’s Research Institute, St. John’s National Academy of Health Sciences, Bangalore 560034, India; (S.K.); (R.M.P.)
| | - Poorvikha Gowda
- St. John’s Medical College, St. John’s National Academy of Health Sciences, Bangalore 560034, India;
| | - Roshini M. Pasanna
- Division of Nutrition, St. John’s Research Institute, St. John’s National Academy of Health Sciences, Bangalore 560034, India; (S.K.); (R.M.P.)
| | - Ambily Sivadas
- Department of Molecular Biology and Genetics, St. John’s Medical College Hospital, St. John’s National Academy of Health Sciences, Bangalore 560034, India;
| | - Harshpal S. Sachdev
- Department of Paediatrics, Sitaram Bhartia Institute of Science and Research, New Delhi 110016, India;
| | - Anura V. Kurpad
- Department of Physiology, St. John’s Medical College, St. John’s National Academy of Health Sciences, Bangalore 560034, India;
| | - Sarita Devi
- Division of Nutrition, St. John’s Research Institute, St. John’s National Academy of Health Sciences, Bangalore 560034, India; (S.K.); (R.M.P.)
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Dong G, Xu W, Xu L. Causal Effect of Macronutrient and Micronutrient Intake on Stroke: A Two-Sample Mendelian Randomization Study. Nutrients 2024; 16:2818. [PMID: 39275138 PMCID: PMC11397079 DOI: 10.3390/nu16172818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/22/2024] [Accepted: 08/22/2024] [Indexed: 09/16/2024] Open
Abstract
(1) Background: Estimating the causal association between nutrient intake, as a modifiable risk factor, and stroke risk is beneficial for the prevention and management of stroke. However, observational studies are unavoidably influenced by confounding factors and reverse causation. (2) Methods: We performed a two-sample Mendelian randomization (MR) to estimate the effects of nutrient intake on stroke risk. Summary statistics for nutrients, including 4 macronutrients and 14 micronutrients, were derived from 15 genome-wide association studies (GWAS). Data on stroke and its subtypes were sourced from the MEGASTROKE consortium. (3) Results: Genetically predicted magnesium levels, as the protective factors, were significantly associated with a lower risk of cardioembolic stroke (OR: 0.011, 95% CI: 0-0.25, p-value: 0.005) in the IVW method. Additionally, vitamin C reduced the risk of cardioembolic stroke (OR: 0.759, 95% CI: 0.609-0.946, p-value: 0.014) and vitamin B9 reduced the risk of small vessel stroke (OR: 0.574, 95% CI: 0.393-0.839, p-value: 0.004) with the IVW method. However, the association of vitamin B6 with an increased risk of large-artery stroke (OR: 1.546, 95% CI: 1.009-2.37, p-value: 0.046) in the Wald ratio method should be interpreted cautiously due to the limited number of SNPs. There was also suggestive evidence that magnesium might decrease the risk of both any stroke and ischemic stroke. (4) Conclusions: Our MR analysis highlights the protective roles of magnesium, vitamin C, and vitamin B9 in stroke prevention, making them key targets for public health strategies. However, the findings related to vitamin B6 are less certain and require further validation.
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Affiliation(s)
- Guozhang Dong
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210009, China
| | - Wanqian Xu
- Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen 361023, China
| | - Lin Xu
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210009, China
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Wei Z, Xiong Q, Liang L, Wu Z, Chen Z. Circulating micronutrient levels and respiratory infection susceptibility and severity: a bidirectional Mendelian randomization analysis. Front Nutr 2024; 11:1373179. [PMID: 39176028 PMCID: PMC11338864 DOI: 10.3389/fnut.2024.1373179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 07/29/2024] [Indexed: 08/24/2024] Open
Abstract
Background Limited and inconclusive data from observational studies and randomized controlled trials exist on the levels of circulating micronutrients in the blood and their association with respiratory infections. Methods A Mendelian randomization (MR) analysis was conducted to assess the impact of 12 micronutrients on the risk of three types of infections [upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), and pneumonia] and their 14 subtypes. This study utilized a bidirectional MR approach to evaluate causal relationships and included a range of sensitivity analyses and multivariable MR to address potential heterogeneity and pleiotropy. The threshold for statistical significance was set at p < 1.39 × 10-3. Results Meta-analysis revealed that higher levels of circulating copper were significantly associated with a reduced risk of URTI (odds ratio (OR) = 0.926, 95% CI: 0.890 to 0.964, p = 0.000195). Additionally, copper demonstrated a suggestive association with a reduced risk of LRTI (p = 0.0196), and Vitamin B6 was nominally associated with a reduced risk of pneumonia (p = 0.048). Subtype analyses further indicated several suggestive associations: copper reduces the risk of acute pharyngitis (p = 0.029), vitamin C increases the risk of critical care admissions for pneumonia (p = 0.032) and LRTI (p = 0.021), and folate reduces the risk of viral pneumonia (p = 0.042). No significant connections were observed for other micronutrients. Conclusion We observed a genetically predicted potential protective effect of copper in susceptibility to upper respiratory infections. This provides new insights for further research into the role of micronutrients in the prevention and treatment of infection.
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Affiliation(s)
- Zhengxiao Wei
- Department of Clinical Laboratory, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Qingqing Xiong
- Department of Scientific Research and Teaching, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Li Liang
- Department of Tuberculosis, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Zhangjun Wu
- Department of Clinical Laboratory, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Zhu Chen
- Department of Scientific Research and Teaching, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
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Changhai L, Zaichun W, Bo Y, Dan L, Shaohua W. Micronutrients and Allergic Diseases: A Mendelian Randomization Study. Int Arch Allergy Immunol 2024; 186:41-51. [PMID: 39106841 DOI: 10.1159/000540376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/09/2024] [Indexed: 08/09/2024] Open
Abstract
INTRODUCTION Previous studies have indicated a controversy regarding the association between dietary micronutrient concentrations and the risk of allergic diseases. In this study, we employed Mendelian randomization (MR) analysis using data from two samples to investigate the causal relationship between circulating micronutrient concentrations and three allergic diseases. METHODS In this study, we considered 16 circulating micronutrients as exposure variables (beta carotene, calcium, copper, folate, iron, lycopene, magnesium, phosphorus, selenium, vitamin A1, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, and zinc); and three common allergic diseases (allergic asthma [AA], atopic dermatitis [AD], and allergic rhinitis [AR]) as outcomes. The inverse variance weighted (IVW) method was primarily applied for MR analysis, supplemented by MR-Egger and weighted-median methods to corroborate the IVW results; and sensitivity analysis was conducted to ensure the robustness of the MR assumptions. RESULTS Our results revealed that an increase in serum phosphorus and zinc concentrations may diminish the risk of AA, while for AD an increase in serum zinc concentration may reduce the risk, but an increase in serum vitamin C concentration may elevate the risk. As for AR, an increase in serum phosphorus and selenium concentrations appeared to be associated with a reduced risk. We did not find evidence for an association between other micronutrients and the risk of allergic diseases. CONCLUSION Our study indicates that an increase in serum phosphorus and zinc concentrations may reduce the risk of AA, while an increase in serum zinc concentration may reduce the risk of AD, but an increase in serum vitamin C concentration may elevate the risk of AD. An increase in serum phosphorus and selenium concentrations is associated with a reduced risk of AR. This provides additional support for research on the effects of micronutrients on allergic diseases.
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Affiliation(s)
- Long Changhai
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China,
| | - Wu Zaichun
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yang Bo
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Li Dan
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wang Shaohua
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Huang T, Lu F. Genetically predicted circulating concentrations of micronutrients and risk of hypertensive disorders of pregnancy: a Mendelian randomization study. Arch Gynecol Obstet 2024; 310:1019-1025. [PMID: 38194093 DOI: 10.1007/s00404-023-07331-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 12/01/2023] [Indexed: 01/10/2024]
Abstract
PURPOSE Epidemiological studies examining the association between circulating micronutrients and the risk of hypertensive disorders during pregnancy (HDP) have produced inconsistent results. Therefore, we conducted a Mendelian randomization (MR) analysis to evaluate the potential causal relationship between micronutrients and HDP. METHODS Nine micronutrients (beta-carotene, vitamin B6, vitamin B12, calcium, zinc, selenium, copper, folate, and phosphorus) were selected as the exposure factors. Summary data for gestational hypertension (14,727 cases and 196,143 controls) and preeclampsia/eclampsia (7212 cases and 174,266 controls) were extracted from the FinnGen consortium. The MR analysis employed the inverse variance weighted method and conducted a range of sensitivity analyses. RESULTS The inverse variance weighted method indicated no significant causal relationship between nine genetically predicted micronutrient concentrations and gestational hypertension, as well as preeclampsia/eclampsia. Sensitivity analyses suggested the absence of pleiotropy. CONCLUSION There is no strong evidence to support the causation between circulating micronutrients and hypertensive disorder during pregnancy.
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Affiliation(s)
- Ting Huang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Fan Lu
- Department of Emergency, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China.
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Bouguerra K, Tazir M, Melouli H, Khelil M. The methylenetetrahydrofolate reductase C677T and A1298C genetic polymorphisms and plasma homocysteine in Alzheimer's disease in an Algerian population. Int J Neurosci 2024; 134:918-923. [PMID: 36580407 DOI: 10.1080/00207454.2022.2158825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/02/2022] [Accepted: 12/10/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND The etiology of Alzheimer's disease (AD) is multifactorial. The most important challenge of research is the identification of potential biomarkers associated with AD pathogenesis that may significantly contribute to early diagnosis of the disease. We aim to explore an eventual association of the C677T and A1298C genetic polymorphisms in the MTHFR gene with AD risk in an Algerian population. METHODS This case-control study involved comparing a group of 106 patients that had developed AD to another group of 104 non-demented individuals. The MTHFR genotypes were determined using PCR-RFLP method. Additionally, the homocysteine level was evaluated. RESULTS Genotypes analysis did not show an association for both MTHFR677CT and 677TT variants with AD risk (OR = 1.12; p = 0.66; OR = 1.76; p = 0.09) respectively. As expected, the 677CC wild type genotype showed a protective role against AD (OR = 0.52; p = 0.03). For 1298AC MTHFR variant, the distribution of different genotypes did not show a statistical significant difference between the two cohorts. However the silmutaneous carrier, CT/AC presented association with AD (OR = 5.96; p = 0.05). On the other hand, carrier-state of MTHFR T allele showed a relationship with AD (OR = 1.98; p = 0.02). Additionally, hyperhomocysteinemia seems to be a risk factor for AD (OR = 1.08; p = 0.02). CONCLUSION Our exploration reveals that the silmutaneous carrier, CT/AC, carrier-state of MTHFR T allele, and hyperhomocysteinemia seem to be risk factors for AD.
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Affiliation(s)
- Khadidja Bouguerra
- Département de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, Université des Sciences et Technologie Houari Boumediene, Alger, Algérie
| | - Meriem Tazir
- Service de Neurologie, Centre Hospitalo-Universitaire (CHU) Mustapha Bacha, Alger, Algérie
| | - Hamid Melouli
- Service virus et oncogènes, Institut Pasteur, Alger, Algérie
| | - Malika Khelil
- Département de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, Université des Sciences et Technologie Houari Boumediene, Alger, Algérie
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Kotowski MJ, Ostrowski P, Sieńko J, Czerny B, Tejchman K, Machaliński B, Górska A, Mrozikiewicz AE, Bogacz A. The Importance of the FUT2 rs602662 Polymorphism in the Risk of Cardiovascular Complications in Patients after Kidney Transplantation. Int J Mol Sci 2024; 25:6562. [PMID: 38928269 PMCID: PMC11203847 DOI: 10.3390/ijms25126562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/05/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 levels in the body. Vitamin B12 deficiency associated with hyperhomocysteinemia is a major risk factor for cardiovascular diseases (CVDs), which are one of the main causes of death in patients after kidney transplantation. The aim of our study was to determine the impact of the rs602662 (G>A) polymorphism of the FUT2 gene on the functionality of transplanted kidneys and the risk of CVD in patients after kidney transplantation. The study included 402 patients treated with immunosuppression (183 patients taking cyclosporine (CsA) and 219 patients taking tacrolimus (TAC)). The analysis of the FUT2 rs602662 (G>A) polymorphism was performed using real-time PCR. Patients with CsA were more likely to be underweight (1.64% vs. 0.91%) and obese (27.87% vs. 15.98%), while those taking TAC were more likely to be of normal weight (39.27%) or overweight (43.84%). No statistically significant differences were observed comparing the mean blood pressure, both systolic and diastolic. The renal profile showed a higher median urea nitrogen concentration in patients with CsA (26.45 mg/dL (20.60-35.40) vs. 22.95 mg/dL (17.60-33.30), p = 0.004). The observed frequency of rs602662 alleles of the FUT2 gene was similar in the analyzed groups. The A allele was present in 43.7% of patients with CsA and 41.1% of those taking TAC (OR = 0.898; 95% CI: 0.678-1.189; p = 0.453). In the group with CsA, the GG genotype was present in 32.2% of patients, the GA in 48.1% and the AA in 19.7%. A similar distribution was obtained in the TAC group: GG-33.8%, GA-50.2%, and AA-16.0%. An association of genotypes containing the G allele with a higher incidence of hypertension was observed. The G allele was present in 65% of people with hypertension and in 56% of patients with normal blood pressure (p = 0.036). Moreover, the evaluation of the renal parameters showed no effect of the FUT2 polymorphism on the risk of organ rejection because the levels of creatinine, eGFR, potassium, and urea nitrogen were prognostic of successful transplantation. Our results suggest that the rs6022662 FUT2 polymorphism may influence the risk of cardiovascular diseases.
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Affiliation(s)
- Maciej Józef Kotowski
- Department of General Surgery and Transplantology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.J.K.); (P.O.); (K.T.)
| | - Piotr Ostrowski
- Department of General Surgery and Transplantology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.J.K.); (P.O.); (K.T.)
| | - Jerzy Sieńko
- Institute of Physical Culture Sciences, University of Szczecin, 70-453 Szczecin, Poland;
| | - Bogusław Czerny
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibres and Medicinal Plants, Kolejowa 2, 62-064 Plewiska, Poland; (B.C.); (A.G.)
- Department of Pharmacology and Pharmacoeconomics, Pomeranian Medical University in Szczecin, Żołnierska 48, 71-230 Szczecin, Poland
| | - Karol Tejchman
- Department of General Surgery and Transplantology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.J.K.); (P.O.); (K.T.)
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland;
| | - Aleksandra Górska
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibres and Medicinal Plants, Kolejowa 2, 62-064 Plewiska, Poland; (B.C.); (A.G.)
| | - Aleksandra E. Mrozikiewicz
- Department of Obstetrics and Women’s Diseases, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland;
| | - Anna Bogacz
- Department of Personalized Medicine and Cell Therapy, Regional Blood Center, Marcelińska 44, 60-354 Poznan, Poland
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Lv S, Ding Y, Huang J, He Y, Xie R, Shi X, Ye W. Genetic prediction of micronutrient levels and the risk of colorectal polyps: A mendelian randomization study. Clin Nutr 2024; 43:1405-1413. [PMID: 38691983 DOI: 10.1016/j.clnu.2024.04.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 05/03/2024]
Abstract
OBJECTIVE Previous epidemiological and experimental studies have yielded conflicting results regarding the influence of human micronutrient levels on the risk of colorectal polyps (CP). In our study, we conducted a two-sample Mendelian randomization (MR) investigation to probe the link between 13 human micronutrients (calcium, selenium, magnesium, phosphorus, folate, vitamins B-6, B-12, C, D, beta-carotene, iron, zinc, and copper) and the genetic susceptibility to CP. METHODS Summary statistics for CP (n = 463,010) were obtained from pan-European genome-wide association studies, and instrumental variables for 13 micronutrients were screened from published genome-wide association studies (GWAS). After selecting suitable instrumental variables, we performed a two-sample MR study, deploying sensitivity analyses to judge heterogeneity and pleiotropy, using inverse variance weighted methods as our primary estimation tool. RESULTS Our study identified that a genetic predisposition to elevated toenail and circulating selenium or serum β-carotene concentrations lowers the risk of CP occurrence. However, no statistically significant association was observed between the other 11 micronutrients and the risk of CP. CONCLUSION The study findings provide evidence that the micronutrient selenium and β-carotene may confer protective effects against the development of CP.
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Affiliation(s)
- Siyao Lv
- Department of Gastroenterology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Yunyi Ding
- Department of Nephrology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Junli Huang
- Department of Geriatrics, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Yixin He
- Gynaecologic Department of Traditional Chinese Medicine, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Ruijie Xie
- Division of Clinical Epidemiology and Aging Research, University of Heidelberg, Heidelberg, 69117, Germany.
| | - Xiaohong Shi
- Department of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China.
| | - Wei Ye
- Department of Gastroenterology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310053, China.
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Luo L, Chen G, Zhou Y, Xiang Y, Peng J. Dietary intake, antioxidants, minerals and vitamins in relation to childhood asthma: a Mendelian randomization study. Front Nutr 2024; 11:1401881. [PMID: 38846540 PMCID: PMC11153797 DOI: 10.3389/fnut.2024.1401881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 05/10/2024] [Indexed: 06/09/2024] Open
Abstract
Background Currently, there is limited and inconsistent evidence regarding the risk association between daily dietary intake, antioxidants, minerals, and vitamins with Childhood Asthma (CA). Therefore, this study employs Mendelian Randomization (MR) methodology to systematically investigate the causal relationships between daily dietary intake, serum antioxidants, serum minerals, and the circulating levels of serum vitamins with CA. Methods This study selected factors related to daily dietary intake, including carbohydrates, proteins, fats, and sugars, as well as serum antioxidant levels (lycopene, uric acid, and β-carotene), minerals (calcium, copper, selenium, zinc, iron, phosphorus, and magnesium), and vitamins (vitamin A, vitamin B6, folate, vitamin B12, vitamin C, vitamin D, and vitamin E), using them as Instrumental Variables (IVs). Genetic data related to CA were obtained from the FinnGen and GWAS Catalog databases, with the primary analytical methods being Inverse Variance Weighting (IVW) and sensitivity analysis. Results Following MR analysis, it is observed that sugar intake (OR: 0.71, 95% CI: 0.55-0.91, P: 0.01) is inversely correlated with the risk of CA, while the intake of serum circulating magnesium levels (OR: 1.63, 95% CI: 1.06-2.53, P: 0.03), fats (OR: 1.44, 95% CI: 1.06-1.95, P: 0.02), and serum vitamin D levels (OR: 1.14, 95% CI: 1.04-1.25, P: 0.02) are positively associated with an increased risk of CA. Conclusion This study identified a causal relationship between the daily dietary intake of sugars and fats, as well as the magnesium and vitamin D levels in serum, and the occurrence of CA. However, further in-depth research is warranted to elucidate the specific mechanisms underlying these associations.
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Affiliation(s)
- Liang Luo
- School of TCM Health Care, Leshan Vocational of Technical College, Leshan, Sicuan Province, China
| | - Guanglei Chen
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China
| | - Yan Zhou
- School of TCM Health Care, Leshan Vocational of Technical College, Leshan, Sicuan Province, China
| | - YaJun Xiang
- School of TCM Health Care, Leshan Vocational of Technical College, Leshan, Sicuan Province, China
| | - Jing Peng
- School of TCM Health Care, Leshan Vocational of Technical College, Leshan, Sicuan Province, China
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Tsukamoto M, Hishida A, Tamura T, Nagayoshi M, Okada R, Kubo Y, Kato Y, Hamajima N, Nishida Y, Shimanoe C, Ibusuki R, Shibuya K, Takashima N, Nakamura Y, Kusakabe M, Nakamura Y, Koyanagi YN, Oze I, Nishiyama T, Suzuki S, Watanabe I, Matsui D, Otonari J, Ikezaki H, Katsuura-Kamano S, Arisawa K, Kuriki K, Nakatochi M, Momozawa Y, Takeuchi K, Wakai K, Matsuo K. GWAS of Folate Metabolism With Gene-environment Interaction Analysis Revealed the Possible Role of Lifestyles in the Control of Blood Folate Metabolites in Japanese: The J-MICC Study. J Epidemiol 2024; 34:228-237. [PMID: 37517992 PMCID: PMC10999522 DOI: 10.2188/jea.je20220341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/30/2023] [Indexed: 08/01/2023] Open
Abstract
BACKGROUND The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites, as well as to detect related gene-environment interactions in Japanese. METHODS We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B12 (VB12) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene-environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed. RESULTS For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5 × 10-8). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB12. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity >33% on Hcy (β = 0.039, 0.038 and -0.054, P = 0.018, 0.021 and <0.001, respectively) and the interaction of MTHFR C677T with ever drinking on FA (β = 0.033, P = 0.048). CONCLUSION The present GWAS revealed the folate metabolism-associated genetic loci and gene-environment interactions with drinking and physical activity in Japanese, suggesting the possibility of future personalized cardiovascular disease prevention.
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Affiliation(s)
- Mineko Tsukamoto
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Tamura
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mako Nagayoshi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Rieko Okada
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoko Kubo
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasufumi Kato
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichiro Nishida
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | | | - Rie Ibusuki
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kenichi Shibuya
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Naoyuki Takashima
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan
| | - Yasuyuki Nakamura
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan
| | - Miho Kusakabe
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Yohko Nakamura
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Yuriko N. Koyanagi
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Takeshi Nishiyama
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Isao Watanabe
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Daisuke Matsui
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Jun Otonari
- Department of Psychosomatic Medicine, Kyushu University Graduate School of Medical Sciences, Faculty of Medical Sciences, Fukuoka, Japan
| | - Hiroaki Ikezaki
- Department of Comprehensive General Internal Medicine, Kyushu University Graduate School of Medical Sciences, Faculty of Medical Sciences, Fukuoka, Japan
| | - Sakurako Katsuura-Kamano
- Department of Preventive Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Kokichi Arisawa
- Laboratory of Public Health, Division of Nutritional Sciences, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kiyonori Kuriki
- Laboratory of Public Health, Division of Nutritional Sciences, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Masahiro Nakatochi
- Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kenji Takeuchi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of International and Community Oral Health, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Nasri K, Ben Jamaa N, Gaigi SS, Feki M, Marrakchi R. Association of MTHFR (C677T, A1298C) and MTRR A66G polymorphisms with fatty acids profile and risk of neural tube defects. Birth Defects Res 2024; 116:e2333. [PMID: 38716581 DOI: 10.1002/bdr2.2333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/29/2024] [Accepted: 03/22/2024] [Indexed: 05/14/2024]
Abstract
OBJECTIVE This study aims to determine if 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms were associated with fatty acid (FA) levels in mothers of fetuses with neural tube defects (NTDs) and whether these associations were modified by environmental factors. METHODS Plasma FA composition was assessed using capillary gas chromatography. Concentrations of studied FA were compared between 42 mothers of NTDs fetuses and 30 controls as a function of each polymorphism by the Kruskal-Wallis nonparametric test. RESULTS In MTHFR gene C677T polymorphism, cases with (CT + TT) genotype had lower monounsaturated FAs (MUFA) and omega-3 polyunsaturated FA (n-3 PUFA) levels, but higher omega-6 polyunsaturated FAs (n-6 PUFA) and omega-6 polyunsaturated FAs: omega-3 polyunsaturated FAs (n-6:n-3) ratio levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype had lower MUFA levels, but higher PUFA and n-6 PUFA levels. Controls with (AG + GG) genotype had lower n-6 PUFA levels. In MTHFR gene C677T polymorphism, cases with smoking spouses and (CT + TT) genotype had lower MUFA and n-3 PUFA levels, but higher PUFA, n-6 PUFA, and n-6:n-3 ratio levels. Cases with (CT + TT) genotype and who used sauna during pregnancy had lower n-3 PUFA levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype and who used sauna during pregnancy had higher PUFA and n-6 PUFA levels. CONCLUSIONS Further research is required to clarify the association of FA metabolism and (MTHFR, MTRR) polymorphisms with NTDs.
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Affiliation(s)
- Kaouther Nasri
- Faculty of Sciences of Bizerte, University of Carthage, Bizerte, Tunisia
- Service of Embryo-Fetopathology, Center for Maternity and Neonatology of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Nadia Ben Jamaa
- Department of Histology-Embryology, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Soumeya Siala Gaigi
- Service of Embryo-Fetopathology, Center for Maternity and Neonatology of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Moncef Feki
- Department of Biochemistry, Rabta Hospital, Tunis El Manar University Jebbari, Tunis, Tunisia
| | - Raja Marrakchi
- Laboratory of Human Genetics, Immunology and Pathology, Faculty of Sciences of Tunis, Tunis El Manar University, Tunis, Tunisia
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Wang Z, Xia K, Li J, Liu Y, Zhou Y, Zhang L, Tang L, Zeng X, Fan D, Yang Q. Essential Nutrients and White Matter Hyperintensities: A Two-Sample Mendelian Randomization Study. Biomedicines 2024; 12:810. [PMID: 38672165 PMCID: PMC11047968 DOI: 10.3390/biomedicines12040810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/24/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Stroke and dementia have been linked to the appearance of white matter hyperintensities (WMHs). Meanwhile, diffusion tensor imaging (DTI) might capture the microstructural change in white matter early. Specific dietary interventions may help to reduce the risk of WMHs. However, research on the relationship between specific nutrients and white matter changes is still lacking. We aimed to investigate the causal effects of essential nutrients (amino acids, fatty acids, mineral elements, and vitamins) on WMHs and DTI measures, including fraction anisotropy (FA) and mean diffusivity (MD), by a Mendelian randomization analysis. We selected single nucleotide polymorphisms (SNPs) associated with each nutrient as instrumental variables to assess the causal effects of nutrient-related exposures on WMHs, FA, and MD. The outcome was from a recently published large-scale European Genome Wide Association Studies pooled dataset, including WMHs (N = 18,381), FA (N = 17,663), and MD (N = 17,467) data. We used the inverse variance weighting (IVW) method as the primary method, and sensitivity analyses were conducted using the simple median, weighted median, and MR-Egger methods. Genetically predicted serum calcium level was positively associated with WMHs risk, with an 8.1% increase in WMHs risk per standard deviation unit increase in calcium concentration (OR = 1.081, 95% CI = 1.006-1.161, p = 0.035). The plasma linoleic acid level was negatively associated with FA (OR = 0.776, 95% CI = 0.616-0.978, p = 0.032). Our study demonstrated that genetically predicted calcium was a potential risk factor for WMHs, and linoleic acid may be negatively associated with FA, providing evidence for interventions from the perspective of gene-environment interactions.
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Affiliation(s)
- Zhengrui Wang
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Peking University Health Science Center, Beijing 100191, China
| | - Kailin Xia
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
| | - Jiayi Li
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Peking University Health Science Center, Beijing 100191, China
| | - Yanru Liu
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Peking University Health Science Center, Beijing 100191, China
| | - Yumou Zhou
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Peking University Health Science Center, Beijing 100191, China
| | - Linjing Zhang
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
| | - Lu Tang
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
| | - Xiangzhu Zeng
- Department of Radiology, Peking University Third Hospital, Beijing 100191, China
| | - Dongsheng Fan
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing 100191, China
- Key Laboratory for Neuroscience, National Health Commission, Ministry of Education, Peking University, Beijing 100191, China
| | - Qiong Yang
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
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Qiu Y, Li C, Huang Y, Wu C, Li F, Zhang X, Xia D. Exploring the causal associations of micronutrients on urate levels and the risk of gout: A Mendelian randomization study. Clin Nutr 2024; 43:1001-1012. [PMID: 38484526 DOI: 10.1016/j.clnu.2024.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 02/21/2024] [Accepted: 03/04/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND & AIMS Growing evidence has indicated a potential association between micronutrient levels, urate levels, and the risk of gout. However, the causal association underlying these associations still remains uncertain. Previous observational studies and randomized controlled trials investigating the association between micronutrients, urate levels, and the risk of gout have been limited in their scope and depth. The aim of this study was to utilize Mendelian randomization (MR) to investigate the causal associations between genetically predicted micronutrient levels, urate levels, and the risk of gout. METHODS In this study, we conducted a comprehensive examination of 10 specific micronutrients (vitamin B6, vitamin B12, vitamin C, vitamin D, folate, calcium, iron, copper, zinc, and selenium) as potential exposures. Two-sample MR analyses were performed to explore their causal associations with urate levels and the risk of gout. In these analyses, gout data were collected from the Global Biobank Meta-Analysis Initiative (N = 1,069,839, N cases = 30,549) and urate levels data from CKDGen Consortium (N = 288,649) by utilizing publicly available summary statistics from independent cohorts of European ancestry. We performed inverse-variance weighted MR analyses as main analyses, along with a range of sensitivity analyses, such as MR-Egger, weighted median, simple mode, weighted mode, Steiger filtering, MR-PRESSO, and Radial MR analysis, to ensure the robustness of our findings. RESULTS The results of our study indicate that there were negative associations between serum vitamin B12 and urate levels, as well as serum folate and the risk of gout. Specifically, we found a negative association between vitamin B12 levels and urate levels, with a β coefficient of -0.324 (95% CI -0.0581 to -0.0066, P = 0.0137) per one standard deviation (SD) increase. Similarly, a negative association was observed between folate levels and gout risk, with an odds ratio of 0.8044 (95% CI 0.6637 to 0.9750, P = 0.0265) per one SD increase. On the other hand, we identified positive associations between serum calcium levels and both urate levels and the risk of gout. Specifically, there was a positive association between serum calcium levels and urate levels (β coefficient: 0.0994, 95% CI 0.0519 to 0.1468, P = 4.11E-05) per one SD increase. Furthermore, a positive association was found between serum calcium levels and the risk of gout, with an odds ratio of 1.1479 (95% CI 1.0460 to 1.2598, P = 0.0036) per one SD increase. These findings were robust in extensive sensitivity analyses. By employing MR-PRESSO and Radial MR to eliminate outliers, the observed associations have been reinforced. No clear associations were found between the other micronutrients and the urate levels, as well as the risk of gout. CONCLUSION Our findings provided evidence that there were negative associations between serum vitamin B12 and urate levels, as well as serum folate and the risk of gout, while positive associations existed between the serum calcium levels and urate levels, as well as the risk of gout.
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Affiliation(s)
- Yu Qiu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Cantao Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Huang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chenxi Wu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fenfen Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaoxi Zhang
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Daozong Xia
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
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21
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Huang Q, Hu Z, Zheng Q, Mao X, Lv W, Wu F, Fu D, Lu C, Zeng C, Wang F, Zeng Q, Fang Q, Hood L. A Proactive Intervention Study in Metabolic Syndrome High-Risk Populations Using Phenome-Based Actionable P4 Medicine Strategy. PHENOMICS (CHAM, SWITZERLAND) 2024; 4:91-108. [PMID: 38884061 PMCID: PMC11169348 DOI: 10.1007/s43657-023-00115-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 06/13/2023] [Accepted: 06/16/2023] [Indexed: 06/18/2024]
Abstract
The integration of predictive, preventive, personalized, and participatory (P4) healthcare advocates proactive intervention, including dietary supplements and lifestyle interventions for chronic disease. Personal profiles include deep phenotypic data and genetic information, which are associated with chronic diseases, can guide proactive intervention. However, little is known about how to design an appropriate intervention mode to precisely intervene with personalized phenome-based data. Here, we report the results of a 3-month study on 350 individuals with metabolic syndrome high-risk that we named the Pioneer 350 Wellness project (P350). We examined: (1) longitudinal (two times) phenotypes covering blood lipids, blood glucose, homocysteine (HCY), and vitamin D3 (VD3), and (2) polymorphism of genes related to folic acid metabolism. Based on personalized data and questionnaires including demographics, diet and exercise habits information, coaches identified 'actionable possibilities', which combined exercise, diet, and dietary supplements. After a 3-month proactive intervention, two-thirds of the phenotypic markers were significantly improved in the P350 cohort. Specifically, we found that dietary supplements and lifestyle interventions have different effects on phenotypic improvement. For example, dietary supplements can result in a rapid recovery of abnormal HCY and VD3 levels, while lifestyle interventions are more suitable for those with high body mass index (BMI), but almost do not help the recovery of HCY. Furthermore, although people who implemented only one of the exercise or diet interventions also benefited, the effect was not as good as the combined exercise and diet interventions. In a subgroup of 226 people, we examined the association between the polymorphism of genes related to folic acid metabolism and the benefits of folate supplementation to restore a normal HCY level. We found people with folic acid metabolism deficiency genes are more likely to benefit from folate supplementation to restore a normal HCY level. Overall, these results suggest: (1) phenome-based data can guide the formulation of more precise and comprehensive interventions, and (2) genetic polymorphism impacts clinical responses to interventions. Notably, we provide a proactive intervention example that is operable in daily life, allowing people with different phenome-based data to design the appropriate intervention protocol including dietary supplements and lifestyle interventions. Supplementary Information The online version contains supplementary material available at 10.1007/s43657-023-00115-z.
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Affiliation(s)
- Qiongrong Huang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, CAS Center for Excellence in Nanoscience, Beijing, 100190 China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049 China
| | - Zhiyuan Hu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, CAS Center for Excellence in Nanoscience, Beijing, 100190 China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049 China
- Beijing P4 Healthcare Institute, 316 Wanfeng Road, Beijing, 100161 China
- Health Management Institute, The Second Medical Center, National Clinical Research Center for Geriatric Diseases, Chinese People’s Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853 China
- School of Nanoscience and Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049 China
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350108 Fujian China
- School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205 Hubei China
| | - Qiwen Zheng
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101 China
| | - Xuemei Mao
- Beijing P4 Healthcare Institute, 316 Wanfeng Road, Beijing, 100161 China
| | - Wenxi Lv
- Beijing P4 Healthcare Institute, 316 Wanfeng Road, Beijing, 100161 China
| | - Fei Wu
- Beijing P4 Healthcare Institute, 316 Wanfeng Road, Beijing, 100161 China
| | - Dapeng Fu
- Beijing Zhongguancun Hospital, No. 12, Zhongguancun South Road, Haidian District, Beijing, 100190 China
| | - Cuihong Lu
- Beijing Zhongguancun Hospital, No. 12, Zhongguancun South Road, Haidian District, Beijing, 100190 China
| | - Changqing Zeng
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101 China
| | - Fei Wang
- Health Management Institute, The Second Medical Center, National Clinical Research Center for Geriatric Diseases, Chinese People’s Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853 China
| | - Qiang Zeng
- Health Management Institute, The Second Medical Center, National Clinical Research Center for Geriatric Diseases, Chinese People’s Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853 China
| | - Qiaojun Fang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, CAS Center for Excellence in Nanoscience, Beijing, 100190 China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049 China
- School of Nanoscience and Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Leroy Hood
- Health Management Institute, The Second Medical Center, National Clinical Research Center for Geriatric Diseases, Chinese People’s Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853 China
- Institute for Systems Biology, Seattle, WA 98109 USA
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22
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Wei Z, Liu Y, Mei X, Zhong J, Huang F. Circulating micronutrient levels and their association with sepsis susceptibility and severity: a Mendelian randomization study. Front Genet 2024; 15:1353118. [PMID: 38435062 PMCID: PMC10904592 DOI: 10.3389/fgene.2024.1353118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 02/01/2024] [Indexed: 03/05/2024] Open
Abstract
Background: Sepsis, a global health challenge, necessitates a nuanced understanding of modifiable factors for effective prevention and intervention. The role of trace micronutrients in sepsis pathogenesis remains unclear, and their potential connection, especially with genetic influences, warrants exploration. Methods: We employed Mendelian randomization (MR) analyses to assess the causal relationship between genetically predicted blood levels of nine micronutrients (calcium, β-carotene, iron, magnesium, phosphorus, vitamin C, vitamin B6, vitamin D, and zinc) and sepsis susceptibility, severity, and subtypes. The instrumental variables for circulating micronutrients were derived from nine published genome-wide association studies (GWAS). In the primary MR analysis, we utilized summary statistics for sepsis from two independent databases (UK Biobank and FinnGen consortium), for initial and replication analyses. Subsequently, a meta-analysis was conducted to merge the results. In secondary MR analyses, we assessed the causal effects of micronutrients on five sepsis-related outcomes (severe sepsis, sepsis-related death within 28 days, severe sepsis-related death within 28 days, streptococcal septicaemia, and puerperal sepsis), incorporating multiple sensitivity analyses and multivariable MR to address potential heterogeneity and pleiotropy. Results: The study revealed a significant causal link between genetically forecasted zinc levels and reduced risk of severe sepsis-related death within 28 days (odds ratio [OR] = 0.450; 95% confidence interval [CI]: 0.263, 0.770; p = 3.58 × 10-3). Additionally, suggestive associations were found for iron (increased risk of sepsis), β-carotene (reduced risk of sepsis death) and vitamin C (decreased risk of puerperal sepsis). No significant connections were observed for other micronutrients. Conclusion: Our study highlighted that zinc may emerges as a potential protective factor against severe sepsis-related death within 28 days, providing theoretical support for supplementing zinc in high-risk critically ill sepsis patients. In the future, larger-scale data are needed to validate our findings.
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Affiliation(s)
- Zhengxiao Wei
- Department of Clinical Laboratory, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Yingfen Liu
- Department of Clinical Laboratory, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Xue Mei
- Department of Infectious Diseases, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Jing Zhong
- Department of Clinical Laboratory, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Fuhong Huang
- Department of Ultrasound, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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23
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Chu V, Fascetti AJ, Larsen JA, Montano M, Giulivi C. Factors influencing vitamin B6 status in domestic cats: age, disease, and body condition score. Sci Rep 2024; 14:2037. [PMID: 38263201 PMCID: PMC10806207 DOI: 10.1038/s41598-024-52367-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 01/17/2024] [Indexed: 01/25/2024] Open
Abstract
Limited studies are available on vitamin B6 status in domestic cats. To this end, we evaluated glutamate-oxaloacetate transaminase (GOT) activity in hemolysates with and without pyridoxal 5'-phosphate addition in two feline populations: a cohort of 60 healthy, domestic (sexually intact and specific pathogen-free) cats maintained under strictly controlled conditions with appropriate diets housed at the Feline Nutrition and Pet Care Center, and a cohort of 57 cats randomly selected between December 2022 to January 2023 that visited the Veterinary Medicine Teaching Hospital to seek care under different circumstances. The GOT activity expressed as the ratio with and without pyridoxal 5'-phosphate addition (primary activation ratio; PAR) decreased significantly with age in the healthy cohort. The PAR values normalized to age established a cut-off for vitamin B6 deficiency in both cohorts, identifying 17 of 101 animals as vitamin B6 deficient. Using machine learning, a partition-based model (decision tree) was built to identify the most important factors that predicted vitamin B6 deficiency while using the resulting tree to make predictions for new observations. This analysis, performed with all 101 cats, revealed that the diagnosis of an infectious, chronic or acute condition (0.55) was the main contributor, followed by age (0.26), and body condition score (optimal-overweight; 0.19). Thus, our study supports that vitamin B6 supplementation may be indicated in junior to adult animals diagnosed with an infectious, chronic, or acute conditions or healthy cats with body weight ranging from optimal to overweight. In older cats, even if healthy, underweight to optimal cats appear to be at risk of vitamin B6 deficiency.
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Affiliation(s)
- Vy Chu
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Andrea J Fascetti
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Jennifer A Larsen
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Maria Montano
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Cecilia Giulivi
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA.
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDH, University of California Davis, Sacramento, CA, USA.
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24
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Niu YY, Aierken A, Feng L. Unraveling the link between dietary factors and cardiovascular metabolic diseases: Insights from a two-sample Mendelian Randomization investigation. Heart Lung 2024; 63:72-77. [PMID: 37826923 DOI: 10.1016/j.hrtlng.2023.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/29/2023] [Accepted: 09/30/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND When specific nutrients are inadequate, vulnerability to cardiovascular and metabolic illnesses increases. The data linking dietary nutrition with these illnesses, however, has been sparse in the past observational research and randomized controlled trials. OBJECTIVES A Mendelian randomization (MR) analysis was performed to assess the influence of macronutrients (fat, protein, sugar, and carbohydrates) and micronutrients (β-carotene, folate, calcium, iron, copper, magnesium, phosphorus, selenium, zinc, vitamin C, vitamin D, vitamin B, and vitamin B12) on the susceptibility to cardiovascular metabolic disorders, including coronary artery disease, heart failure, ischemic stroke, and type 2 diabetes. METHODS We employed a two-sample Mendelian randomization (MR) analysis, utilizing inverse variance weighting and conducting comprehensive sensitivity assessments. We obtained publicly accessible summary data from separate cohorts comprising individuals of European ancestry. The level of statistical significance was established at a threshold of P < 0. 00074. RESULTS Based on our research findings, we have established a causal association between the consumption of circulating fat and the development of cardiovascular and metabolic diseases. The study found that an increase of one standard deviation in fat consumption was associated with a decreased risk of heart failure, with an odds ratio of 0. 56 (95 % CI: 0. 40-0. 79; p = 0. 0007). Notably, various sensitivity analyses confirmed the robustness of this association. Conversely, we did not find any significant correlation between other dietary components and the risk of cardiovascular and metabolic disorders. CONCLUSION Our research findings demonstrate a conspicuous impact of dietary fat consumption on the susceptibility to heart failure, independent of coronary artery disease, diabetes, and stroke. Consequently, it is indicated that dietary factors are unrelated to the predisposition to cardiovascular metabolic disorders.
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Affiliation(s)
- Yue-Yue Niu
- Beijing University of Chinese Medicine, Beijing 100029, China; Cadres Health Protection Department, China Academy of Chinese Medical Sciences Guang'anmen Hospital, No. 5, beixiange, Xicheng District, Beijing 100053, China
| | - Aikeremu Aierken
- Beijing University of Chinese Medicine, Beijing 100029, China; Cadres Health Protection Department, China Academy of Chinese Medical Sciences Guang'anmen Hospital, No. 5, beixiange, Xicheng District, Beijing 100053, China
| | - Ling Feng
- Cadres Health Protection Department, China Academy of Chinese Medical Sciences Guang'anmen Hospital, No. 5, beixiange, Xicheng District, Beijing 100053, China.
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25
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Scotti L, da Silva PR, Monteiro AFM, de Araújo RSA, do Nascimento VL, Monteiro KLC, de Aquino TM, Dos Santos Silva WF, da Silva Junior EF, Scotti MT, Mendonça Junior FJB. The Multitarget Action of Vitamins in the Ischemic Stroke. Curr Top Med Chem 2024; 24:2465-2488. [PMID: 39301898 DOI: 10.2174/0115680266316939240909070627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/08/2024] [Accepted: 08/19/2024] [Indexed: 09/22/2024]
Abstract
A stroke, also known as a cerebral hemorrhage, occurs when there is an interruption in the blood supply to a part of the brain, resulting in damage to brain cells. This issue is one of the leading causes of death in developed countries, currently killing about 5 million people annually. Individuals who survive ischemic stroke often face serious vision problems, paralysis, dementia, and other sequelae. The numerous efforts to prevent and/or treat stroke sequelae seem insufficient, which is concerning given the increasing global elderly population and the well-known association between aging and stroke risk. In this review, we aim to present and discuss the importance of vitamins in stroke prevention and/or incidence. Vitamins from diet or dietary supplements influence the body at various levels; they are a relevant factor but are reported only in isolated articles. This review reports and updates the multitarget role of vitamins involved in reducing stroke risk.
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Affiliation(s)
- Luciana Scotti
- Post-Graduate Program in Natural and Synthetic Bioactive Compounds, Federal University of Paraíba (UFPB), João Pessoa, Paraiba, Brazil
| | - Pablo Rayff da Silva
- Postgraduate Program in Dentistry, Health Sciences Center, Federal University of Paraíba, João Pessoa, Paraíba, Brazil
| | - Alex France M Monteiro
- Post-Graduate Program in Natural and Synthetic Bioactive Compounds, Federal University of Paraíba (UFPB), João Pessoa, Paraiba, Brazil
- Postgraduate Program in Chemistry, Department of Chemistry, Federal Rural University of Pernambuco, Campus I-Recife/PE, Brazil
| | | | - Vanessa Lima do Nascimento
- Research Group on Therapeutic Strategies - GPET, Institute of Chemistry and Biotechnology, Federal University of Alagoas (UFAL), Maceió, Brazil
| | - Kadja Luana Chagas Monteiro
- Research Group on Therapeutic Strategies - GPET, Institute of Chemistry and Biotechnology, Federal University of Alagoas (UFAL), Maceió, Brazil
| | - Thiago Mendonça de Aquino
- Research Group on Therapeutic Strategies - GPET, Institute of Chemistry and Biotechnology, Federal University of Alagoas (UFAL), Maceió, Brazil
| | - Wadja Feitosa Dos Santos Silva
- Research Group on Therapeutic Strategies - GPET, Institute of Chemistry and Biotechnology, Federal University of Alagoas (UFAL), Maceió, Brazil
| | - Edeildo Ferreira da Silva Junior
- Research Group on Therapeutic Strategies - GPET, Institute of Chemistry and Biotechnology, Federal University of Alagoas (UFAL), Maceió, Brazil
| | - Marcus T Scotti
- Post-Graduate Program in Natural and Synthetic Bioactive Compounds, Federal University of Paraíba (UFPB), João Pessoa, Paraiba, Brazil
| | - Francisco Jaime Bezerra Mendonça Junior
- Post-Graduate Program in Natural and Synthetic Bioactive Compounds, Federal University of Paraíba (UFPB), João Pessoa, Paraiba, Brazil
- Laboratory of Synthesys and Drug Delivery - LSVM, State University of Paraíba (UEPB), João Pessoa, Brazil
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Chen L, Yang T, Wang T, Sun M, Qin J. Relationships between Maternal Folic Acid Supplementation and GATA4 Gene Polymorphisms in Patients with Non-Chromosomal Congenital Heart Disease: A Hospital-Based Case-Control Study in China. Nutrients 2023; 15:4478. [PMID: 37892553 PMCID: PMC10610291 DOI: 10.3390/nu15204478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
This study aimed to investigate the relationships between maternal FA supplementation and nine single-nucleotide variants of the GATA4 gene in non-chromosomal CHD and further explore the gene-environment interactions associated with CHD. A total of 585 CHD patients and 600 controls were recruited in the case-control study. Maternal FA (FA-containing multivitamin) supplementation information and nine polymorphisms of the GATA4 gene were collected in this study. Adjusted ORs (aOR) and their 95% confidence intervals (CIs) were calculated using proper statistical methods to analyze the relationships between the two main exposures of interest with respect to CHD. After adjusting the suspicious confounding factors, a significantly increased risk for CHD in offspring was found with non-FA supplementation before/during the pregnancy to CHD in offspring (aOR = 1.58, 95% CI: 1.01-2.48). We suggested taking FA supplementation before/during the pregnancy to prevent CHD in offspring, especially in the preconception period (aOR = 0.53, 95% CI: 0.32-0.90). The genetic results showed that the polymorphisms of rs4841588, rs12458, and rs904018 under specific genotypes and genetic models were significantly related to CHD. The gene-environment interaction between rs10108052 and FA supplementation before/during pregnancy could increase the risk of CHD (aOR = 5.38, 95% CI: 1.67-17.09, Pinteraction = 0.004). Relationships between maternal FA supplementation and specific polymorphisms of the GATA4 gene, as well as the gene-environment interaction, were significantly associated with CHD in offspring.
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Affiliation(s)
- Letao Chen
- Infection Control Center, Xiangya Hospital, Central South University, Changsha 410017, China;
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410017, China
| | - Tubao Yang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410017, China; (T.Y.); (M.S.)
| | - Tingting Wang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410017, China; (T.Y.); (M.S.)
| | - Mengting Sun
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410017, China; (T.Y.); (M.S.)
| | - Jiabi Qin
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410017, China; (T.Y.); (M.S.)
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Kim JY, Song M, Kim MS, Natarajan P, Do R, Myung W, Won HH. An atlas of associations between 14 micronutrients and 22 cancer outcomes: Mendelian randomization analyses. BMC Med 2023; 21:316. [PMID: 37605270 PMCID: PMC10441703 DOI: 10.1186/s12916-023-03018-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 08/02/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND Micronutrients, namely vitamins and minerals, are associated with cancer outcomes; however, their reported effects have been inconsistent across studies. We aimed to identify the causally estimated effects of micronutrients on cancer by applying the Mendelian randomization (MR) method, using single-nucleotide polymorphisms associated with micronutrient levels as instrumental variables. METHODS We obtained instrumental variables of 14 genetically predicted micronutrient levels and applied two-sample MR to estimate their causal effects on 22 cancer outcomes from a meta-analysis of the UK Biobank (UKB) and FinnGen cohorts (overall cancer and 21 site-specific cancers, including breast, colorectal, lung, and prostate cancer), in addition to six major cancer outcomes and 20 cancer subset outcomes from cancer consortia. We used sensitivity MR methods, including weighted median, MR-Egger, and MR-PRESSO, to assess potential horizontal pleiotropy or heterogeneity. Genome-wide association summary statistical data of European descent were used for both exposure and outcome data, including up to 940,633 participants of European descent with 133,384 cancer cases. RESULTS In total, 672 MR tests (14 micronutrients × 48 cancer outcomes) were performed. The following two associations met Bonferroni significance by the number of associations (P < 0.00016) in the UKB plus FinnGen cohorts: increased risk of breast cancer with magnesium levels (odds ratio [OR] = 1.281 per 1 standard deviation [SD] higher magnesium level, 95% confidence interval [CI] = 1.151 to 1.426, P < 0.0001) and increased risk of colorectal cancer with vitamin B12 level (OR = 1.22 per 1 SD higher vitamin B12 level, 95% CI = 1.107 to 1.345, P < 0.0001). These two associations remained significant in the analysis of the cancer consortia. No significant heterogeneity or horizontal pleiotropy was observed. Micronutrient levels were not associated with overall cancer risk. CONCLUSIONS Our results may aid clinicians in deciding whether to regulate the intake of certain micronutrients, particularly in high-risk groups without nutritional deficiencies, and may help in the design of future clinical trials.
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Affiliation(s)
- Jong Yeob Kim
- Samsung Advanced Institute for Health Sciences & Technology (SAIHST) Sungkyunkwan University, Samsung Medical Center, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Minku Song
- Samsung Advanced Institute for Health Sciences & Technology (SAIHST) Sungkyunkwan University, Samsung Medical Center, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Min Seo Kim
- Samsung Advanced Institute for Health Sciences & Technology (SAIHST) Sungkyunkwan University, Samsung Medical Center, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
- Medical and Population Genetics and Cardiovascular Disease Initiative Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Cardiovascular Research Center Massachusetts General Hospital, Boston, MA, USA
| | - Pradeep Natarajan
- Medical and Population Genetics and Cardiovascular Disease Initiative Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Cardiovascular Research Center Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ron Do
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Woojae Myung
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hong-Hee Won
- Samsung Advanced Institute for Health Sciences & Technology (SAIHST) Sungkyunkwan University, Samsung Medical Center, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea.
- Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Li J, Xia K, Wang Z, Liu Y, Tong Y, Wang Y, Zhou Y, Zhang L, Tang L, Fan D, Yang Q. Essential nutrients and cerebral small vessel diseases: a two-sample Mendelian randomization study. Front Nutr 2023; 10:1172587. [PMID: 37426181 PMCID: PMC10325681 DOI: 10.3389/fnut.2023.1172587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
Background Previous studies have suggested a potential association between nutrients and cerebral small vessel disease (CSVD), but this association has not been fully addressed. Object We intended to clarify the causal associations between four categories of essential nutrients (amino acids, polyunsaturated fatty acids, minerals and vitamins) and two acute manifestations of CSVD (intracerebral hemorrhage and small vessel stroke) using two-sample Mendelian randomization (MR) analysis. Method We obtained European-based large-scale genome-wide association studies (GWASs) related to CSVD (6,255 cases and 233,058 controls) and nutrient concentrations. Causality evaluation mainly included the results of the inverse variance-weighted (IVW) method. The simple median method, the weighted median method and the MR-Egger method were adopted for sensitivity analyses. Results For ICH or SVS, increased levels of phenylalanine (OR = 1.188, p < 0.001) and dihomo-gamma-linolenic acid (DGLA) (OR = 1.153, p = 0.001) showed risk effects, while docosapentaenoic acid (DPA) (OR = 0.501, p < 0.001), zinc (OR = 0.919, p < 0.001), and arachidonic acid (OR = 0.966, p = 0.007) showed protective effects. For lobar hemorrhage or SVS, AA (OR = 0.978, p < 0.001), zinc (OR = 0.918, p < 0.001), and retinol (OR = 0.753, p < 0.001) showed risk effects; DPA (OR = 0.682, p = 0.022), gamma-linolenic acid (OR = 0.120, p = 0.033) and 25(OH)D (OR = 0.874, p = 0.040) showed protective effects. For nonlobar hemorrhage or SVS, DGLA (OR = 1.088, p < 0.001) and phenylalanine (OR = 1.175, p = 0.001) showed risk effects. Conclusion Our study analyzed the effect of nutrients on CSVD risk from a genetic perspective, with implications for CSVD prevention through nutrient supplementation.
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Affiliation(s)
- Jiayi Li
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Peking University Health Science Center, Beijing, China
| | - Kailin Xia
- Department of Neurology, Peking University Third Hospital, Beijing, China
| | - Zhengrui Wang
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Peking University Health Science Center, Beijing, China
| | - Yanru Liu
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Peking University Health Science Center, Beijing, China
| | - Yicheng Tong
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Peking University Health Science Center, Beijing, China
| | - Yuwei Wang
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Peking University Health Science Center, Beijing, China
| | - Yumou Zhou
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Peking University Health Science Center, Beijing, China
| | - Linjing Zhang
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China
| | - Lu Tang
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China
| | - Dongsheng Fan
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China
| | - Qiong Yang
- Department of Neurology, Peking University Third Hospital, Beijing, China
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Packer RJ, Shrine N, Hall R, Melbourne CA, Thompson R, Williams AT, Paynton ML, Guyatt AL, Allen RJ, Lee PH, John C, Campbell A, Hayward C, de Vries M, Vonk JM, Davitte J, Hessel E, Michalovich D, Betts JC, Sayers I, Yeo A, Hall IP, Tobin MD, Wain LV. Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection. Eur Respir J 2023; 61:2201667. [PMID: 37263751 PMCID: PMC10284065 DOI: 10.1183/13993003.01667-2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/17/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. METHODS We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (p<5×10-8) were investigated in additional independent studies, were fine-mapped and putative causal genes identified by gene expression analysis. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs). RESULTS From a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 cases and 17 627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease. CONCLUSIONS Novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.
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Affiliation(s)
- Richard J Packer
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Nick Shrine
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Robert Hall
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Carl A Melbourne
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Rebecca Thompson
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Alex T Williams
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Megan L Paynton
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Anna L Guyatt
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Richard J Allen
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Paul H Lee
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Catherine John
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Maaike de Vries
- University of Groningen, University Medical Center Groningen, Department of Epidemiology and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
| | - Judith M Vonk
- University of Groningen, University Medical Center Groningen, Department of Epidemiology and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
| | | | | | | | | | - Ian Sayers
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | | | - Ian P Hall
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Martin D Tobin
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Louise V Wain
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
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30
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Flatby HM, Ravi A, Damås JK, Solligård E, Rogne T. Circulating levels of micronutrients and risk of infections: a Mendelian randomization study. BMC Med 2023; 21:84. [PMID: 36882828 PMCID: PMC9993583 DOI: 10.1186/s12916-023-02780-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 02/12/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND Micronutrients play an essential role at every stage of the immune response, and deficiencies can therefore lead to increased susceptibility to infections. Previous observational studies and randomized controlled trials of micronutrients and infections are limited. We performed Mendelian randomization (MR) analyses to evaluate the effect of blood levels of eight micronutrients (copper, iron, selenium, zinc, beta-carotene, vitamin B12, vitamin C, and vitamin D) on the risk of three infections (gastrointestinal infections, pneumonia, and urinary tract infections). METHODS Two-sample MR was conducted using publicly available summary statistics from independent cohorts of European ancestry. For the three infections, we used data from UK Biobank and FinnGen. Inverse variance-weighted MR analyses were performed, together with a range of sensitivity analyses. The threshold for statistical significance was set at P < 2.08E-03. RESULTS We found a significant association between circulating levels of copper and risk of gastrointestinal infections, where a one standard deviation increase in blood levels of copper was associated with an odds ratio of gastrointestinal infections of 0.91 (95% confidence interval 0.87 to 0.97, P = 1.38E-03). This finding was robust in extensive sensitivity analyses. There was no clear association between the other micronutrients and the risk of infection. CONCLUSIONS Our results strongly support a role of copper in the susceptibility to gastrointestinal infections.
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Affiliation(s)
- Helene M. Flatby
- Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Prinsesse Kristinas gate 3, Akutten og Hjerte-lunge-senteret, 3. etg, 7491 Trondheim, Norway
- Clinic of Anaesthesia and Intensive Care, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Anuradha Ravi
- Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Prinsesse Kristinas gate 3, Akutten og Hjerte-lunge-senteret, 3. etg, 7491 Trondheim, Norway
- Clinic of Anaesthesia and Intensive Care, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Jan K. Damås
- Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Prinsesse Kristinas gate 3, Akutten og Hjerte-lunge-senteret, 3. etg, 7491 Trondheim, Norway
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Infectious Diseases, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Erik Solligård
- Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Prinsesse Kristinas gate 3, Akutten og Hjerte-lunge-senteret, 3. etg, 7491 Trondheim, Norway
- Clinic of Anaesthesia and Intensive Care, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Tormod Rogne
- Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Prinsesse Kristinas gate 3, Akutten og Hjerte-lunge-senteret, 3. etg, 7491 Trondheim, Norway
- Department of Chronic Disease Epidemiology and Center for Perinatal, Pediatric and Environmental Epidemiology, Yale School of Public Health, New Haven, CT USA
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Wang L, Li X, Montazeri A, MacFarlane AJ, Momoli F, Duthie S, Senekal M, Eguiagaray IM, Munger R, Bennett D, Campbell H, Rubini M, McNulty H, Little J, Theodoratou E. Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank. Am J Clin Nutr 2023; 117:564-575. [PMID: 36811473 PMCID: PMC7614280 DOI: 10.1016/j.ajcnut.2023.01.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 01/04/2023] [Accepted: 01/09/2023] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Although a number of health outcomes such as CVDs, metabolic-related outcomes, neurological disorders, pregnancy outcomes, and cancers have been identified in relation to B vitamins, evidence is of uneven quality and volume, and there is uncertainty about putative causal relationships. OBJECTIVES To explore the effects of B vitamins and homocysteine on a wide range of health outcomes based on a large biorepository linking biological samples and electronic medical records. METHODS First, we performed a phenome-wide association study (PheWAS) to investigate the associations of genetically predicted plasma concentrations (genetic component of the circulating concentrations) of folate, vitamin B6, vitamin B12, and their metabolite homocysteine with a wide range of disease outcomes (including both prevalent and incident events) among 385,917 individuals in the UK Biobank. Second, 2-sample Mendelian randomization (MR) analysis was used to replicate any observed associations and detect causality. We considered MR P <0.05 as significant for replication. Third, dose-response, mediation, and bioinformatics analyses were carried out to examine any nonlinear trends and to disentangle the underlying mediating biological mechanisms for the identified associations. RESULTS In total, 1117 phenotypes were tested in each PheWAS analysis. After multiple corrections, 32 phenotypic associations of B vitamins and homocysteine were identified. Two-sample MR analysis supported that 3 of them were causal, including associations of higher plasma vitamin B6 with lower risk of calculus of kidney (OR: 0.64; 95% CI: 0.42, 0.97; P = 0.033), higher homocysteine concentration with higher risk of hypercholesterolemia (OR: 1.28, 95% CI: 1.04, 1.56; P = 0.018), and chronic kidney disease (OR: 1.32, 95% CI: 1.06, 1.63; P = 0.012). Significant nonlinear dose-response relationships were observed for the associations of folate with anemia, vitamin B12 with vitamin B-complex deficiencies, anemia and cholelithiasis, and homocysteine with cerebrovascular disease. CONCLUSIONS This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.
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Affiliation(s)
- Lijuan Wang
- School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Xue Li
- School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Azita Montazeri
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Franco Momoli
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Susan Duthie
- School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen, United Kingdom
| | - Marjanne Senekal
- Department of Human Biology, University of Cape Town, Cape Town, South Africa
| | - Ines Mesa Eguiagaray
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Ron Munger
- Department of Nutrition and Food Sciences and the Center for Epidemiologic Studies, Utah State University, Logan, UT, USA
| | - Derrick Bennett
- Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Harry Campbell
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Michele Rubini
- Department of Neuroscience and rehabilitation, University of Ferrara, Ferrara, Italy
| | - Helene McNulty
- Nutrition Innovation Centre for Food and Health, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Julian Little
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom; Cancer Research UK Edinburgh Centre, The University of Edinburgh MRC Institute of Genetics and Cancer, Edinburgh, United Kingdom.
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Dietary Factors and Endometrial Cancer Risk: A Mendelian Randomization Study. Nutrients 2023; 15:nu15030603. [PMID: 36771310 PMCID: PMC9920466 DOI: 10.3390/nu15030603] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 01/27/2023] Open
Abstract
Given the strong association between obesity and endometrial cancer risk, dietary factors may play an important role in the development of this cancer. However, observational studies of micro- and macronutrients and their role in endometrial cancer risk have been inconsistent. Clarifying these relationships are important to develop nutritional recommendations for cancer prevention. We performed two-sample Mendelian randomization (MR) to investigate the effects of circulating levels of 15 micronutrients (vitamin A (retinol), folate, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc) as well as corrected relative macronutrient intake (protein, carbohydrate, sugar and fat) on risks of endometrial cancer and its subtypes (endometrioid and non-endometrioid histologies). Genetically predicted vitamin C levels were found to be strongly associated with endometrial cancer risk. There was some evidence that genetically predicted relative intake of macronutrients (carbohydrate, sugar and fat) affects endometrial cancer risk. No other significant association were observed. Conclusions: In summary, these findings suggest that vitamin C and macronutrients influence endometrial cancer risk but further investigation is required.
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Guevara-Ramírez P, Cadena-Ullauri S, Ruiz-Pozo VA, Tamayo-Trujillo R, Paz-Cruz E, Simancas-Racines D, Zambrano AK. Genetics, genomics, and diet interactions in obesity in the Latin American environment. Front Nutr 2022; 9:1063286. [PMID: 36532520 PMCID: PMC9751379 DOI: 10.3389/fnut.2022.1063286] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 10/25/2022] [Indexed: 08/25/2023] Open
Abstract
Obesity is a chronic disease characterized by abnormal or excessive fat accumulation that could impact an individual's health; moreover, the World Health Organization (WHO) has declared obesity a global epidemic since 1997. In Latin America, in 2016, reports indicated that 24.2% of the adult population was obese. The environmental factor or specific behaviors like dietary intake or physical activity have a vital role in the development of a condition like obesity, but the interaction of genes could contribute to that predisposition. Hence, it is vital to understand the relationship between genes and disease. Indeed, genetics in nutrition studies the genetic variations and their effect on dietary response; while genomics in nutrition studies the role of nutrients in gene expression. The present review represents a compendium of the dietary behaviors in the Latin American environment and the interactions of genes with their single nucleotide polymorphisms (SNPs) associated with obesity, including the risk allele frequencies in the Latin American population. Additionally, a bibliographical selection of several studies has been included; these studies examined the impact that dietary patterns in Latin American environments have on the expression of numerous genes involved in obesity-associated metabolic pathways.
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Affiliation(s)
- Patricia Guevara-Ramírez
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Santiago Cadena-Ullauri
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Viviana A. Ruiz-Pozo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Rafael Tamayo-Trujillo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Elius Paz-Cruz
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Daniel Simancas-Racines
- Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Ana Karina Zambrano
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
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Genetic Aspects of Micronutrients Important for Inflammatory Bowel Disease. Life (Basel) 2022; 12:life12101623. [PMID: 36295058 PMCID: PMC9604584 DOI: 10.3390/life12101623] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/07/2022] [Accepted: 10/08/2022] [Indexed: 11/16/2022] Open
Abstract
Inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are complex diseases whose etiology is associated with genetic and environmental risk factors, among which are diet and gut microbiota. To date, IBD is an incurable disease and the main goal of its treatment is to reduce symptoms, prevent complications, and improve nutritional status and the quality of life. Patients with IBD usually suffer from nutritional deficiency with imbalances of specific micronutrient levels that contribute to the further deterioration of the disease. Therefore, along with medications usually used for IBD treatment, therapeutic strategies also include the supplementation of micronutrients such as vitamin D, folic acid, iron, and zinc. Micronutrient supplementation tailored according to individual needs could help patients to maintain overall health, avoid the triggering of symptoms, and support remission. The identification of individuals’ genotypes associated with the absorption, transport and metabolism of micronutrients can modify future clinical practice in IBD and enable individualized treatment. This review discusses the personalized approach with respect to genetics related to micronutrients commonly used in inflammatory bowel disease treatment.
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Ramos-Levi A, Barabash A, Valerio J, García de la Torre N, Mendizabal L, Zulueta M, de Miguel MP, Diaz A, Duran A, Familiar C, Jimenez I, del Valle L, Melero V, Moraga I, Herraiz MA, Torrejon MJ, Arregi M, Simón L, Rubio MA, Calle-Pascual AL. Genetic variants for prediction of gestational diabetes mellitus and modulation of susceptibility by a nutritional intervention based on a Mediterranean diet. Front Endocrinol (Lausanne) 2022; 13:1036088. [PMID: 36313769 PMCID: PMC9612917 DOI: 10.3389/fendo.2022.1036088] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Hypothesis Gestational diabetes mellitus (GDM) entails a complex underlying pathogenesis, with a specific genetic background and the effect of environmental factors. This study examines the link between a set of single nucleotide polymorphisms (SNPs) associated with diabetes and the development of GDM in pregnant women with different ethnicities, and evaluates its potential modulation with a clinical intervention based on a Mediterranean diet. Methods 2418 women from our hospital-based cohort of pregnant women screened for GDM from January 2015 to November 2017 (the San Carlos Cohort, randomized controlled trial for the prevention of GDM ISRCTN84389045 and real-world study ISRCTN13389832) were assessed for evaluation. Diagnosis of GDM was made according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Genotyping was performed by IPLEX MassARRAY PCR using the Agena platform (Agena Bioscience, SanDiego, CA). 110 SNPs were selected for analysis based on selected literature references. Statistical analyses regarding patients' characteristics were performed in SPSS (Chicago, IL, USA) version 24.0. Genetic association tests were performed using PLINK v.1.9 and 2.0 software. Bioinformatics analysis, with mapping of SNPs was performed using STRING, version 11.5. Results Quality controls retrieved a total 98 SNPs and 1573 samples, 272 (17.3%) with GDM and 1301 (82.7%) without GDM. 1104 (70.2%) were Caucasian (CAU) and 469 (29.8%) Hispanic (HIS). 415 (26.4%) were from the control group (CG), 418 (26.6%) from the nutritional intervention group (IG) and 740 (47.0%) from the real-world group (RW). 40 SNPs (40.8%) presented some kind of significant association with GDM in at least one of the genetic tests considered. The nutritional intervention presented a significant association with GDM, regardless of the variant considered. In CAU, variants rs4402960, rs7651090, IGF2BP2; rs1387153, rs10830963, MTNR1B; rs17676067, GLP2R; rs1371614, DPYSL5; rs5215, KCNJ1; and rs2293941, PDX1 were significantly associated with an increased risk of GDM, whilst rs780094, GCKR; rs7607980, COBLL1; rs3746750, SLC17A9; rs6048205, FOXA2; rs7041847, rs7034200, rs10814916, GLIS3; rs3783347, WARS; and rs1805087, MTR, were significantly associated with a decreased risk of GDM, In HIS, variants significantly associated with increased risk of GDM were rs9368222, CDKAL1; rs2302593, GIPR; rs10885122, ADRA2A; rs1387153, MTNR1B; rs737288, BACE2; rs1371614, DPYSL5; and rs2293941, PDX1, whilst rs340874, PROX1; rs2943634, IRS1; rs7041847, GLIS3; rs780094, GCKR; rs563694, G6PC2; and rs11605924, CRY2 were significantly associated with decreased risk for GDM. Conclusions We identify a core set of SNPs in their association with diabetes and GDM in a large cohort of patients from two main ethnicities from a single center. Identification of these genetic variants, even in the setting of a nutritional intervention, deems useful to design preventive and therapeutic strategies.
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Affiliation(s)
- Ana Ramos-Levi
- Endocrinology and Nutrition Department, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid, Spain
| | - Ana Barabash
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- Facultad de Medicina. Medicina II Department, Universidad Complutense de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Johanna Valerio
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Nuria García de la Torre
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | | | | | - Maria Paz de Miguel
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- Facultad de Medicina. Medicina II Department, Universidad Complutense de Madrid, Madrid, Spain
| | - Angel Diaz
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- Facultad de Medicina. Medicina II Department, Universidad Complutense de Madrid, Madrid, Spain
| | - Alejandra Duran
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- Facultad de Medicina. Medicina II Department, Universidad Complutense de Madrid, Madrid, Spain
| | - Cristina Familiar
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Inés Jimenez
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Laura del Valle
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Veronica Melero
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Inmaculada Moraga
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Miguel A. Herraiz
- Gynecology and Obstetrics Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - María José Torrejon
- Clinical Laboratory Department Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Maddi Arregi
- Patia Europe, Clinical Laboratory, San Sebastián, Spain
| | | | - Miguel A. Rubio
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- Facultad de Medicina. Medicina II Department, Universidad Complutense de Madrid, Madrid, Spain
| | - Alfonso L. Calle-Pascual
- Endocrinology and Nutrition Department, Hospital Clínico Universitario San Carlos and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- Facultad de Medicina. Medicina II Department, Universidad Complutense de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
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Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Pregnant Women of a Homogeneous Spanish Population: The Need for Revisiting the Current Vitamin Supplementation Strategies. Nutrients 2022; 14:nu14132702. [PMID: 35807880 PMCID: PMC9268853 DOI: 10.3390/nu14132702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 02/05/2023] Open
Abstract
Polymorphisms of genes involved in the metabolism and transport of folate and cobalamin could play relevant roles in pregnancy outcomes. This study assessed the prevalence of genetic polymorphisms of folate and cobalamin metabolism-related genes such as MTHFR, MTR, CUBN, and SLC19A1 in pregnant women of a homogeneous Spanish population according to conception, pregnancy, delivery, and newborns complications. This study was conducted on 149 nulliparous women with singleton pregnancies. Sociodemographic and obstetrics variables were recorded, and all patients were genotyped in the MTHFR, MTR, CUBN, and SLC10A1 polymorphisms. The distribution of genotypes detected in this cohort was similar to the population distribution reported in Europe, highlighting that more than 50% of women were carriers of risk alleles of the studied genes. In women with the MTHFR risk allele, there was a statistically significant higher frequency of assisted fertilisation and a higher frequency of preeclampsia and preterm birth. Moreover, CUBN (rs1801222) polymorphism carriers showed a statistically significantly lower frequency of complications during delivery. In conclusion, the prevalence of genetic variants related to folic acid and vitamin B12 metabolic genes in pregnant women is related to mother and neonatal outcomes. Knowing the prevalence of these polymorphisms may lead to a personalised prescription of vitamin intake.
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Daniel N, Bouras E, Tsilidis KK, Hughes DJ. Genetically Predicted Circulating Concentrations of Micronutrients and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study. Front Nutr 2022; 9:842315. [PMID: 35558754 PMCID: PMC9085481 DOI: 10.3389/fnut.2022.842315] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which since 2019 has caused over 5 million deaths to date. The pathogenicity of the virus is highly variable ranging from asymptomatic to fatal. Evidence from experimental and observational studies suggests that circulating micronutrients may affect COVID-19 outcomes. Objectives To complement and inform observational studies, we investigated the associations of genetically predicted concentrations of 12 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, vitamin D, and zinc) with SARS-CoV-2 infection risk and COVID-19 severity using Mendelian randomization (MR). Methods Two-sample MR was conducted using 87,870 individuals of European descent with a COVID-19 diagnosis and 2,210,804 controls from the COVID-19 host genetics initiative. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. Results Compared to the general population, nominally significant associations were noted for higher genetically predicted vitamin B-6 (Odds ratio per standard deviation [ORSD]: 1.06; 95% confidence interval [CI]: 1.00, 1.13; p-value = 0.036) and lower magnesium concentrations (ORSD: 0.33; 95%CI: 0.11, 0.96; P = 0.042) with COVID-19 infection risk. However, the association for magnesium was not consistent in some sensitivity analyses, and sensitivity analyses could not be performed for vitamin B-6 as only two genetic instruments were available. Genetically predicted levels of calcium, folate, β-carotene, copper, iron, vitamin B-12, vitamin D, selenium, phosphorus, or zinc were not associated with the outcomes from COVID-19 disease. Conclusion These results, though based only on genetically predicated circulating micronutrient concentrations, provide scant evidence for possible associations of micronutrients with COVID-19 outcomes.
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Affiliation(s)
- Neil Daniel
- Cancer Biology and Therapeutics Laboratory, School of Biomedical and Biomolecular Sciences, Conway Institute, University College Dublin, Dublin, Ireland
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.,Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - David J Hughes
- Cancer Biology and Therapeutics Laboratory, School of Biomedical and Biomolecular Sciences, Conway Institute, University College Dublin, Dublin, Ireland
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Schorgg P, Karavasiloglou N, Beyer A, Cantwell M, Danquah I, Gojda J, Rohrmann S, Cassidy A, Bärnighausen T, Cahova M, Kühn T. Increased vitamin B6 turnover is associated with greater mortality risk in the general US population: A prospective biomarker study. Clin Nutr 2022; 41:1343-1356. [DOI: 10.1016/j.clnu.2022.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/02/2022] [Accepted: 04/20/2022] [Indexed: 11/03/2022]
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Cheng TYD, Ilozumba MN, Balavarca Y, Neuhouser ML, Miller JW, Beresford SAA, Zheng Y, Song X, Duggan DJ, Toriola AT, Bailey LB, Green R, Caudill MA, Ulrich CM. Associations between Genetic Variants and Blood Biomarkers of One-Carbon Metabolism in Postmenopausal Women from the Women's Health Initiative Observational Study. J Nutr 2022; 152:1099-1106. [PMID: 34967850 PMCID: PMC8971010 DOI: 10.1093/jn/nxab444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/17/2021] [Accepted: 12/24/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. METHODS In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.
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Affiliation(s)
| | | | - Yesilda Balavarca
- Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany
| | - Marian L Neuhouser
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Joshua W Miller
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Shirley A A Beresford
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Yingye Zheng
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Xiaoling Song
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - David J Duggan
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Adetunji T Toriola
- Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Lynn B Bailey
- Department of Foods and Nutrition, University of Georgia, Athens, GA, USA
| | - Ralph Green
- Department of Pathology and Laboratory Medicine, University of California Davis, Davis, CA, USA
| | - Marie A Caudill
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
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Katsa ME, Gil APR. Vitamin B-Related Gene Polymorphisms and Cardiovascular Disease. Endocr Metab Immune Disord Drug Targets 2022; 22:979-984. [PMID: 35346016 DOI: 10.2174/1381612828666220328115605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/29/2022] [Accepted: 02/11/2022] [Indexed: 11/22/2022]
Abstract
Hyperhomocysteinemia is an independent risk factor for atherosclerosis, even in early childhood. A mutation in genes which code homocysteine metabolism enzymes or deficiency of specific vitamin cofactors may cause hyperhomocysteinemia. Vitamin B complex has been correlated with serum homocysteine levels. Any abnormality in its metabolism or nutritional deficiency may lead to hyperhomocysteinemia. Both vitamin B complex and homocysteine levels are partly genetically determined. Specifically, the most studied polymorphism is 677T-C in exon 5 of the 5,10- methylenetetrahydrofolate reductase (MTHFR) gene, which plays an important role in folate's metabolism. This polymorphism has been shown correlated with hypertension and cardiovascular disease. Polymorphisms in methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L) gene have also been correlated with increased risk for coronary artery disease. Other common serious polymorphisms regard the area with high linkage disequilibrium, which included the neuroblastoma breakpoint family, NBPF3 gene, and ~ 12-50 kb upstream of the tissue nonspecific alkaline phosphatase gene. Finally, the polymorphisms which have been mostly associated with vitamin B12 concentration are the rs11254363 polymorphism at intron 52 of the intrinsic factor vitamin B12 receptor of the CUBN and the rs526934 polymorphism at intron 8 of transcobalamin I. To sum up, several polymorphisms have already been associated with vitamin B complexes and therefore homocysteine level, which highlights the complex nature of vitamin B genetics.
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Affiliation(s)
- Maria Efthymia Katsa
- Laboratory of Biology and Biochemistry, Faculty of Health Sciences, Department of Nursing, University of Peloponnese, Tripoli, Greece
- School of Health Sciences and Education, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece
| | - Andrea Paola Rojas Gil
- Laboratory of Biology and Biochemistry, Faculty of Health Sciences, Department of Nursing, University of Peloponnese, Tripoli, Greece
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Kozyraki R, Verroust P, Cases O. Cubilin, the intrinsic factor-vitamin B12 receptor. VITAMINS AND HORMONES 2022; 119:65-119. [PMID: 35337634 DOI: 10.1016/bs.vh.2022.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Cubilin (CUBN), the intrinsic factor-vitamin B12 receptor is a large endocytic protein involved in various physiological functions: vitamin B12 uptake in the gut; reabsorption of albumin and maturation of vitamin D in the kidney; nutrient delivery during embryonic development. Cubilin is an atypical receptor, peripherally associated to the plasma membrane. The transmembrane proteins amnionless (AMN) and Lrp2/Megalin are the currently known molecular partners contributing to plasma membrane transport and internalization of Cubilin. The role of Cubilin/Amn complex in the handling of vitamin B12 in health and disease has extensively been studied and so is the role of the Cubilin-Lrp2 tandem in renal pathophysiology. Accumulating evidence strongly supports a role of Cubilin in some developmental defects including impaired closure of the neural tube. Are these defects primarily caused by the dysfunction of a specific Cubilin ligand or are they secondary to impaired vitamin B12 or protein uptake? We will present the established Cubilin functions, discuss the developmental data and provide an overview of the emerging implications of Cubilin in the field of cardiovascular disease and cancer pathogenesis.
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Affiliation(s)
- Renata Kozyraki
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France.
| | - Pierre Verroust
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France
| | - Olivier Cases
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France
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Dietary-Derived Essential Nutrients and Amyotrophic Lateral Sclerosis: A Two-Sample Mendelian Randomization Study. Nutrients 2022; 14:nu14050920. [PMID: 35267896 PMCID: PMC8912818 DOI: 10.3390/nu14050920] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/18/2022] [Indexed: 02/01/2023] Open
Abstract
Previous studies have suggested a close but inconsistent relationship between essential nutrients and the risk of amyotrophic lateral sclerosis (ALS), and whether this association is causal remains unknown. We aimed to investigate the potential causal relation between essential nutrients (essential amino acids, essential fatty acids, essential minerals, and essential vitamins) and the risk of ALS using Mendelian randomization (MR) analysis. Large-scale European-based genome-wide association studies' (GWASs) summary data related to ALS (assembling 27,205 ALS patients and 110,881 controls) and essential nutrient concentrations were separately obtained. MR analysis was performed using the inverse variance-weighted (IVW) method, and sensitivity analysis was conducted by the weighted median method, simple median method, MR-Egger method and MR-PRESSO method. We found a causal association between genetically predicted linoleic acid (LA) and the risk of ALS (OR: 1.066; 95% CI: 1.011-1.125; p = 0.019). An inverse association with ALS risk was noted for vitamin D (OR: 0.899; 95% CI: 0.819-0.987; p = 0.025) and for vitamin E (OR: 0.461; 95% CI: 0.340-0.626; p = 6.25 × 10-7). The sensitivity analyses illustrated similar trends. No causal effect was observed between essential amino acids and minerals on ALS. Our study profiled the effects of diet-derived circulating nutrients on the risk of ALS and demonstrated that vitamin D and vitamin E are protective against the risk of ALS, and LA is a suggested risk factor for ALS.
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Mu C, Zhao Y, Han C, Tian D, Guo N, Zhang C, Zhu R, Zhang X, Zhang J, Liu X. Genetically Predicted Circulating Concentrations of Micronutrients and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study. Front Genet 2022; 12:811699. [PMID: 35111203 PMCID: PMC8801789 DOI: 10.3389/fgene.2021.811699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/29/2021] [Indexed: 11/13/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.
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Affiliation(s)
- Changqing Mu
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yating Zhao
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chen Han
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Dandan Tian
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Na Guo
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chenguang Zhang
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ruixia Zhu
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiaoqian Zhang
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jian Zhang
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Shenyang, China
- Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Xu Liu
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Xu Liu,
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Jian Z, Wang M, Jin X, Li H, Wang K. Diet-Derived Antioxidants and Risk of Kidney Stone Disease: Results From the NHANES 2007-2018 and Mendelian Randomization Study. Front Nutr 2022; 8:738302. [PMID: 34993217 PMCID: PMC8724258 DOI: 10.3389/fnut.2021.738302] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 11/15/2021] [Indexed: 02/05/2023] Open
Abstract
We aimed to explore the associations between diet-derived antioxidants and kidney stone disease (KSD) risk in this study. We performed weighted multivariable-adjusted logistic regression to assess the associations between the six main diet-derived antioxidants and the risk of KSD by using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2018. Then, we used the Mendelian randomization (MR) approach to verify the causal relationships between circulating antioxidants levels and KSD risk. Genetic tools were extracted from published genome-wide association studies (GWAS). Summary data for KSD was from the FinnGen study and UK biobank. Inverse variance weighted (IVW) was the primary analysis. The 26,438 participants, including 2,543 stone formers, were included for analyses. There were no significant associations between retinol, vitamin B6, vitamin C, vitamin E, and lycopene intake with the risk of KSD across all the quartile categories. Similarly, pooled odds ratio (OR) for KSD risk in genetically predicted per unit change were 1.25 (95% CI: 0.39, 4.02; p = 0.712), 1.14 (95% CI: 0.84, 1.53; p = 0.400), 0.75 (95% CI: 0.52, 1.10; p = 0.141), 1.66 (95% CI: 0.80, 3.46; p = 0.178), 1.27 (95% CI: 0.29, 5.62; p = 0.756), and 0.92 (95% CI: 0.76, 1.12; p = 0.417) for retinol, β-carotene, vitamin B6, vitamin C, α-tocopherol, and lycopene, respectively. The above estimates were replicated in the secondary analyses using UK biobank data. Our study did not support a causal association between circulating antioxidants levels and KSD risk. However, these findings should be verified in larger sample-size MR due to the pleiotropy and other limitations.
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Affiliation(s)
- Zhongyu Jian
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Menghua Wang
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, China
| | - Xi Jin
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, China
| | - Kunjie Wang
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, China
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Liu T, Momin M, Zhou H, Zheng Q, Fan F, Jia J, Liu M, Bao M, Li J, Huo Y, Liu J, Zhang Y, Mao X, Han X, Hu Z, Zeng C, Liu F, Zhang Y. Exome-Wide Association Study Identifies East Asian-Specific Missense Variant MTHFR C136T Influencing Homocysteine Levels in Chinese Populations RH: ExWAS of tHCY in a Chinese Population. Front Genet 2021; 12:717621. [PMID: 34707639 PMCID: PMC8542906 DOI: 10.3389/fgene.2021.717621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 09/02/2021] [Indexed: 02/01/2023] Open
Abstract
Plasma total homocysteine (tHCY) is a known risk factor of a wide range of complex diseases. No genome scans for tHCY have been conducted in East Asian populations. Here, we conducted an exome-wide association study (ExWAS) for tHCY in 5,175 individuals of Chinese Han origin, followed by a replication study in 668 Chinese individuals. The ExWAS identified two loci, 1p36.22 (lead single-nucleotide polymorphism (SNP) rs1801133, MTHFR C677T) and 16q24.3 (rs1126464, DPEP1), showing exome-wide significant association with tHCY (p < 5E-7); and both loci have been previously associated with tHCY in non-East Asian populations. Both SNPs were replicated in the replication study (p < 0.05). Conditioning on the genotype of C677T and rs1126464, we identified a novel East Asian-specific missense variant rs138189536 (C136T) of MTHFR (p = 6.53E-10), which was also significant in the replication study (p = 9.8E-3). The C136T and C677T variants affect tHCY in a compound heterozygote manner, where compound heterozygote and homozygote genotype carriers had on average 43.4% increased tHCY than had other genotypes. The frequency of the homozygote C677T genotype showed an inverse-U-shaped geospatial pattern globally with a pronounced frequency in northern China, which coincided with the high prevalence of hyperhomocysteinemia (HHCY) in northern China. A logistic regression model of HHCY status considering sex, age, and the genotypes of the three identified variants reached an area under the receiver operating characteristic curve (AUC) value of 0.74 in an independent validation cohort. These genetic observations provide new insights into the presence of multiple causal mutations at the MTHFR locus, highlight the role of genetics in HHCY epidemiology among different populations, and provide candidate loci for future functional studies.
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Affiliation(s)
- Tianzi Liu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center for Bioinformation, Beijing, China
| | - Mohetaboer Momin
- Department of Cardiology, Peking University First Hospital, Beijing, China.,Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China
| | - Huiyue Zhou
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center for Bioinformation, Beijing, China
| | - Qiwen Zheng
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center for Bioinformation, Beijing, China
| | - Fangfang Fan
- Department of Cardiology, Peking University First Hospital, Beijing, China.,Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China
| | - Jia Jia
- Department of Cardiology, Peking University First Hospital, Beijing, China.,Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China
| | - Mengyuan Liu
- Department of Cardiology, Peking University First Hospital, Beijing, China.,Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China
| | - Minghui Bao
- Department of Cardiology, Peking University First Hospital, Beijing, China.,Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China
| | - Jianping Li
- Department of Cardiology, Peking University First Hospital, Beijing, China.,Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China
| | - Yong Huo
- Department of Cardiology, Peking University First Hospital, Beijing, China.,Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China
| | - Jialin Liu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center for Bioinformation, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yaning Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center for Bioinformation, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Xuemei Mao
- Beijing P4 Healthcare Institute, Beijing, China
| | - Xiao Han
- Beijing P4 Healthcare Institute, Beijing, China
| | - Zhiyuan Hu
- Beijing P4 Healthcare Institute, Beijing, China.,CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, China.,School of Nanoscience and Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
| | - Changqing Zeng
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center for Bioinformation, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Fan Liu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center for Bioinformation, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yan Zhang
- Department of Cardiology, Peking University First Hospital, Beijing, China.,Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China
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46
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Ching SC, Wen LJ, Ismail NIM, Looi I, Kooi CW, Peng LS, Mui LS, Tamibmaniam J, Muninathan P, Hooi OB, Ali SMM, Hassan MRA, Mohamad MS, Griffiths LR, Wei LK. SLC17A3 rs9379800 and Ischemic Stroke Susceptibility at the Northern Region of Malaysia. J Stroke Cerebrovasc Dis 2021; 30:105908. [PMID: 34384670 DOI: 10.1016/j.jstrokecerebrovasdis.2021.105908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/24/2021] [Accepted: 05/19/2021] [Indexed: 10/20/2022] Open
Abstract
OBJECTIVES The relationships of Paired Like Homeodomain 2 (PITX2), Ninjurin 2 (NINJ2), TWIST-Related Protein 1 (TWIST1), Ras Interacting Protein 1 (Rasip1), Solute Carrier Family 17 Member 3 (SLC17A3), Methylmalonyl Co-A Mutase (MUT) and Fer3 Like BHLH Transcription Factor (FERD3L) polymorphisms and gene expression with ischemic stroke have yet to be determined in Malaysia. Hence, this study aimed to explore the associations of single nucleotide polymorphisms (SNPs) and gene expression with ischemic stroke risk among population who resided at the Northern region of Malaysia. MATERIALS AND METHODS Study subjects including 216 ischemic stroke patients and 203 healthy controls were recruited upon obtaining ethical clearance. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assays. Gene expression levels were quantified by real-time polymerase chain reaction assays. Statistical and genetic analyses were conducted with SPSS version 22.2, PLINK version 1.07 and multifactor dimensionality reduction software. RESULTS Study subjects with G allele, CG or GG genotypes of SLC17A3 rs9379800 demonstrated increased risk of ischemic stroke with the odds ratios ranging from 1.76-fold to 3.14-fold (p<0.05). When stratified study subjects according to the ethnicity, SLC17A3 rs9379800 G allele and CG genotype contributed to 2.14- and 2.96-fold of ischemic stroke risk among Malay population significantly, in the multivariate analysis (p<0.05). However, no significant associations were observed for PITX2, NINJ2, TWIST1, Rasip1, and MUT polymorphisms with ischemic stroke risk in the multivariate analysis for the pooled cases and controls as well as when stratified them according to the ethnicity. Lower mRNA expression levels of Rasip1, SLC17A3, MUT and FERD3L were observed among cases (p<0.05). After FDR adjustment, the mRNA level of SLC17A3 remained significantly associated with ischemic stroke among Malay population (q=0.034). CONCLUSION In conclusion, this study suggests that SLC17A3 rs9379800 polymorphism and its gene expression contribute to significant ischemic stroke risk among Malaysian population, particularly the Malay who resided at the Northern Region of the country. Our findings can provide useful information for the future diagnosis, management and treatment of ischemic stroke patients.
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Affiliation(s)
- Shu Chai Ching
- Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Lim Jing Wen
- Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Nor Ismaliza Mohd Ismail
- Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Irene Looi
- Clinical Research Centre, Seberang Jaya Hospital, Ministry of Health, Penang, Malaysia
| | - Cheah Wee Kooi
- Clinical Research Centre, Taiping Hospital, Jalan Tamingsari, Taiping, Perak, Malaysia
| | - Long Soo Peng
- Clinical Research Centre, Seberang Jaya Hospital, Ministry of Health, Penang, Malaysia
| | - Lee Soon Mui
- Clinical Research Centre, Seberang Jaya Hospital, Ministry of Health, Penang, Malaysia
| | | | - Prema Muninathan
- Clinical Research Centre, Taiping Hospital, Jalan Tamingsari, Taiping, Perak, Malaysia
| | - Ong Beng Hooi
- Clinical Research Centre, Hospital Sultanah Bahiyah, Kedah, Malaysia
| | | | | | - Mohd Saberi Mohamad
- Department of Genetics and Genomics, College of Medical and Health Sciences, United Arab Emirates University, United Arab Emirates
| | - Lyn R Griffiths
- Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD, Australia
| | - Loo Keat Wei
- Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Bandar Barat, 31900 Kampar, Perak, Malaysia.
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47
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Fuzo CA, da Veiga Ued F, Moco S, Cominetti O, Métairon S, Pruvost S, Charpagne A, Carayol J, Torrieri R, Silva WA, Descombes P, Kaput J, Monteiro JP. Contribution of genetic ancestry and polygenic risk score in meeting vitamin B12 needs in healthy Brazilian children and adolescents. Sci Rep 2021; 11:11992. [PMID: 34099811 PMCID: PMC8184816 DOI: 10.1038/s41598-021-91530-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 05/25/2021] [Indexed: 02/08/2023] Open
Abstract
Polymorphisms in genes related to the metabolism of vitamin B12 haven’t been examined in a Brazilian population.
To (a) determine the correlation between the local genetic ancestry components and vitamin B12 levels using ninety B12-related genes; (b) determine associations between these genes and their SNPs with vitamin B12 levels; (c) determine a polygenic risk score (PRS) using significant variants. This cross-sectional study included 168 children and adolescents, aged 9–13 years old. Total cobalamin was measured in plasma. Genotyping arrays and whole exome data were combined to yield ~ 7000 SNPs in 90 genes related to vitamin B12. The Efficient Local Ancestry Inference was used to estimate local ancestry for African (AFR), Native American, and European (EUR). The association between the genotypes and vitamin B12 levels were determined with generalized estimating equation.
Vitamin B12 levels were driven by positive (EUR) and negative (AFR, AMR) correlations with genetic ancestry. A set of 36 variants were used to create a PRS that explained 42% of vitamin level variation.
Vitamin B12 levels are influenced by genetic ancestry and a PRS explained almost 50% of the variation in plasma cobalamin in Brazilian children and adolescents.
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Affiliation(s)
- Carlos Alessandro Fuzo
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutics Sciences, University of São Paulo, Ribeirão Preto, Brazil
| | - Fábio da Veiga Ued
- Department of Pediatrics and Department of Health Sciences, Ribeirão Preto Medical School, Nutrition and Metabolism Section, University of São Paulo, Avenida Bandeirantes, 3900, Bairro Monte Alegre, Ribeirão Preto, SP, 14040-900, Brazil
| | - Sofia Moco
- Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteite Amsterdam, Amsterdam, The Netherlands
| | - Ornella Cominetti
- Nestlé Research, Société Des Produits Nestlé SA, EPFL Innovation Park, H, 1015, Lausanne, Switzerland
| | - Sylviane Métairon
- Nestlé Research, Société Des Produits Nestlé SA, EPFL Innovation Park, H, 1015, Lausanne, Switzerland
| | - Solenn Pruvost
- Nestlé Research, Société Des Produits Nestlé SA, EPFL Innovation Park, H, 1015, Lausanne, Switzerland
| | - Aline Charpagne
- Nestlé Research, Société Des Produits Nestlé SA, EPFL Innovation Park, H, 1015, Lausanne, Switzerland.,Sophia Genetics, Campus Biotech, 1202, Geneva, Switzerland
| | - Jerome Carayol
- Nestlé Research, Société Des Produits Nestlé SA, EPFL Innovation Park, H, 1015, Lausanne, Switzerland
| | - Raul Torrieri
- Center for Medical Genomics, Ribeirão Preto Medical School Hospital, University of São Paulo, Ribeirão Preto, Brazil
| | - Wilson Araujo Silva
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Patrick Descombes
- Nestlé Research, Société Des Produits Nestlé SA, EPFL Innovation Park, H, 1015, Lausanne, Switzerland
| | - Jim Kaput
- Nestlé Research, Société Des Produits Nestlé SA, EPFL Innovation Park, H, 1015, Lausanne, Switzerland.,, Vydiant, Folsom, CA, USA
| | - Jacqueline Pontes Monteiro
- Department of Pediatrics and Department of Health Sciences, Ribeirão Preto Medical School, Nutrition and Metabolism Section, University of São Paulo, Avenida Bandeirantes, 3900, Bairro Monte Alegre, Ribeirão Preto, SP, 14040-900, Brazil.
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48
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Tsilidis KK, Papadimitriou N, Dimou N, Gill D, Lewis SJ, Martin RM, Murphy N, Markozannes G, Zuber V, Cross AJ, Burrows K, Lopez DS, Key TJ, Travis RC, Perez-Cornago A, Hunter DJ, van Duijnhoven FJB, Albanes D, Arndt V, Berndt SI, Bézieau S, Bishop DT, Boehm J, Brenner H, Burnett-Hartman A, Campbell PT, Casey G, Castellví-Bel S, Chan AT, Chang-Claude J, de la Chapelle A, Figueiredo JC, Gallinger SJ, Giles GG, Goodman PJ, Gsur A, Hampe J, Hampel H, Hoffmeister M, Jenkins MA, Keku TO, Kweon SS, Larsson SC, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, Milne RL, Moreno V, Nan H, Nassir R, Newcomb PA, Offit K, Pharoah PDP, Platz EA, Potter JD, Qi L, Rennert G, Sakoda LC, Schafmayer C, Slattery ML, Snetselaar L, Schenk J, Thibodeau SN, Ulrich CM, Van Guelpen B, Harlid S, Visvanathan K, Vodickova L, Wang H, White E, Wolk A, Woods MO, Wu AH, Zheng W, Bueno-de-Mesquita B, Boutron-Ruault MC, Hughes DJ, Jakszyn P, Kühn T, Palli D, Riboli E, Giovannucci EL, Banbury BL, Gruber SB, Peters U, Gunter MJ. Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study. Am J Clin Nutr 2021; 113:1490-1502. [PMID: 33740060 PMCID: PMC8168352 DOI: 10.1093/ajcn/nqab003] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk. CONCLUSIONS These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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Affiliation(s)
- Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Nikos Papadimitriou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Niki Dimou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Sarah J Lewis
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Richard M Martin
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- University Hospitals Bristol National Health Service Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, United Kingdom
| | - Neil Murphy
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Georgios Markozannes
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Verena Zuber
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Medical Research Council Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Kimberley Burrows
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - David S Lopez
- Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX, USA
| | - Timothy J Key
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Ruth C Travis
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Aurora Perez-Cornago
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - David J Hunter
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | | | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Stéphane Bézieau
- Medical Genetics Service, University Hospital Center (CHU) Nantes, Nantes, France
| | - D Timothy Bishop
- , Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Juergen Boehm
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Biomedical Research Network Center for Liver and Digestive Diseases (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA
- Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg, Hamburg, Germany
| | - Albert de la Chapelle
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Steven J Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Phyllis J Goodman
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria
| | - Jochen Hampe
- Department of Medicine I, University Hospital Dresden, Dresden University of Technology (TU Dresden), Dresden, Germany
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea
| | - Susanna C Larsson
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | | | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Annika Lindblom
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Vicente Martín
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Biomedicine Institute (IBIOMED), University of León, León, Spain
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Victor Moreno
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Oncology Data Analytics Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Hongmei Nan
- Department of Epidemiology, Richard M Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA
- IU Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - Kenneth Offit
- Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Paul D P Pharoah
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Centre for Public Health Research, Massey University, Wellington, New Zealand
| | - Lihong Qi
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, USA
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Clemens Schafmayer
- Department of General Surgery, University Hospital Rostock, Rostock, Germany
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Linda Snetselaar
- Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA, USA
| | - Jeanette Schenk
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Stephen N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Hansong Wang
- University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Michael O Woods
- Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Anna H Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Bas Bueno-de-Mesquita
- Formerly, Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Marie-Christine Boutron-Ruault
- Faculty of Medicine, CESP, University of Paris-Sud, Faculty of Medicine UVSQ, INSERM, University of Paris-Saclay, Villejuif, France
- Centre for Research in Epidemiology and Population Health (CESP), Gustave Roussy, Villejuif, France
| | - David J Hughes
- Cancer Biology and Therapeutics Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Paula Jakszyn
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Blanquerna Faculty of Health Sciences, Ramon Llull University, Barcelona, Spain
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network-ISPRO, Florence, Italy
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Edward L Giovannucci
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA
- Department of Nutrition, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Stephen B Gruber
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
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49
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O'Logbon J, Crook M, Steed D, Harrington DJ, Sobczyńska-Malefora A. Ethnicity influences total serum vitamin B 12 concentration: a study of Black, Asian and White patients in a primary care setting. J Clin Pathol 2021; 75:598-604. [PMID: 33952588 DOI: 10.1136/jclinpath-2021-207519] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/21/2021] [Accepted: 04/06/2021] [Indexed: 11/03/2022]
Abstract
AIMS A growing body of evidence suggests that ethnicity and race influence vitamin B12 metabolism and status yet clinical awareness of this is poor, causing doubts regarding diagnosis and treatment. Moreover, deficiency and insufficiency cut-offs are universally applied for this test in most diagnostic settings. The objective of this study was to assess serum vitamin B12 concentrations in Black, Asian and White primary care patients in London, UK, particularly in patients of Black or Black British ethnic origin and establish if there is a need for specific reference ranges. METHODS Serum B12 results from 49 414 patients were processed between January 2018 and November 2019 using the Architect assay (Abbott Diagnostics) at St. Thomas' Hospital, London, UK. Age, sex and ethnicity data were collected from the laboratory Health Informatics Team. RESULTS Black patients (n=13 806) were found to have significantly higher serum vitamin B12 concentration across all age groups and both sexes, especially Nigerian patients (median B12 505 pmol/L,IQR: 362-727, n=891), compared with Asian and White ethnic groups (p<0.001). Binary logistic regression analysis revealed that the Black or Black British ethnic group had the strongest association with elevated serum B12 (>652 pmol/L) (adjusted OR 3.38, 95% CI 3.17 to 3.61, p<0.0001). CONCLUSIONS It is likely that a combination of genetic and acquired/environmental factors are responsible for the ethnic differences in serum B12. This suggests that there is a need for ethnic-specific reference ranges with indications for the incorporation of age and sex too.
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Affiliation(s)
- Jessica O'Logbon
- GKT School of Medicine, King's College London Faculty of Life Sciences and Medicine, London, UK jessica.o'
| | - Martin Crook
- Clinical Biochemistry and Metabolic Medicine, Guy's, St Thomas' Trust, London, UK.,Clinical Biochemistry and Metabolic Medicine, Lewisham and Greenwich Trust, London, UK.,Hon Professor in Biochemical Medicine, King's College London, London, UK
| | - David Steed
- Viapath Informatics, Viapath, Francis House, St Thomas' Hospital, London, UK
| | - Dominic Jon Harrington
- Faculty of Life Sciences and Medicine, King's College London, London, UK.,The Nutristasis Unit, Viapath, St. Thomas' Hospital, London, UK
| | - Agata Sobczyńska-Malefora
- Faculty of Life Sciences and Medicine, King's College London, London, UK.,The Nutristasis Unit, Viapath, St. Thomas' Hospital, London, UK
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50
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Yuan S, Mason AM, Carter P, Burgess S, Larsson SC. Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study. BMC Med 2021; 19:97. [PMID: 33888102 PMCID: PMC8063383 DOI: 10.1186/s12916-021-01977-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 03/29/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Whether a modestly elevated homocysteine level is causally associated with an increased risk of cardiovascular disease remains unestablished. We conducted a Mendelian randomization study to assess the associations of circulating total homocysteine (tHcy) and B vitamin levels with cardiovascular diseases in the general population. METHODS Independent single nucleotide polymorphisms associated with tHcy (n = 14), folate (n = 2), vitamin B6 (n = 1), and vitamin B12 (n = 14) at the genome-wide significance level were selected as instrumental variables. Summary-level data for 12 cardiovascular endpoints were obtained from genetic consortia, the UK Biobank study, and the FinnGen consortium. RESULTS Higher genetically predicted circulating tHcy levels were associated with an increased risk of stroke. For each one standard deviation (SD) increase in genetically predicted tHcy levels, the odds ratio (OR) was 1.11 (95% confidence interval (CI), 1.03, 1.21; p = 0.008) for any stroke, 1.26 (95% CI, 1.05, 1.51; p = 0.013) for subarachnoid hemorrhage, and 1.11 (95% CI, 1.03, 1.21; p = 0.011) for ischemic stroke. Higher genetically predicted folate levels were associated with decreased risk of coronary artery disease (ORSD, 0.88; 95% CI, 0.78, 1.00, p = 0.049) and any stroke (ORSD, 0.86; 95% CI, 0.76, 0.97, p = 0.012). Genetically predicted increased vitamin B6 levels were associated with a reduced risk of ischemic stroke (ORSD, 0.88; 95% CI, 0.81, 0.97, p = 0.009). None of these associations persisted after multiple testing correction. There was no association between genetically predicted vitamin B12 and cardiovascular disease. CONCLUSIONS This study reveals suggestive evidence that B vitamin therapy and lowering of tHcy may reduce the risk of stroke, particularly subarachnoid hemorrhage and ischemic stroke.
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Affiliation(s)
- Shuai Yuan
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobelsväg 13, 17177, Stockholm, Sweden
| | - Amy M Mason
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK
| | - Paul Carter
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Stephen Burgess
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobelsväg 13, 17177, Stockholm, Sweden.
- Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
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