Macro and micronutrients may play an important role in osteoporosis development; however, observational studies have yielded inconsistent results. Clarifying these associations is vital to the development of nutritional recommendations aimed at preventing osteoporosis.

Utilizing the largest available genome-wide association study (GWAS) summary statistics to date, we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of energy-adjusted macronutrient intake (fat, protein, carbohydrate, and sugar) and circulating levels of 20 micronutrients (ten each for vitamins and minerals) on heel estimated bone mineral density (eBMD), a promising marker for osteoporosis risk and fracture susceptibility. Sensitivity, sex-specific, and one-sample MR analyses were applied to further validate and annotate the results.

Among all nutrients, four genetically predicted circulating levels of micronutrients were suggestively associated with eBMD (vitamin A: β IVW = - 0.054, PIVW = 3.70 × 10-2; vitamin B12: β IVW = - 0.020, PIVW = 3.71 × 10-6; vitamin E: β IVW = 0.277, PIVW = 3.22 × 10-2; selenium: β IVW = 0.023, PIVW = 5.37 × 10-3; all Pintercept > 0.05). All these results were also considered robust, as sensitivity analyses yielded directionally consistent results. However, only the causal effects of vitamin B12 and selenium on eBMD remained significant after Bonferroni correction and were not confounded by obesity, smoking status, or alcohol consumption. Sex-specific analysis revealed a male-specific causal association between vitamin E and eBMD ( β IVW = 0.275, PIVW = 9.81 × 10-14). Additionally, using individuallevel data from the UK Biobank cohort, one-sample MR analysis found no causal relationships between diet-derived nutrient intake and eBMD in the overall population, as well as in the females or the males.

Our findings suggest that appropriate levels of plasma vitamin B12 and adequate levels of serum selenium are crucial for delaying bone loss and promoting bone health, emphasizing the need for nutritional recommendations to maintain optimal levels of these nutrients to promote eBMD and prevent osteoporosis.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Elevated folate levels correlate with morning-type preferences ("morning birds"), while higher concentrations of vitamin B6 are associated with evening-type preferences ("evening owls").

Diabetes mellitus (DM) links the risk of cardiovascular diseases. Inverse to the enhanced expression of matrix metalloproteinases (MMPs), the development of aortic aneurysm is lower in diabetic population. We examined the hypothesis that DM-induced alteration of metal ion levels declines the activity of MMPs to decrease aortic aneurysm risk.

By culturing vascular smooth muscle cells (VSMCs) or macrophages with different concentrations of glucose in the medium, we confirmed that high glucose significantly increased the expression of fibronectin and CTGF in VSMCs, and induced MMP2 expression and MMP9 secretion in macrophages. We also established an abdominal aortic aneurysm model in streptozotocin-induced diabetic mice and evaluated aneurysm development six weeks later. Compared to the healthy controls, diabetic mice had significantly lower levels of Zn2+ and Mg2+ in serum and developed significantly smaller sizes of aneurysms with higher expression of fibronectin and CTGF; but dietary zinc supplementation to diabetic mice effectively neutralized these differences. Gelatin zymography assay indicated that the enzymatic digestion activity of MMP2 was changed under different concentrations of ZnSO4 and MgSO4. Clinical data analysis also confirmed that DM, serum Zn2+ level, and aortic aneurysm risk closely correlated with each other.

It seems that DM-induced alteration of metal ion levels declines the activity of MMPs to negate aortic aneurysm development. Our data provide novel mechanistical insight and therapeutic strategy for aortic aneurysms.

Mucin 1 (or MUC1) is a heterodimeric transmembrane glycoprotein expressed on the apical surface of polarized epithelial cells in several tissues including the kidney. Recent studies have revealed several novel roles of MUC1 in the kidney, potentially including bacterial infection, mineral balance, and genetic interstitial kidney disease, even though MUC1 levels are reduced not only in the kidney but also in all tissues due to MUC1 mutations. A careful localization of MUC1 in discrete segments of the nephron is the first step in understanding the multiple functional roles of MUC1 in the kidney. Most published reports of MUC1 expression to date have been largely confined to cultured cells, tumor tissues, and selective nephron segments of experimental rodents, and very few studies have been performed using human kidney tissues. Given the rising attention to the role of MUC1 in differing components of renal physiology, we carefully examined the kidney distribution of MUC1 in both human and mouse kidney sections using well-defined markers for different nephron segments or cell types. We further extended our investigation to include sections of early stages of mouse kidney development and upon injury in humans. We included staining for MUC1 in urothelial cells, the highly specialized epithelial cells lining the renal pelvis and bladder. These data implicate a role for MUC1 in antimicrobial defense. Our study provides the groundwork to test the physiological relevance of MUC1 in the urinary tract.NEW & NOTEWORTHY MUC1 is a transmembrane glycoprotein expressed on the apical surface of polarized epithelial tissues and most carcinomas. MUC1 may play novel roles in the kidney including defense against infections. Here, we examine the expression of MUC1 in mouse and human kidneys. We show that the distal nephron and the urinary system are the predominant sites of expression of both message and protein, implicating segment-specific roles including distal nephron defense against ascending bacteria.

The aim of this study was to (1) determine complex interactions between macro- and micro-elements present in blood serum and ejaculate of common carp (Cyprinus carpio), and (2) examine the association between alterations in these macro- and micro-elements with markers of oxidative stress. Blood and ejaculate from 10 male carp were collected in the summer period on the experimental pond in Kolíňany (West Slovak Lowland). Reactive oxygen species (ROS), total antioxidant capacity (TAC), protein carbonyls (PC), and malondialdehyde (MDA) levels were measured in blood serum and ejaculate using spectrophotometric methods. The amounts of elements (Ag, Al, Ba, Co, Li, Mo, Ca, K, Na, and Mg) in all samples were quantified using inductively coupled plasma optical emission spectrophotometry. Data demonstrated significant differences in elemental concentrations between blood and ejaculate, specifically significantly higher ejaculate levels were detected for Ag, Al, Ba, Co, Li, Mo, K, and Mg. Potassium was the most abundant macro-element in the ejaculate, while sodium was the most abundant in blood serum. Among the micro-elements, Al was predominant in both types of samples. It is noteworthy that oxidative status markers including ROS, TAC, and MDA were significantly higher in ejaculate indicating the presence of oxidative stress in C. carpio reproductive tissue. The positive correlations between Mg and Ca in blood serum and ejaculate suggest these elements play a functional role in metabolic and physiological processes. In contrast, the positive correlations of Ba and Al with markers of oxidative stress indicated the association of these metals with induction of oxidative stress. Our findings provide insights into the association of metals with biomarkers of physiological function as well as adverse effects in C. carpio.

Blood composition is indicative of health-related traits such as immunity and metabolism. The use of molecular genetics to investigate alterations in these attributes in laying ducks is a novel approach. Our objective was to employ genome - wide association studies (GWAS) and haplotype - sharing analysis to identify genomic regions and potential genes associated with 11 blood components in Shaoxing ducks. Our findings revealed 35 SNPs and 1 SNP associated with low-density lipoprotein cholesterol (LDL) and globulin (GLB), respectively. We identified 36 putative candidate genes for the LDL trait in close proximity to major QTLs and key loci. Based on their biochemical and physiological properties, TRA2A, NPY, ARHGEF26, DHX36, and AADAC are the strongest putative candidate genes. Through linkage disequilibrium analysis and haplotype sharing analysis, we identified three haplotypes and one haplotype, respectively, that were significantly linked with LDL and GLB. These haplotypes could be selected as potential candidate haplotypes for molecular breeding of Shaoxing ducks. Additionally, we utilized a bootstrap test to verify the reliability of GWAS with small experimental samples. The test can be accessed at https://github.com/xuwenwu24/Bootstrap-test.

Various vitamins and minerals have been implicated in the aetiology of depression.

To estimate the effects of micronutrient exposures on major depressive disorder (MDD) and recurrent depression (rMDD) using Mendelian randomisation (MR), a method using genetic data to estimate causal effects given certain assumptions.

We undertook a comprehensive bidirectional MR study of multiple micronutrient exposures on MDD and rMDD. Summary statistics were obtained from the Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWASs) of MDD (cases = 116,209; controls = 314,566) and rMDD (cases = 17,451; controls = 62,482).

None of the micronutrients with available genetic instruments were strongly associated with MDD or rMDD using traditional MR methods. However, using methods to increase analytical power by accounting for genetically correlated variants (e.g., cIVW) highlighted five micronutrients with possible causal effects. Point estimates for rMDD were the largest magnitude, with three micronutrients suggestive of a protective effect: serum iron (ORcIVW 0.90 per SD increase; 95% CI 0.85-0.95; p = 0.0003); erythrocyte copper (ORcIVW 0.97; 95% CI 0.95-0.99; p = 0.0004); and 25(OH) vitamin D (ORcIVW 0.81; 0.66-0.99; p = 0.04). Apparent adverse effects of increased selenium on the risk of MDD (ORcIVW 1.03; 95% CI 1.02-1.05; p = 0.0003) and rMDD (ORcIVW 1.08; 95% CI 1.00-1.08; p = 0.06), and serum magnesium on rMDD (ORcIVW 1.21; 1.01-1.44; p = 0.04); were less consistent between methods and may be driven by pleiotropy.

Our results suggest weak evidence for a protective effect of iron, copper and 25(OH)D on major depressive outcomes, with mixed evidence for selenium and magnesium. There was no evidence to support a causal effect of any other micronutrients on MDD or rMDD, although genetic instruments were lacking, with insufficient power to detect small but important effects. Future micronutrient supplementation trials should ensure ample statistical power given modest causal effect estimates and consider potential risks of supplementation, as some micronutrient effect estimates suggested potential harm in excess.

Although age-dependent alterations in urinary magnesium (Mg2+) excretion have been described, the underlying mechanism remains elusive. As heritability significantly contributes to variations in urinary Mg2+ excretion, we measured urinary Mg2+ excretion at different ages in a cohort of genetically variable Diversity Outbred (DO) mice. Compared with animals aged 6 mo, an increase in Mg2+ excretion was observed at 12 and 18 mo. Quantitative trait locus (QTL) analysis revealed an association of a locus on chromosome 10 with Mg2+ excretion at 6 mo of age, with Oit3 (encoding oncoprotein-induced transcript 3; OIT3) as our primary candidate gene. To study the possible role of OIT3 in renal Mg2+ handling, we generated and characterized Oit3 knockout (Oit3-/-) mice. Although a slightly lower serum Mg2+ concentration was present in male Oit3-/- mice, this effect was not observed in female Oit3-/- mice. In addition, urinary Mg2+ excretion and the expression of renal magnesiotropic genes were unaltered in Oit3-/- mice. For animals aged 12 and 18 mo, QTL analysis revealed an association with a locus on chromosome 19, which contains the gene encoding TRPM6, a known Mg2+ channel involved in renal Mg2+ reabsorption. Comparison with RNA sequencing (RNA-Seq) data revealed that Trpm6 mRNA expression is inversely correlated with the QTL effect, implying that TRPM6 may be involved in age-dependent changes in urinary Mg2+ excretion in mice. In conclusion, we show here that variants in Oit3 and Trpm6 are associated with urinary Mg2+ excretion at distinct periods of life, although OIT3 is unlikely to affect renal Mg2+ handling.NEW & NOTEWORTHY Aging increased urinary magnesium (Mg2+) excretion in mice. We show here that variation in Oit3, a candidate gene for the locus associated with Mg2+ excretion in young mice, is unlikely to be involved as knockout of Oit3 did not affect Mg2+ excretion. Differences in the expression of the renal Mg2+ channel TRPM6 may contribute to the variation in urinary Mg2+ excretion in older mice.

(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.

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.

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.

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.

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.

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.

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.

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.

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.

Previous studies showed the conflicting associations between circulating micronutrient levels and systemic lupus erythematosus (SLE). Therefore, we aimed to clarify the causal association between circulating micronutrient levels and the risk of SLE by two-sample Mendelian randomization (MR) analysis.

56 single nucleotide polymorphisms (SNPs) significantly associated with 14 circulating micronutrients (vitamin A, B6, B9, B12, C, D and E, phosphorus, calcium, magnesium, copper, iron, zinc, and selenium) in published genome-wide association studies (GWAS) were used as instrumental variables (IVs). And summary statistics related to SLE were obtained from the IEU OpenGWAS database. We used the MR Steiger test to estimate the possible causal direction between circulating micronutrients and SLE. In the MR analysis, inverse variance weighting (IVW) method and the Wald ratio was as the main methods., Moreover, the MR-Pleiotropy residuals and outliers method (MR-PRESSO), Cochrane's Q-test, MR-Egger intercept method and leave-one-out analyses were applied as sensitivity analyses. Additionally, we conducted a retrospective analysis involving the 20,045 participants from the Third National Health and Nutritional Examination Survey (NHANES III). Weight variables were provided in the NHANES data files. Univariate and multivariate logistic regression analyses were performed to determine the associations between circulating micronutrients and SLE.

The MR estimates obtained from the IVW method revealed potential negative correlations between circulating calcium (OR: 0.06, 95% CI: 0.01-0.49, P = 0.009), iron levels (OR: 0.63, 95% CI: 0.43-0.92, P = 0.016) and the risk of SLE. The results remained robust, even under various pairs of sensitivity analyses. Our retrospective analysis demonstrated that the levels of vitamin D, serum total calcium, and serum iron were significantly lower in SLE patients (N = 40) when compared to the control group (N = 20,005). Multivariate logistic regression analysis further established that increased levels of vitamin D and serum total calcium served as protective factors against SLE.

Our results provided genetic evidence supporting the potential protective role of increasing circulating calcium in the risk of SLE. Maintaining adequate levels of calcium may help reduce the risk of SLE.

This study examines the causal relationships between serum micronutrients and site-specific osteoarthritis (OA) using Mendelian Randomization (MR).

This study performed a two-sample MR analysis to explore causal links between 21 micronutrients and 11 OA outcomes. These outcomes encompass overall OA, seven site-specific manifestations, and three joint replacement subtypes. Sensitivity analyses using MR methods, such as the weighted median, MR-Egger, and MR-PRESSO, assessed potential horizontal pleiotropy and heterogeneity. Genome-wide association summary statistical data were utilized for both exposure and outcome data, including up to 826,690 participants with 177,517 OA cases. All data was sourced from Genome-wide association studies datasets from 2009 to 2023.

In the analysis of associations between 21 micronutrients and 11 OA outcomes, 15 showed Bonferroni-corrected significance (P < 0.000216), without significant heterogeneity or horizontal pleiotropy. Key findings include strong links between gamma-tocopherol and spine OA (OR = 1.70), and folate with hand OA in finger joints (OR = 1.15). For joint replacements, calcium showed a notable association with a reduced likelihood of total knee replacement (TKR) (OR = 0.52) and total joint replacement (TJR) (OR = 0.56). Serum iron was significantly associated with an increased risk of total hip replacement (THR) (OR = 1.23), while folate indicated a protective effect (OR = 0.95). Various sex-specific associations were also uncovered.

These findings underscore the critical role of micronutrients in osteoarthritis, providing valuable insights for preventive care and potential enhancement of treatment outcomes.

Observational investigations recommend that mineral supplements were associated with a higher risk of polycystic ovary syndrome (PCOS) and its risk factors (insulin resistance, hyperandrogenism, and obesity), but the relationship with risk of PCOS, hyperandrogenism, obesity, and insulin resistance was unclear. This study was to investigate the potential causal impact of genetically predicted levels of magnesium (Mg), calcium (Ca), selenium (Se), zinc (Zn), iron (Fe), and omega-3 (ω-3) on polycystic ovary syndrome (PCOS) and its associated risk factors. A two-sample Mendelian randomization (MR) analysis was conducted. The genetic variations obtained from GWAS of individuals with European ancestry were found to be associated with the genetically predicted levels of Ca, Mg, Zn, Se, Fe, or ω-3. The data obtained from the FinnGen Consortium and MAGIC were utilized for the outcome of GWAS. The study found that there was a correlation between genetically predicted higher levels of Se and a reduced risk of insulin resistance, with a decrease of 2.2% according to random-effect IVW (OR 0.978, 95% CI 0.960-0.996, p = 0.015). The association between genetically determined mineral levels and PCOS was found to be limited, with an odds ratio (OR) ranging from 0.875 (95% CI: 0.637-1.202, p value = 0.411) for Ca. Limited scientific proof was found for the efficacy of other genetically determined mineral levels on hyperandrogenism, obesity, and insulin resistance. These findings suggested a causal relationship between genetically predicted higher levels of Se and a reduced risk of insulin resistance. Nonetheless, there is limited evidence supporting a causal association between various genetically determined mineral levels and the risk factors associated with PCOS.

Serum biochemical indicators serve as vital proxies that reflect the physiological state and functions of different organs. The genetic parameters and molecular mechanisms underlying serum biochemical indicators of sheep (Ovis aries) have not been well understood. Therefore, the aim of the present study was to identify the genetic architecture and genomic loci underlying ten serum biochemical indicators in sheep, including alanine transaminase, aspartate transferase, lactate dehydrogenase, cholesterol, glucose, phosphorus, calcium, creatinine, urea and total protein levels. We implemented genetic parameter estimations and GWASs for each trait in 422 Akkaraman lambs. Overall, low to moderate heritability estimates were found in the range of 0.14-0.55. Additionally, low to high genetic correlations were observed among traits. In total, 23 SNP loci were associated with serum biochemical indicators leading to 19 genes. These were SPTA1, MGST2, CACUL1, IGFBP7, PARD3, PHB1, SLC15A5, TRIM35, RGS6, NUP93, CNTNAP2, SLC7A11, B3GALT5, DPP10, HST2ST1, NRP1, LRP1B, MAP3K9 and ENSOARG00020040484.1, as well as LOC101103187, LOC101117162, LOC105611309 and LOC101118029. To our knowledge, these data provide the first associations between SPTA1 and serum cholesterol and between ENSOARG00020040484.1 and serum glucose. The current findings provide a comprehensive inventory of the relationships between serum biochemical parameters, genetic variants and disease-relevant characteristics. This information may facilitate the identification of therapeutic targets and fluid biomarkers and establish a strong framework for comprehending the pathobiology of complex diseases as well as providing targets for sheep genetic improvement programs.

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.

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.

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.

The study findings provide evidence that the micronutrient selenium and β-carotene may confer protective effects against the development of CP.

Previous observational studies have discovered a connection between depression and mineral status. Confirming this potential connection is challenging due to confounding factors and potential reverse causality which is inherent in observational studies.

We performed a Mendelian randomization (MR) analysis to estimate the causal association of serum minerals with depression. Leveraging summary-level data on depression, a genome-wide association study (GWAS) was applied. The data on serum minerals were collected from the FinnGen Biobank database. MR assessments representing causality were produced by inverse-variance weighted approaches with multiplicative random and fixed effects.

Sensitivity analyses were performed to validate the reliability of the results. A noteworthy correlation emerged between serum zinc levels and reduced risk of depression. An odds ratio (OR) of 0.917 for depression associated with a one standard deviation increase in serum zinc levels (OR = 0.968; 95% CI = 0.953-0.984, p = 1.19 × 10-4, random effects model inverse variance weighted (IVW)); (OR = 0.928; 95% CI = 0.634-1.358, p = 0.766, MR Egger). Sensitivity assessments supported this causation. However, the risk of depression did not exhibit an association with other minerals.

In summary, a higher zinc concentration is causally associated with a reduced depression risk. This MR outcome may assist clinicians in the regulation of specific mineral intake, particularly for high-risk patients with serum zinc deficiencies.

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.

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.

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.

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.

Specific nutrients found in food, such as minerals, antioxidants, and macronutrients, have a significant impact on immune function and human health. However, there is currently limited research exploring the relationship between specific nutrients, immune system function, and thyroid dysfunction commonly observed in autoimmune thyroid diseases, which manifest predominantly as hyperthyroidism or hypothyroidism. Therefore, the objective of this study was to investigate the connections between dietary traits and thyroid dysfunction, as well as the potential mediating role of immune cells, using Mendelian randomization (MR) analysis.

The two-step MR analysis used single-nucleotide polymorphisms as instruments, with a threshold of p < 5e-08 for nutrients and thyroid dysfunction, and p < 5e-06 for immune cells. Data from different GWAS databases and UK Biobank were combined to analyze 8 antioxidants and 7 minerals, while the data for 4 macronutrients came from a cohort of 235,000 individuals of European. The outcome data (hypothyroidism, N = 3340; hyperthyroidism, N = 1840; free thyroxin [FT4], N = 49,269; thyroid-stimulating hormone [TSH], N = 54,288) were source from the ThyroidOmics consortium. Immune trait data, including 731 immune phenotypes, were collected from the GWAS catalog.

The results revealed that nutrient changes, such as lycopene, toenail and blood selenium, and α-tocopherol, impacted the immune system. Immune cells also affected thyroid function, with cDC cells promoting hypothyroidism and median fluorescence intensity (MFI) phenotypes correlating strongly with FT4 levels. Toenail and blood selenium reduce the relative cell counts (RCC) phenotypes of immune cells (CD62L- plasmacytoid DC %DC and transitional B cells %Lymphocyte), thereby diminishing its promoting effect on hypothyroidis. Furthermore, toenail and blood selenium mainly impacted phenotypes in three types of T cells (CD25 + ⁣ + CD8br, CD3 on CD45RA- CD4+, and CD45RA on Terminally Differentiated CD8br), reinforcing the negative regulation of FT4 levels.

The role of immune cells as mediators in the relationship between nutrients and thyroid dysfunction highlights their potential as diagnostic or therapeutic markers. Toenail and blood selenium levels can indirectly impact hypothyroidism by influencing the RCC levels of two types of immune cells, and can indirectly affect FT4 levels by influencing three types of T cells.

To assess the association of serum magnesium with prevalent and incident metabolic syndrome (MetS) and its individual components in the general population and to examine any effect modification by chronic kidney disease (CKD) status.

We analysed longitudinal data from the population-based KORA F4/FF4 study, including 2996 participants (387 with CKD) for cross-sectional analysis and 1446 participants (88 with CKD) for longitudinal analysis. Associations with MetS, as well as single components of MetS, were assessed by adjusted regression models. Nonlinearity was tested by restricted cubic splines and analyses were stratified by CKD. Causality was evaluated by two-sample Mendelian randomization (MR).

Serum magnesium (1 SD) was inversely associated with prevalent MetS (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.83, 0.98). The association was more pronounced in individuals with CKD (OR 0.75, 95% CI 0.59, 0.94). Among MetS components, serum magnesium was negatively associated with elevated fasting glucose (OR 0.78, 95% CI 0.71, 0.88) and, again, this association was more pronounced in individuals with CKD (OR 0.67, 95% CI 0.53, 0.84). Serum magnesium was not associated with incident MetS or its components. Restricted cubic spline analysis revealed a significant nonlinear inverse relationship of serum magnesium with MetS and elevated fasting glucose. MR analysis suggested an inverse causal effect of serum magnesium on MetS (OR 0.91, 95% CI 0.85, 0.97).

Serum magnesium is associated with prevalent, but not incident MetS, and this effect is stronger in individuals with CKD. MR analysis implies a potential, albeit weak, causal role of magnesium in MetS.

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.

The Shroom (Shrm) family of actin-binding proteins has a unique and highly conserved Apx/Shrm Domain 2 (ASD2) motif. Shroom protein directs the subcellular localization of Rho-associated kinase (ROCK), which remodels the actomyosin cytoskeleton and changes cellular morphology via its ability to phosphorylate and activate non-muscle myosin II. Therefore, the Shrm-ROCK complex is critical for the cellular shape and the development of many tissues, including the neural tube, eye, intestines, heart, and vasculature system. Importantly, the structure and expression of Shrm proteins are also associated with neural tube defects, chronic kidney disease, metastasis of carcinoma, and X-link mental retardation. Therefore, a better understanding of Shrm-mediated signaling transduction pathways is essential for the development of new therapeutic strategies to minimize damage resulting in abnormal Shrm proteins. This paper provides a comprehensive overview of the various Shrm proteins and their roles in morphogenesis and disease.

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.

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.

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.

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.

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.

People with type 2 diabetes have a tenfold higher prevalence of hypomagnesemia, which is suggested to be caused by low dietary magnesium intake, medication use, and genetics. This study aims to identify the genetic loci that influence serum magnesium concentration in 3466 people with type 2 diabetes. The GWAS models were adjusted for age, sex, eGFR, and HbA1c. Associated traits were identified using publicly available data from GTEx consortium, a human kidney eQTL atlas, and the Open GWAS database. The GWAS identified a genome-wide significant locus in TAF3 (p = 2.9 × 10-9) in people with type 2 diabetes. In skeletal muscle, loci located in TAF3 demonstrate an eQTL link to ATP5F1C, a gene that is involved in the formation of Mg2+-ATP. Serum Mg2+ levels were associated with MUC1/TRIM46 (p = 2.9 × 10-7), SHROOM3 (p = 4.0 × 10-7), and SLC22A7 (p = 1.0 × 10-6) at nominal significance, which is in combination with the eQTL data suggesting that they are possible candidates for renal failure. Several genetic loci were in agreement with previous genomic studies which identified MUC1/TRIM46 (Pmeta = 6.9 × 10-29, PQ = 0.81) and SHROOM3 (Pmeta = 2.9 × 10-27, PQ = 0.04) to be associated with serum Mg2+ in the general population. In conclusion, serum magnesium concentrations are associated with genetic variability around the regions of TAF3, MUC1/TRIM46, SHROOM3, and SLC22A7 in type 2 diabetes.

Recent observational studies have reported associations between serum mineral nutrient levels, gut microbiota composition, and neurological, psychiatric, and metabolic diseases. However, the causal effects of mineral nutrients on gut microbiota and their causal associations with diseases remain unclear and require further investigation. This study aimed to identify the associations between serum mineral nutrients, gut microbiota, and risk of neurological, psychiatric, and metabolic diseases using Mendelian randomization (MR). We conducted an MR study using the large-scale genome-wide association study (GWAS) summary statistics of 5 serum mineral nutrients, 196 gut microbes at the phylum, order, family, and genus levels, and a variety of common neurological, psychiatric, and metabolic diseases. Initially, the independent causal associations of mineral nutrients and gut microbiota with diseases were examined by MR. Subsequently, the causal effect of mineral nutrients on gut microbiota was estimated to investigate whether specific gut microbes mediated the association between mineral nutrients and diseases. Finally, we performed sensitivity analyses to assess the robustness of the study results. After correcting for multiple testing, we identified a total of 33 causal relationships among mineral nutrients, gut microbiota, and diseases. Specifically, we found 4 causal relationships between 3 mineral nutrition traits and 3 disease traits, 15 causal associations between 14 gut microbiota traits and 6 disease traits, and 14 causal associations involving 4 mineral nutrition traits and 15 gut microbiota traits. Meanwhile, 118 suggestive associations were identified. The current study reveals multiple causal associations between serum mineral nutrients, gut microbiota, risk of neurological, psychiatric, and metabolic diseases, and potentially provides valuable insights for subsequent nutritional therapies.

Evidence from epidemiological literature on the association of circulating micronutrients with risk of nonalcoholic fatty liver disease (NAFLD) is inconsistent. We aimed to elucidate the causal relationships using Mendelian randomization (MR). Single-nucleotide polymorphisms associated with 14 circulating micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6, B12, C, D, K1 and zinc) were employed as instrumental variables. Summary level data for NAFLD were obtained from a genome-wide association study (GWAS) meta-analysis of 8434 cases and 770,180 controls (discovery stage) and another two datasets including 1483 NAFLD cases and 17,781 controls (replication stage 1) and 2134 NAFLD cases and 33,433 controls (replication stage 2). Inverse variance-weighted method (IVW) was used as primary analysis, supplemented with a series of sensitivity analysis. Genetically predicted higher β‑carotene levels were suggestively associated with reduced NAFLD risk [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.66-0.99; P = 0.047], whereas the association did not survive the false discovery rates (FDR) correction (PFDR = 0.164). Genetically predicted circulating iron (OR 1.16, 95% CI 1.05-1.29; P = 0.006, PFDR = 0.028), selenium (OR 1.11, 95% CI 1.03-1.20; P = 0.005, PFDR = 0.028) and vitamin B12 (OR 1.08, 95% CI 1.03-1.13; P = 0.002, PFDR = 0.028) were significantly associated with increased risk of NAFLD. Moreover, the findings were consistent in individual datasets (Pheterogeneity > 0.05) and confirmed in sensitivity analysis. Our study provided evidence that circulating iron, selenium and vitamin B12 might be causally linked to the risk of NAFLD, which deserves further exploration of the potential biological mechanism.

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.

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.

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.

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.

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.

To examine the associations of dietary Mg intake with inflammatory biomarkers (C-reactive protein (CRP) and interleukin 6 (IL-6)), and the interaction of dietary Mg intake with single nucleotide polymorphism (SNP) rs3740393, a SNP related to Mg metabolism and transport, on CRP and IL-6 among American Indians (AIs).

This cross-sectional study included AI participants (n = 1,924) from the Strong Heart Family Study (SHFS). Mg intake from foods and dietary supplements was ascertained using a 119-item Block food frequency questionnaire, CRP and IL-6 were measured from blood, and SNP rs3740393 was genotyped using MetaboChip. Generalized estimating equations were used to examine associations of Mg intake, and the interaction between rs3740393 and dietary Mg, with CRP and IL-6.

Reported Mg intake was not associated with CRP or IL-6, irrespective of genotype. A significant interaction (p-interaction = 0.018) was observed between Mg intake and rs3740393 on IL-6. Among participants with the C/C genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.04 (95% CI: -0.10 to 0.17) pg/mL higher. Among participants with the C/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.08 (95% CI: -0.21 to 0.05) pg/mL lower, and among participants with the G/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.19 (95% CI: -0.38 to -0.01) pg/mL lower.

Mg intake may be associated with lower IL-6 with increasing dosage of the G allele at rs3740393. Future research is necessary to replicate this finding and examine other Mg-related genes that influence associations of Mg intake with inflammation.

Previous observational researches have discovered a connection between circulating concentrations of micronutrients and attention deficit hyperactivity disorder (ADHD). However, the results may be influenced by confounding factors and reverse causation. This study aims to explore the causal relationship between circulating concentrations of micronutrients and ADHD using Mendelian randomization (MR). In a two-sample MR context, we used summary data from the major European genome-wide association studies (GWAS) for these illnesses to assess the genetically anticipated effects of circulating concentrations of micronutrients on ADHD risk. In order to achieve this, we took single nucleotide polymorphisms (SNPs) from the GWAS that were highly related with concentrations of nine micronutrients. The corresponding data for ADHD were extracted from the Psychiatric Genomics Consortium. Inverse-variance weighted (IVW) method was used as the main MR analysis, and the reliability of the study's conclusions was assessed using sensitivity analyses. Our MR analyses showed that the copper level may be associated with a reduced risk of ADHD. However, the significance of the research results is weak. There were no clear relationships between other micronutrients and ADHD. Our sensitivity studies confirmed the findings of the primary IVW MR analyses. According to this study, there may be some association between copper level and ADHD, but the significance of the research results is weak, and it is recommended that copper level should be used as a long-term monitoring indicator for further research. The results provide a new idea for the further study of ADHD, and provide guidance for the prevention and treatment of ADHD.

Atrial fibrillation (AF) contributes to stroke development and progression. We aimed to quantify the mediating role of AF in the causal associations between a wide range of risk factors and stroke via a Mendelian randomization (MR) framework.

We assessed the associations of 108 traits with stroke and its subtypes in a 2-sample univariable MR approach, then conducted a bidirectional MR analysis between these 108 traits and AF to evaluate the presence and direction of their causal associations. Finally, to further investigate the extent to which AF mediated the effects of eligible traits on stroke, we applied multivariable and 2-step MR techniques in a mediation analysis where outcomes were restricted to stroke types causally affected by AF (any stroke [AS], any ischemic stroke [AIS], and cardioembolic stroke [CES]).

Among 108 traits, 42 were putatively causal for at least 1 stroke type; of these 42 traits, 20 that had no bidirectional relationship with AF were retained. Finally, 33 associations of 15 eligible traits were examined in the mediation analysis. The mediation analyses for AS, AIS, and CES each included 11 eligible traits. After AF adjustment, the direct effects of all traits on CES were attenuated to null (all p>0.05), while the associations with AS and AIS persisted for most traits (AF-mediated proportion: from 6.6% [95% confidence interval, 2.7 to 0.6] to 52.0% [95% confidence interval, 39.8 to 64.3]).

The causal associations between all eligible traits and CES were largely mediated through AF, while most traits affected AS and AIS independently of AF.

Magnesium (Mg2+ ) is the most abundant divalent cation in cells and plays key roles in almost all biological processes. CBS-pair domain divalent metal cation transport mediators (CNNMs) are a newly characterized class of Mg2+ transporters present throughout biology. Originally discovered in bacteria, there are four CNNM proteins in humans, which are involved in divalent cation transport, genetic diseases, and cancer. Eukaryotic CNNMs are composed of four domains: an extracellular domain, a transmembrane domain, a cystathionine-β-synthase (CBS)-pair domain, and a cyclic nucleotide-binding homology domain. The transmembrane and CBS-pair core are the defining features of CNNM proteins with over 20 000 protein sequences known from over 8000 species. Here, we review the structural and functional studies of eukaryotic and prokaryotic CNNMs that underlie our understanding of their regulation and mechanism of ion transport. Recent structures of prokaryotic CNNMs confirm the transmembrane domain mediates ion transport with the CBS-pair domain likely playing a regulatory role through binding divalent cations. Studies of mammalian CNNMs have identified new binding partners. These advances are driving progress in understanding this deeply conserved and widespread family of ion transporters.

The available evidence regarding the association of antioxidants, minerals, and vitamins with the risk of metabolic syndrome (MetS) traits is currently limited and inconsistent. Therefore, the purpose of this Mendelian randomization (MR) study was to investigate the potential causal relationship between genetically predicted antioxidants, minerals, and vitamins, and MetS.

In this study, we utilized genetic variation as instrumental variable (IV) to capture exposure data related to commonly consumed dietary nutrients, including antioxidants (β-carotene, lycopene, and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc, and selenium), and vitamins (folate, vitamin A, B6, B12, C, D, E, and K1). The outcomes of interest, namely MetS (n = 291,107), waist circumference (n = 462,166), hypertension (n = 463,010), fasting blood glucose (FBG) (n = 281,416), triglycerides (n = 441,016), and high-density lipoprotein cholesterol (HDL-C) (n = 403,943), were assessed using pooled data obtained from the most comprehensive genome-wide association study (GWAS) available. Finally, we applied the inverse variance weighting method as the result and conducted a sensitivity analysis for further validation.

Genetically predicted higher iron (OR = 1.070, 95% CI 1.037-1.105, P = 2.91E-05) and magnesium levels (OR = 1.130, 95% CI 1.058-1.208, P = 2.80E-04) were positively associated with increased risk of MetS. For each component of MetS, higher level of genetically predicted selenium (OR = 0.971, 95% CI 0.957-0.986, P = 1.09E-04) was negatively correlated with HDL-C levels, while vitamin K1 (OR = 1.023, 95% CI 1.012-1.033, P = 2.90E-05) was positively correlated with HDL-C levels. Moreover, genetically predicted vitamin D (OR = 0.985, 95% CI 0.978-0.992, P = 5.51E-5) had a protective effect on FBG levels. Genetically predicted iron level (OR = 1.043, 95% CI 1.022-1.064, P = 4.33E-05) had a risk effect on TG level.

Our study provides evidence that genetically predicted some specific, but not all, antioxidants, minerals, and vitamins may be causally related to the development of MetS traits.

To investigate the causal role of serum magnesium and calcium in epilepsy or any of its subtypes through Mendelian randomization (MR) approach.

Single nucleotide polymorphisms (SNPs) associated with serum magnesium and calcium were used as the instrumental variables. MR analyses were performed using the summary-level data for epilepsy extracted from International League Against Epilepsy Consortium (15,212 cases and 29,677 controls) to obtain the causal estimates. The analyses were replicated using FinnGen data (7224 epilepsy cases and 208,845 controls), and a meta-analysis was then conducted.

The result of combined analyses showed that higher serum magnesium concentrations was associated with a reduced risk of overall epilepsy (odds ratios [OR] = 0.28, 95% confidence interval [CI], 0.12-0.62, p = 0.002). In ILAE, higher serum magnesium was suggestively associated with reduced risks of focal epilepsy (OR = 0.25, 95% CI 0.10-0.62, p = 0.003). However, the results cannot be repeated in sensitivity analyses. As for serum calcium, the results did not reach statistical significance with overall epilepsy (OR = 0.60, 95% CI, 0.31-1.17, p = 0.134). However, genetically predicted serum calcium concentrations showed an inverse association with risk of generalized epilepsy (OR = 0.35, 95% CI, 0.17-0.74, p = 0.006).

The current MR analysis did not support a causal relationship between serum magnesium and epilepsy, but showed a causally negative association between genetically determined serum calcium and generalized epilepsy.

Current studies have reported conflicting associations between circulating micronutrient levels and kidney stone disease (KSD). We aimed to elucidate the causal relationship between circulating micronutrient levels and KSD by a two-sample Mendelian randomization (MR) analysis.

Total of 36 single nucleotide polymorphisms (SNPs) from published genome-wide association studies (GWAS) significantly associated with eight micronutrients (vitamin B12, folic acid, magnesium, iron, phosphorus, copper, zinc, and selenium) were used as instrumental variables. The GWAS summary data associated with KSD (8,060 cases and 301,094 controls) were obtained from the FinnGen consortium. Inverse variance weighted was the main MR analysis method. MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), weighted median and MR-Egger were used to assess pleiotropy and heterogeneity.

Genetically predicted circulating vitamin B12 and zinc levels were causally associated with the risk of KSD (vitamin B12: OR: 1.17, 95% CI: 1.04-1.32, p = 0.008; zinc: OR: 1.15, 95% CI: 1.03-1.28, p = 0.015). We found no evidence that other circulating micronutrients were associated with risk of KSD. p-value for Cochrane Q test, MR Egger intercept test, and MR-PRESSO were >0.05, indicating no significant heterogeneity or horizontal pleiotropy in this MR analysis.

Increasing circulating zinc levels may increase the risk of KSD. More studies are needed to provide evidence on whether genetically predicted circulating vitamin B12 and zinc levels are a risk factor for KSD.

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.

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.

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.

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.