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Aminbakhsh AP, Théberge ET, Burden E, Adejumo CK, Gravely AK, Lehman A, Sedlak TL. Exploring associations between estrogen and gene candidates identified by coronary artery disease genome-wide association studies. Front Cardiovasc Med 2025; 12:1502985. [PMID: 40182431 PMCID: PMC11965610 DOI: 10.3389/fcvm.2025.1502985] [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: 09/27/2024] [Accepted: 03/04/2025] [Indexed: 04/05/2025] Open
Abstract
Introduction Coronary artery disease (CAD) is the leading cause of death around the world, with epidemiological sex and gender differences in prevalence, pathophysiology and outcomes. It has been hypothesized that sex steroids, like estrogen, may contribute to these sex differences. There is a relatively large genetic component to developing CAD, with heritability estimates ranging between 40%-60%. In the last two decades, genome-wide association studies (GWAS) have contributed substantially to advancing the understanding of genetic candidates contributing to CAD. The aim of this study was to determine if genes discovered in CAD GWASs are affected by estrogen via direct modulation or indirect down-stream targets. Methods A scoping review was conducted using MEDLINE and EMBASE for studies of atherosclerotic coronary artery disease and a genome-wide association study (GWAS) design. Analysis was limited to candidate genes with corresponding single nucleotide polymorphisms (SNPs) surpassing genome-wide significance and had been mapped to genes by study authors. The number of studies that conducted sex-stratified analyses with significant genes were quantified. A literature search of the final gene lists was done to examine any evidence suggesting estrogen may modulate the genes and/or gene products. Results There were 60 eligible CAD GWASs meeting inclusion criteria for data extraction. Of these 60, only 36 had genome-wide significant SNPs reported, and only 3 of these had significant SNPs from sex-stratified analyses mapped to genes. From these 36 studies, a total of 61 genes were curated, of which 26 genes (43%) were found to have modulation by estrogen. All 26 were discovered in studies that adjusted for sex. 12/26 genes were also discovered in studies that conducted sex-stratified analyses. 12/26 genes were classified as having a role in lipid synthesis, metabolism and/or lipoprotein mechanisms, while 11/26 were classified as having a role in vascular integrity, and 3/26 were classified as having a role in thrombosis. Discussion This study provides further evidence of the relationship between estrogen, genetic risk and the development of CAD. More sex-stratified research will need to be conducted to further characterize estrogen's relation to sex differences in the pathology and progression of CAD.
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Affiliation(s)
- Ava P. Aminbakhsh
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Emilie T. Théberge
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Elizabeth Burden
- Division of Internal Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Vancouver Coastal Health, Vancouver, BC, Canada
| | - Cindy Kalenga Adejumo
- Division of Internal Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Vancouver Coastal Health, Vancouver, BC, Canada
| | - Annabel K. Gravely
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Anna Lehman
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- Vancouver Coastal Health, Vancouver, BC, Canada
| | - Tara L. Sedlak
- Vancouver Coastal Health, Vancouver, BC, Canada
- Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
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Liu H, Zhang Y, Zhao Y, Li Y, Zhang X, Bao L, Yan R, Yang Y, Zhou H, Zhang J, Song S. Research Progress and Clinical Translation Potential of Coronary Atherosclerosis Diagnostic Markers from a Genomic Perspective. Genes (Basel) 2025; 16:98. [PMID: 39858645 PMCID: PMC11764800 DOI: 10.3390/genes16010098] [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: 12/05/2024] [Revised: 12/31/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Objective: Coronary atherosclerosis (CAD) is characterized by arterial intima lipid deposition, chronic inflammation, and fibrous tissue proliferation, leading to arterial wall thickening and lumen narrowing. As the primary cause of coronary heart disease and acute coronary syndrome, CAD significantly impacts global health. Recent genetic studies have demonstrated CAD's polygenic and multifactorial nature, providing molecular insights for early diagnosis and risk assessment. This review analyzes recent advances in CAD-related genetic markers and evaluates their diagnostic potential, focusing on their applications in diagnosis and risk stratification within precision medicine. Methods: We conducted a systematic review of CAD genomic studies from PubMed and Web of Science databases, analyzing findings from genome-wide association studies (GWASs), gene sequencing, transcriptomics, and epigenomics research. Results: GWASs and sequencing studies have identified key genetic variations associated with CAD, including JCAD/KIAA1462, GUCY1A3, PCSK9, and SORT1, which regulate inflammation, lipid metabolism, and vascular function. Transcriptomic and epigenomic analyses have revealed disease-specific gene expression patterns, DNA methylation signatures, and regulatory non-coding RNAs (miRNAs and lncRNAs), providing new approaches for early detection. Conclusions: While genetic marker research in CAD has advanced significantly, clinical implementation faces challenges including marker dynamics, a lack of standardization, and integration with conventional diagnostics. Future research should prioritize developing standardized guidelines, conducting large-scale prospective studies, and enhancing multi-omics data integration to advance genomic diagnostics in CAD, ultimately improving patient outcomes through precision medicine.
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Affiliation(s)
- Hanxiang Liu
- School of Medical Imaging, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou 221004, China
| | - Yuchen Zhang
- School of Medical Imaging, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou 221004, China
| | - Yueyan Zhao
- Medical and Information College, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou 221004, China
| | - Yuzhen Li
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Xiaofeng Zhang
- Greenwich Hospital, Yale New Haven Health, Greenwich, CT 06519, USA
| | - Lingyu Bao
- Department of Internal Medicine, Montefiore Medical Center Wakefield Campus, 600 East 233rd Street, Bronx, NY 10466, USA (H.Z.)
| | - Rongkai Yan
- Department of Radiology, Ohio State University, Columbus, OH 43210, USA
| | - Yixin Yang
- Department of Clinical Medicine, The First Clinical Medical College, Norman Bethune University of Medical Sciences, Jilin 130021, China
| | - Huixian Zhou
- Department of Internal Medicine, Montefiore Medical Center Wakefield Campus, 600 East 233rd Street, Bronx, NY 10466, USA (H.Z.)
| | - Jinming Zhang
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
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Shine BK, Choi JE, Park YJ, Hong KW. The Genetic Variants Influencing Hypertension Prevalence Based on the Risk of Insulin Resistance as Assessed Using the Metabolic Score for Insulin Resistance (METS-IR). Int J Mol Sci 2024; 25:12690. [PMID: 39684400 DOI: 10.3390/ijms252312690] [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: 10/21/2024] [Revised: 11/24/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024] Open
Abstract
Insulin resistance is a major indicator of cardiovascular diseases, including hypertension. The Metabolic Score for Insulin Resistance (METS-IR) offers a simplified and cost-effective way to evaluate insulin resistance. This study aimed to identify genetic variants associated with the prevalence of hypertension stratified by METS-IR score levels. Data from the Korean Genome and Epidemiology Study (KoGES) were analyzed. The METS-IR was calculated using the following formula: ln [(2 × fasting blood glucose (FBG) + triglycerides (TG)) × body mass index (BMI)]/ ln [high-density lipoprotein cholesterol (HDL-C)]. The participants were divided into tertiles 1 (T1) and 3 (T3) based on their METS-IR scores. Genome-wide association studies (GWAS) were performed for hypertensive cases and non-hypertensive controls within these tertile groups using logistic regression adjusted for age, sex, and lifestyle factors. Among the METS-IR tertile groups, 3517 of the 19,774 participants (17.8%) at T1 had hypertension, whereas 8653 of the 20,374 participants (42.5%) at T3 had hypertension. A total of 113 single-nucleotide polymorphisms (SNPs) reached the GWAS significance threshold (p < 5 × 10-8) in at least one tertile group, mapping to six distinct genetic loci. Notably, four loci, rs11899121 (chr2p24), rs7556898 (chr2q24.3), rs17249754 (ATP2B1), and rs1980854 (chr20p12.2), were significantly associated with hypertension in the high-METS-score group (T3). rs10857147 (FGF5) was significant in both the T1 and T3 groups, whereas rs671 (ALDH2) was significant only in the T1 group. The GWASs identified six genetic loci significantly associated with hypertension, with distinct patterns across METS-IR tertiles, highlighting the role of metabolic context in genetic susceptibility. These findings underscore critical genetic factors influencing hypertension prevalence and provide insights into the metabolic-genetic interplay underlying this condition.
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Affiliation(s)
- Bo-Kyung Shine
- Department of Family Medicine, Medical Center, Dong-A University, Busan 49201, Republic of Korea
| | - Ja-Eun Choi
- Institute of Advanced Technology, Theragen Health Co., Ltd., Seongnam 13493, Republic of Korea
| | - Young-Jin Park
- Department of Family Medicine, Medical Center, Dong-A University, Busan 49201, Republic of Korea
| | - Kyung-Won Hong
- Institute of Advanced Technology, Theragen Health Co., Ltd., Seongnam 13493, Republic of Korea
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Florido MHC, Ziats NP. Endothelial dysfunction and cardiovascular diseases: The role of human induced pluripotent stem cells and tissue engineering. J Biomed Mater Res A 2024; 112:1286-1304. [PMID: 38230548 DOI: 10.1002/jbm.a.37669] [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: 08/28/2023] [Revised: 12/07/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024]
Abstract
Cardiovascular disease (CVD) remains to be the leading cause of death globally today and therefore the need for the development of novel therapies has become increasingly important in the cardiovascular field. The mechanism(s) behind the pathophysiology of CVD have been laboriously investigated in both stem cell and bioengineering laboratories. Scientific breakthroughs have paved the way to better mimic cell types of interest in recent years, with the ability to generate any cell type from reprogrammed human pluripotent stem cells. Mimicking the native extracellular matrix using both organic and inorganic biomaterials has allowed full organs to be recapitulated in vitro. In this paper, we will review techniques from both stem cell biology and bioengineering which have been fruitfully combined and have fueled advances in the cardiovascular disease field. We will provide a brief introduction to CVD, reviewing some of the recent studies as related to the role of endothelial cells and endothelial cell dysfunction. Recent advances and the techniques widely used in both bioengineering and stem cell biology will be discussed, providing a broad overview of the collaboration between these two fields and their overall impact on tissue engineering in the cardiovascular devices and implications for treatment of cardiovascular disease.
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Affiliation(s)
- Mary H C Florido
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
- Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA
| | - Nicholas P Ziats
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
- Departments of Biomedical Engineering and Anatomy, Case Western Reserve University, Cleveland, Ohio, USA
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Malinowski D, Safranow K, Pawlik A. LPL rs264, PROCR rs867186 and PDGF rs974819 Gene Polymorphisms in Patients with Unstable Angina. J Pers Med 2024; 14:213. [PMID: 38392646 PMCID: PMC10890678 DOI: 10.3390/jpm14020213] [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: 01/23/2024] [Revised: 02/11/2024] [Accepted: 02/14/2024] [Indexed: 02/24/2024] Open
Abstract
BACKGROUND Coronary artery disease is caused by changes in the coronary arteries due to the atherosclerotic process and thrombotic changes. A very important role in the development of the atherosclerotic process in the coronary vessels is played by the inflammatory process and the immune response. Due to the important role of lipids and the coagulation process in the atherosclerotic process, research has also focused on genes affecting lipid metabolism and the coagulation system. Lipoprotein lipase (LPL) is an enzyme that metabolises lipids, hydrolysing triglycerides to produce free fatty acids and glycerol. Protein C (PC) is an essential component of coagulation and fibrinolysis. It is activated on the endothelial surface by the membrane-bound thrombin-thrombomodulin complex. Platelet-derived growth factor (PDGF) has a number of important functions in processes related to fibroblast and smooth muscle cell function. Due to their influence on lipid metabolism and coagulation processes, LPL, PROCR (endothelial cell protein C receptor) and PDGF may affect the atherosclerotic process and, thus, the risk of coronary heart disease. The aim of the study was to examine the associations between the LPL rs264, PROCR rs867186 and PDGF rs974819 gene polymorphisms and the risk of unstable angina and selected clinical parameters. METHODS The study included 232 patients with unstable angina and 144 healthy subjects as the control group. Genotyping was performed using real-time PCR. RESULTS There were no statistically significant differences in the distribution of the polymorphisms tested between the patients with unstable angina and the control subjects. The results showed associations between the PROCR rs867186 and PDGF rs974819 polymorphisms and some clinical parameters in patients with unstable angina. In patients with the PDGF rs974819 CC genotype, there were increased values for cholesterol and LDL serum levels in comparison with patients with the PDGF rs974819 CT and TT genotypes. In patients with the PROCR rs867186 AA genotype, HDL serum levels were lower than in patients with the GA genotype. CONCLUSIONS The results of our study did not show that the LPL rs264, PROCR rs867186 and PDGF rs974819 gene polymorphisms were significant risk factors for unstable angina in our population. The results of the study suggest that PDGF rs974819 and PROCR rs867186 may be associated with some parameters of lipid metabolism.
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Affiliation(s)
- Damian Malinowski
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
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Silva S, Nitsch D, Fatumo S. Genome-wide association studies on coronary artery disease: A systematic review and implications for populations of different ancestries. PLoS One 2023; 18:e0294341. [PMID: 38019802 PMCID: PMC10686512 DOI: 10.1371/journal.pone.0294341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 10/28/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Cardiovascular diseases are some of the leading causes of death worldwide, with coronary artery disease leading as one of the primary causes of mortality in both the developing and developed worlds. Despite its prevalence, there is a disproportionately small number of studies conducted in populations of non-European ancestry, with the limited sample sizes of such studies further restricting the power and generalizability of respective findings. This research aimed at understanding the differences in the genetic architecture of coronary artery disease (CAD) in populations of diverse ancestries in order to contribute towards the understanding of the pathophysiology of coronary artery disease. METHODS We performed a systematic review on the 6th of October, 2022 summarizing genome-wide association studies on coronary artery disease, while employing the GWAS Catalog as an independent database to support the search. We developed a framework to assess the methodological quality of each study. We extracted and grouped associated single nucleotide polymorphisms and genes according to ancestry groups of participants. RESULTS We identified 3100 studies, of which, 36 relevant studies were included in this research. Three of the studies that were included were not listed in the GWAS Catalog, highlighting the value of conducting an independent search alongside established databases in order to ensure the full research landscape has been captured. 743,919 CAD case participants from 25 different countries were analysed, with 61% of the studies identified in this research conducted in populations of European ancestry. No studies investigated populations of Africans living in continental Africa or admixed American ancestry groups besides African-Americans, while limited sample sizes were included of population groups besides Europeans and East Asians. This observed disproportionate population representation highlights the gaps in the literature, which limits our ability to understand coronary artery disease as a global disease. 71 genetic loci were identified to be associated with coronary artery disease in more than one article, with ancestry-specific genetic loci identified in each respective population group which were not detected in studies of other ancestries. CONCLUSIONS Although the replication and validation of these variants are still warranted, these finding are indicative of the value of including diverse ancestry populations in GWAS reference panels, as a more comprehensive understanding of the genetic architecture and pathophysiology of CAD can be achieved.
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Affiliation(s)
- Sarah Silva
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
- The African Computational Genomics (TACG) Research Group, MRC/UVRI, and LSHTM, Entebbe, Uganda
| | - Dorothea Nitsch
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Segun Fatumo
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
- The African Computational Genomics (TACG) Research Group, MRC/UVRI, and LSHTM, Entebbe, Uganda
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Houshmand G, Alemzadeh-Ansari MJ, Mazloumzadeh S, Naderi N, Pourirahim M, Heshmatzad K, Maleki M, Kalayinia S. Polymorphism of rs599839 in the PSRC1 gene is associated with coronary artery disease in an Iranian population. J Cardiovasc Thorac Res 2023; 15:168-173. [PMID: 38028723 PMCID: PMC10590467 DOI: 10.34172/jcvtr.2023.31742] [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: 02/13/2023] [Accepted: 07/29/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Coronary artery disease (CAD) is the leading health complication worldwide because of its high prevalence and mortality. The association between CAD susceptibility and the rs599839 (C/T) polymorphism in the human proline and serine-rich coiled-coil (PSRC1) was reported in a genome-wide association study. To validate this association, we performed this case-control study to genotype the 1p13.3 (rs599839) locus in a sample of the Iranian population with CAD (stenosis≥70% in≥1 coronary artery). Methods We performed an association analysis with PCR and Sanger sequencing of rs599839 (C/T) polymorphism and CAD risk in 280 CAD patients and 287 healthy controls defined as a coronary calcium score of zero and no noncalcified plaques in coronary computed tomography angiography. SPSS, version 16.0, was applied for statistical analysis. Results The rs599839 (C/T) locus showed a significant association with CAD (P value<0.001). TT and CT genotypes were associated with CAD (P value<0.001). Furthermore, the dominant status (TT+CT vs. CC) was associated with an increased risk of CAD (OR, 9.14; 95% CI, 3.77 to 22.15; and P value<0.001). Conclusion The study findings indicate strong evidence for rs599839 (C/T) association with CAD risk.
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Affiliation(s)
- Golnaz Houshmand
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Alemzadeh-Ansari
- Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Saeideh Mazloumzadeh
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Niloofar Naderi
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Pourirahim
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Katayoun Heshmatzad
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Maleki
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Kalayinia
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
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Lu Z, Zhang H, Yang Y, Zhao H. Sex differences of the shared genetic landscapes between type 2 diabetes and peripheral artery disease in East Asians and Europeans. Hum Genet 2023:10.1007/s00439-023-02573-x. [PMID: 37341850 DOI: 10.1007/s00439-023-02573-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/12/2023] [Indexed: 06/22/2023]
Abstract
Type 2 diabetes (T2D) is a critical risk factor for peripheral artery disease (PAD). However, the sex differences in genetic basis, causality, and underlying mechanisms of the two diseases are still unclear. Using sex-stratified and ethnic-based GWAS summary, we explored the genetic correlation and causal relationship between T2D and PAD in both ethnicities and sexes by linkage disequilibrium score regression, LAVA and six Mendelian Randomization approaches. We observed stronger genetic correlations between T2D and PAD in females than males in East Asians and Europeans. East Asian females exhibit higher causal effects of T2D on PAD than males. The gene-level analysis found KCNJ11 and ANK1 genes associated with the cross-trait of T2D and PAD in both sexes. Our study provides genetic evidence for the sex difference of genetic correlations and causal relationships between PAD and T2D, indicating the importance of using sex-specific strategies for monitoring PAD in T2D patients.
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Affiliation(s)
- Zhiya Lu
- Department of Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China
| | - Haoyang Zhang
- School of Data and Computer Science, Sun Yat-sen University, Guangzhou, China
| | - Yuanhao Yang
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Huiying Zhao
- Department of Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China.
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Islam T, Rezanur Rahman M, Khan A, Ali Moni M. Integration of Mendelian randomisation and systems biology models to identify novel blood-based biomarkers for stroke. J Biomed Inform 2023; 141:104345. [PMID: 36958462 DOI: 10.1016/j.jbi.2023.104345] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 02/04/2023] [Accepted: 03/16/2023] [Indexed: 03/25/2023]
Abstract
Stroke is the second largest cause of mortality in the world. Genome-wide association studies (GWAS) have identified some genetic variants associated with stroke risk, but their putative functional causal genes are unknown. Hence, we aimed to identify putative functional causal gene biomarkers of stroke risk. We used a summary-based Mendelian randomisation (SMR) approach to identify the pleiotropic associations of genetically regulated traits (i.e., gene expression and DNA methylation) with stroke risk. Using SMR approach, we integrated cis-expression quantitative loci (cis-eQTLs) and cis-methylation quantitative loci (cis-mQTLs) data with GWAS summary statistics of stroke. We also utilised heterogeneity in dependent instruments (HEIDI) test to distinguish pleiotropy from linkage from the observed associations identified through SMR analysis. Our integrative SMR analyses and HEIDI test revealed 45 candidate biomarker genes (FDR < 0.05; PHEIDI>0.01) that were pleiotropically or potentially causally associated with stroke risk. Of those candidate biomarker genes, 10 genes (HTRA1, PMF1, FBN2, C9orf84, COL4A1, BAG4, NEK6, SH2B3, SH3PXD2A, ACAD10) were differentially expressed in genome-wide blood transcriptomics data from stroke and healthy individuals (FDR<0.05). Functional enrichment analysis of the identified candidate biomarker genes revealed gene ontologies and pathways involved in stroke, including "cell aging", "metal ion binding" and "oxidative damage". Based on the evidence of genetically regulated expression of genes through SMR and directly measured expression of genes in blood, our integrative analysis suggests ten genes as blood biomarkers of stroke risk. Furthermore, our study provides a better understanding of the influence of DNA methylation on the expression of genes linked to stroke risk.
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Affiliation(s)
- Tania Islam
- School of Health and Rehabilitation Sciences, Faculty of Health, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Md Rezanur Rahman
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Asaduzzaman Khan
- School of Health and Rehabilitation Sciences, Faculty of Health, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Mohammad Ali Moni
- School of Health and Rehabilitation Sciences, Faculty of Health, The University of Queensland, Brisbane, QLD 4072, Australia.
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Kwak J, Shin D. Gene-Nutrient Interactions in Obesity: COBLL1 Genetic Variants Interact with Dietary Fat Intake to Modulate the Incidence of Obesity. Int J Mol Sci 2023; 24:ijms24043758. [PMID: 36835164 PMCID: PMC9959357 DOI: 10.3390/ijms24043758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/26/2023] [Accepted: 02/02/2023] [Indexed: 02/16/2023] Open
Abstract
The COBLL1 gene is associated with leptin, a hormone important for appetite and weight maintenance. Dietary fat is a significant factor in obesity. This study aimed to determine the association between COBLL1 gene, dietary fat, and incidence of obesity. Data from the Korean Genome and Epidemiology Study were used, and 3055 Korean adults aged ≥ 40 years were included. Obesity was defined as a body mass index ≥ 25 kg/m2. Patients with obesity at baseline were excluded. The effects of the COBLL1 rs6717858 genotypes and dietary fat on incidence of obesity were evaluated using multivariable Cox proportional hazard models. During an average follow-up period of 9.2 years, 627 obesity cases were documented. In men, the hazard ratio (HR) for obesity was higher in CT, CC carriers (minor allele carriers) in the highest tertile of dietary fat intake than for men with TT carriers in the lowest tertile of dietary fat intake (Model 1: HR: 1.66, 95% confidence interval [CI]: 1.07-2.58; Model 2: HR: 1.63, 95% CI: 1.04-2.56). In women, the HR for obesity was higher in TT carriers in the highest tertile of dietary fat intake than for women with TT carriers in the lowest tertile of dietary fat intake (Model 1: HR: 1.49, 95% CI: 1.08-2.06; Model 2: HR: 1.53, 95% CI: 1.10-2.13). COBLL1 genetic variants and dietary fat intake had different sex-dependent effects in obesity. These results imply that a low-fat diet may protect against the effects of COBLL1 genetic variants on future obesity risk.
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Zare Mehrjardi E, Dehghan Tezerjani M, Shemshad Ghad F, Seifati SM. Evaluation of miR-146a (rs2910164) polymorphism in coronary artery disease: Case-control and silico analysis. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Zarkasi KA, Abdullah N, Abdul Murad NA, Ahmad N, Jamal R. Genetic Factors for Coronary Heart Disease and Their Mechanisms: A Meta-Analysis and Comprehensive Review of Common Variants from Genome-Wide Association Studies. Diagnostics (Basel) 2022; 12:2561. [PMID: 36292250 PMCID: PMC9601486 DOI: 10.3390/diagnostics12102561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 11/17/2022] Open
Abstract
Genome-wide association studies (GWAS) have discovered 163 loci related to coronary heart disease (CHD). Most GWAS have emphasized pathways related to single-nucleotide polymorphisms (SNPs) that reached genome-wide significance in their reports, while identification of CHD pathways based on the combination of all published GWAS involving various ethnicities has yet to be performed. We conducted a systematic search for articles with comprehensive GWAS data in the GWAS Catalog and PubMed, followed by a meta-analysis of the top recurring SNPs from ≥2 different articles using random or fixed-effect models according to Cochran Q and I2 statistics, and pathway enrichment analysis. Meta-analyses showed significance for 265 of 309 recurring SNPs. Enrichment analysis returned 107 significant pathways, including lipoprotein and lipid metabolisms (rs7412, rs6511720, rs11591147, rs1412444, rs11172113, rs11057830, rs4299376), atherogenesis (rs7500448, rs6504218, rs3918226, rs7623687), shared cardiovascular pathways (rs72689147, rs1800449, rs7568458), diabetes-related pathways (rs200787930, rs12146487, rs6129767), hepatitis C virus infection/hepatocellular carcinoma (rs73045269/rs8108632, rs56062135, rs188378669, rs4845625, rs11838776), and miR-29b-3p pathways (rs116843064, rs11617955, rs146092501, rs11838776, rs73045269/rs8108632). In this meta-analysis, the identification of various genetic factors and their associated pathways associated with CHD denotes the complexity of the disease. This provides an opportunity for the future development of novel CHD genetic risk scores relevant to personalized and precision medicine.
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Affiliation(s)
- Khairul Anwar Zarkasi
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
- Biochemistry Unit, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (UPNM), Kuala Lumpur 57000, Malaysia
| | - Noraidatulakma Abdullah
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
- Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 50300, Malaysia
| | - Nor Azian Abdul Murad
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
| | - Norfazilah Ahmad
- Epidemiology and Statistics Unit, Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
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Tabaei S, Omraninava M, Mehranfar S, Motallebnezhad M, Tabaee SS. Plasminogen Activator Inhibitor-1 Polymorphisms and Risk of Coronary Artery Disease: Evidence From Meta-Analysis and Trial Sequential Analysis. Biochem Genet 2022; 60:1409-1445. [PMID: 35039979 DOI: 10.1007/s10528-021-10143-x] [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: 05/07/2021] [Accepted: 10/13/2021] [Indexed: 11/29/2022]
Abstract
A systematic review and meta-analysis were conducted to find out if there was association between Plasminogen Activator Inhibitor-1 (PAI-1) gene polymorphisms (- 844 G > A and - 675 4G > 5G) and susceptibility to coronary artery disease (CAD). Search of electronic databases was performed and the pooled odds ratio (OR) and 95% confidence interval (CI) were exerted to evaluate the pooled association between the single-nucleotide polymorphisms (SNPs) and risk of CAD. For - 675 4G > 5G SNP, dominant (OR = 0.90), recessive (OR = 0.90), allelic (OR = 0.91), homozygous (OR = 0.84), and heterozygous (OR = 0.96) models were significantly associated with decreased risk of CAD. Moreover, all five genetic models were associated significantly with decreased CAD risk in the Causation and Arab populations. The results in Asians were marginally significant in recessive, allelic, and homozygote models. The male gender was found to be a risk factor in individuals with PAI-1 4G > 5G SNP in the dominant model (OR = 0.89), recessive model (OR = 0.91), allelic model (OR = 0.92), homozygous model (OR = 0.86), and heterozygous model (OR = 0.91). The results of pooled ORs for overall populations and subgroup analysis by ethnicity reject any association between PAI-1 gene - 844 G > A polymorphism and CAD risk under all genetic comparisons. The results of this meta-analysis indicated that PAI-1 4G > 5G SNP was associated with decreased risk of CAD in the overall population as well as in the Asians, Caucasians, and Arab populations. However, the PAI-1 gene - 844 G > A polymorphism had no significant association with susceptibility to CAD.
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Affiliation(s)
- Samira Tabaei
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Melodi Omraninava
- Department of Infectious Disease, Faculty of Medical Sciences, Sari Branch, Islamic Azad University, Sari, Iran
| | - Sahar Mehranfar
- Department of Genetics and Immunology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Social Determinant of Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Morteza Motallebnezhad
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyedeh Samaneh Tabaee
- Noncommunicable Disease Research Center, Neyshabur University of Medical Sciences, Imam Khomeini Street, 9319116911, Neyshabur, Iran.
- Faculty of Medicine, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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14
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Wei B, Liu Y, Li H, Peng Y, Luo Z. Effect of 9p21.3 (lncRNA and CDKN2A/2B) variant on lipid profile. Front Cardiovasc Med 2022; 9:946289. [PMID: 36158791 PMCID: PMC9489913 DOI: 10.3389/fcvm.2022.946289] [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: 05/17/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
Background Several 9p21.3 variants, such as rs1333049, rs4977574, rs10757274, rs10757278, and rs10811661, identified from recent genome-wide association studies (GWASs) are reported to be associated with coronary artery disease (CAD) susceptibility but independent of dyslipidemia. This study investigated whether these 9p21.3 variants influenced lipid profiles. Methods and results By searching the PubMed and Cochrane databases, 101,099 individuals were included in the analysis. The consistent finding for the rs1333049 C allele on lipid profiles increased the triglyceride (TG) levels. Moreover, the rs4977574 G allele and the rs10757274 G allele, respectively, increased low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels. However, the rs10811661 C allele largely reduced LDL-C levels. Subgroup analyses indicated that the effects of the rs1333049 C allele, rs4977574 G allele, and rs10757274 G allele on lipid profiles were stronger in Whites compared with Asians. In contrast, the effect of the rs10811661 C allele on lipid profiles was stronger in Asians compared with Whites. Conclusion The rs1333049 C allele, rs4977574 G allele, and rs10757274 G allele of lncRNA, and the rs10811661 G allele of CDKN2A/2B had a significant influence on lipid levels, which may help the understanding of the underlying mechanisms between 9p21.3 variants and CAD.
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Affiliation(s)
- Baozhu Wei
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, China
- *Correspondence: Baozhu Wei,
| | - Yang Liu
- Department of Endocrinology, China Resources and WISCO General Hospital, Wuhan, China
| | - Hang Li
- Department of Gerontology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yuanyuan Peng
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Zhi Luo
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Zhi Luo,
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15
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Xiu X, Zhang H, Xue A, Cooper DN, Yan L, Yang Y, Yang Y, Zhao H. Genetic evidence for a causal relationship between type 2 diabetes and peripheral artery disease in both Europeans and East Asians. BMC Med 2022; 20:300. [PMID: 36042491 PMCID: PMC9429730 DOI: 10.1186/s12916-022-02476-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 07/12/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Observational studies have revealed that type 2 diabetes (T2D) is associated with an increased risk of peripheral artery disease (PAD). However, whether the two diseases share a genetic basis and whether the relationship is causal remain unclear. It is also unclear as to whether these relationships differ between ethnic groups. METHODS By leveraging large-scale genome-wide association study (GWAS) summary statistics of T2D (European-based: Ncase = 21,926, Ncontrol = 342,747; East Asian-based: Ncase = 36,614, Ncontrol = 155,150) and PAD (European-based: Ncase = 5673, Ncontrol = 359,551; East Asian-based: Ncase = 3593, Ncontrol = 208,860), we explored the genetic correlation and putative causal relationship between T2D and PAD in both Europeans and East Asians using linkage disequilibrium score regression and seven Mendelian randomization (MR) models. We also performed multi-trait analysis of GWAS and two gene-based analyses to reveal candidate variants and risk genes involved in the shared genetic basis between T2D and PAD. RESULTS We observed a strong genetic correlation (rg) between T2D and PAD in both Europeans (rg = 0.51; p-value = 9.34 × 10-15) and East Asians (rg = 0.46; p-value = 1.67 × 10-12). The MR analyses provided consistent evidence for a causal effect of T2D on PAD in both ethnicities (odds ratio [OR] = 1.05 to 1.28 for Europeans and 1.15 to 1.27 for East Asians) but not PAD on T2D. This putative causal effect was not influenced by total cholesterol, body mass index, systolic blood pressure, or smoking initiation according to multivariable MR analysis, and the genetic overlap between T2D and PAD was further explored employing an independent European sample through polygenic risk score regression. Multi-trait analysis of GWAS revealed two novel European-specific single nucleotide polymorphisms (rs927742 and rs1734409) associated with the shared genetic basis of T2D and PAD. Gene-based analyses consistently identified one gene ANKFY1 and gene-gene interactions (e.g., STARD10 [European-specific] to AP3S2 [East Asian-specific]; KCNJ11 [European-specific] to KCNQ1 [East Asian-specific]) associated with the trans-ethnic genetic overlap between T2D and PAD, reflecting a common genetic basis for the co-occurrence of T2D and PAD in both Europeans and East Asians. CONCLUSIONS Our study provides the first evidence for a genetically causal effect of T2D on PAD in both Europeans and East Asians. Several candidate variants and risk genes were identified as being associated with this genetic overlap. Our findings emphasize the importance of monitoring PAD status in T2D patients and suggest new genetic biomarkers for screening PAD risk among patients with T2D.
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Affiliation(s)
- Xuehao Xiu
- Department of Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China
| | - Haoyang Zhang
- Department of Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China.,School of Data and Computer Science, Sun Yat-sen University, Guangzhou, 510000, China
| | - Angli Xue
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.,Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - David N Cooper
- Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Li Yan
- Department of Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China
| | - Yuedong Yang
- School of Data and Computer Science, Sun Yat-sen University, Guangzhou, 510000, China.
| | - Yuanhao Yang
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. .,Mater Research Institute, Translational Research Institute, Brisbane, QLD, Australia.
| | - Huiying Zhao
- Department of Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China.
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16
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Mitok KA, Keller MP, Attie AD. Sorting through the extensive and confusing roles of sortilin in metabolic disease. J Lipid Res 2022; 63:100243. [PMID: 35724703 PMCID: PMC9356209 DOI: 10.1016/j.jlr.2022.100243] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 01/06/2023] Open
Abstract
Sortilin is a post-Golgi trafficking receptor homologous to the yeast vacuolar protein sorting receptor 10 (VPS10). The VPS10 motif on sortilin is a 10-bladed β-propeller structure capable of binding more than 50 proteins, covering a wide range of biological functions including lipid and lipoprotein metabolism, neuronal growth and death, inflammation, and lysosomal degradation. Sortilin has a complex cellular trafficking itinerary, where it functions as a receptor in the trans-Golgi network, endosomes, secretory vesicles, multivesicular bodies, and at the cell surface. In addition, sortilin is associated with hypercholesterolemia, Alzheimer's disease, prion diseases, Parkinson's disease, and inflammation syndromes. The 1p13.3 locus containing SORT1, the gene encoding sortilin, carries the strongest association with LDL-C of all loci in human genome-wide association studies. However, the mechanism by which sortilin influences LDL-C is unclear. Here, we review the role sortilin plays in cardiovascular and metabolic diseases and describe in detail the large and often contradictory literature on the role of sortilin in the regulation of LDL-C levels.
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Affiliation(s)
- Kelly A Mitok
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Mark P Keller
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Alan D Attie
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
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17
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Leptidis S, Papakonstantinou E, Diakou KI, Pierouli K, Mitsis T, Dragoumani K, Bacopoulou F, Sanoudou D, Chrousos GP, Vlachakis D. Epitranscriptomics of cardiovascular diseases (Review). Int J Mol Med 2022; 49:9. [PMID: 34791505 PMCID: PMC8651226 DOI: 10.3892/ijmm.2021.5064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/20/2021] [Indexed: 11/09/2022] Open
Abstract
RNA modifications have recently become the focus of attention due to their extensive regulatory effects in a vast array of cellular networks and signaling pathways. Just as epigenetics is responsible for the imprinting of environmental conditions on a genetic level, epitranscriptomics follows the same principle at the RNA level, but in a more dynamic and sensitive manner. Nevertheless, its impact in the field of cardiovascular disease (CVD) remains largely unexplored. CVD and its associated pathologies remain the leading cause of death in Western populations due to the limited regenerative capacity of the heart. As such, maintenance of cardiac homeostasis is paramount for its physiological function and its capacity to respond to environmental stimuli. In this context, epitranscriptomic modifications offer a novel and promising therapeutic avenue, based on the fine‑tuning of regulatory cascades, necessary for cardiac function. This review aimed to provide an overview of the most recent findings of key epitranscriptomic modifications in both coding and non‑coding RNAs. Additionally, the methods used for their detection and important associations with genetic variations in the context of CVD were summarized. Current knowledge on cardiac epitranscriptomics, albeit limited still, indicates that the impact of epitranscriptomic editing in the heart, in both physiological and pathological conditions, holds untapped potential for the development of novel targeted therapeutic approaches in a dynamic manner.
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Affiliation(s)
- Stefanos Leptidis
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - Eleni Papakonstantinou
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - Kalliopi Io Diakou
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - Katerina Pierouli
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - Thanasis Mitsis
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - Konstantina Dragoumani
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - Flora Bacopoulou
- Laboratory of Molecular Endocrinology, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
- First Department of Pediatrics, Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, Medical School, Aghia Sophia Children's Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Despina Sanoudou
- Fourth Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, Medical School, 'Attikon' Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
- Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - George P. Chrousos
- Laboratory of Molecular Endocrinology, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
- First Department of Pediatrics, Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, Medical School, Aghia Sophia Children's Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Vlachakis
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
- Laboratory of Molecular Endocrinology, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
- First Department of Pediatrics, Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care, Medical School, Aghia Sophia Children's Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
- School of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London WC2R 2LS, UK
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18
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Li YY, Wang H, Zhang YY. CDKN2B-AS1 gene rs4977574 A/G polymorphism and coronary heart disease: A meta-analysis of 40,979 subjects. J Cell Mol Med 2021; 25:8877-8889. [PMID: 34418317 PMCID: PMC8435436 DOI: 10.1111/jcmm.16849] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 06/05/2021] [Accepted: 07/31/2021] [Indexed: 12/23/2022] Open
Abstract
It has been implied that there is a possible relationship between cyclin‐dependent protein kinase inhibitors antisense RNA 1 (CDKN2B‐AS1) gene rs4977574 A/G polymorphism and coronary heart disease (CHD) susceptibility. However, as the research results are discrepant, no distinct consensus on this issue has been reached so far. In order to further elaborate the latent association of the CDKN2B‐AS1 gene rs4977574 A/G polymorphism and CHD, this present meta‐analysis was conducted. There were 40,979 subjects of 17 individual studies in the present meta‐analysis. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated to determine the association strength. Considering the significant heterogeneity among the individual studies, the random‐effect models were used. In the current meta‐analysis, a significant association between CDKN2B‐AS1 gene rs4977574 A/G polymorphism and CHD was found under allelic (OR: 1.18, 95% CI: 1.08–1.29, p = 4.83×10−4), recessive (OR: 1.36, 95% CI: 1.11–1.67, p = 0.003), dominant (OR: 0.71, 95% CI: 0.58–0.86, p = 6.26×10−4), heterozygous (OR:1.210, 95% CI: 1.076–1.360, p = 0.001), homozygous (OR: 1.394, 95% CI: 1.163–1.671, p = 3.31×10−4) and additive (OR: 1.180, 95% CI: 1.075–1.295, p = 4.83×10−4) genetic models. A more significant association between them was found in the Asian population than that in the whole population under these genetic models (p < 0.05). However, no significant association between them was found in the Caucasian population (p > 0.05). CDKN2B‐AS1 gene rs4977574 A/G polymorphism was associated with CHD susceptibility, especially in the Asian population. G allele of CDKN2B‐AS1 gene rs4977574 A/G polymorphism is the risk allele for CHD.
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Affiliation(s)
- Yan-Yan Li
- Clinical Research Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Wang
- Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yang-Yang Zhang
- Department of General Practice, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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19
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Møller PL, Rohde PD, Winther S, Breining P, Nissen L, Nykjaer A, Bøttcher M, Nyegaard M, Kjolby M. Sortilin as a Biomarker for Cardiovascular Disease Revisited. Front Cardiovasc Med 2021; 8:652584. [PMID: 33937362 PMCID: PMC8085299 DOI: 10.3389/fcvm.2021.652584] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/22/2021] [Indexed: 11/13/2022] Open
Abstract
Genetic variants in the genomic region containing SORT1 (encoding the protein sortilin) are strongly associated with cholesterol levels and the risk of coronary artery disease (CAD). Circulating sortilin has therefore been proposed as a potential biomarker for cardiovascular disease. Multiple studies have reported association between plasma sortilin levels and cardiovascular outcomes. However, the findings are not consistent across studies, and most studies have small sample sizes. The aim of this study was to evaluate sortilin as a biomarker for CAD in a well-characterized cohort with symptoms suggestive of CAD. In total, we enrolled 1,173 patients with suspected stable CAD referred to coronary computed tomography angiography. Sortilin was measured in plasma using two different technologies for quantifying circulating sortilin: a custom-made enzyme-linked immunosorbent assay (ELISA) and OLINK Cardiovascular Panel II. We found a relative poor correlation between the two methods (correlation coefficient = 0.21). In addition, genotyping and whole-genome sequencing were performed on all patients. By whole-genome regression analysis of sortilin levels measured with ELISA and OLINK, two independent cis protein quantitative trait loci (pQTL) on chromosome 1p13.3 were identified, with one of them being a well-established risk locus for CAD. Incorporating rare genetic variants from whole-genome sequence data did not identify any additional pQTLs for plasma sortilin. None of the traditional CAD risk factors, such as sex, age, smoking, and statin use, were associated with plasma sortilin levels. Furthermore, there was no association between circulating sortilin levels and coronary artery calcium score (CACS) or disease severity. Sortilin did not improve discrimination of obstructive CAD, when added to a clinical pretest probability (PTP) model for CAD. Overall, our results indicate that studies using different methodologies for measuring circulating sortilin should be compared with caution. In conclusion, the well-known SORT1 risk locus for CAD is linked to lower sortilin levels in circulation, measured with ELISA; however, the effect sizes are too small for sortilin to be a useful biomarker for CAD in a clinical setting of low- to intermediate-risk chest-pain patients.
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Affiliation(s)
| | - Palle D. Rohde
- Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark
| | - Simon Winther
- Department of Cardiology, Gødstrup Hospital, NIDO, Herning, Denmark
| | - Peter Breining
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- PROMEMO and DANDRITE, Aarhus University, Aarhus, Denmark
| | - Louise Nissen
- Department of Cardiology, Gødstrup Hospital, NIDO, Herning, Denmark
| | - Anders Nykjaer
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- PROMEMO and DANDRITE, Aarhus University, Aarhus, Denmark
| | - Morten Bøttcher
- Department of Cardiology, Gødstrup Hospital, NIDO, Herning, Denmark
| | - Mette Nyegaard
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Mads Kjolby
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- PROMEMO and DANDRITE, Aarhus University, Aarhus, Denmark
- Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
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20
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Seyedian SM, Bijanzadeh M, Ahmadi F, Haghighizadeh MH. Association between Endothelial nitric oxide synthase and Hepatic lipase gene polymorphisms with the risk of coronary artery disease in Southern Iran population - A case control study. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2021; 40:423-433. [PMID: 33673789 DOI: 10.1080/15257770.2021.1892130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Coronary artery disease is a multifactorial genetic disease caused by the interaction between genetic and environmental factors. Angiography is the gold standard method for the diagnosis and determining the stage of cardiac disorder. The rs1800588 at the Hepatic Lipase gene and rs1799983 at the endothelial nitric oxide synthase (eNOS) gene are two candidate SNP that result in increased risk of this disease. The aim of this study was to find out the associations of the two mentioned polymorphisms with angiographically proven coronary artery patients in a southern Iranian population. In this study, this two polymorphisms in 287 patients and 229 matched controls were confirmed by angiography and analyzed. Genotype analysis was carried out by PCR and RFLP. Data showed that a significant difference for the eNOS gene polymorphism (p = 0.004) and a non-significant difference for the Hepatic lipase polymorphism (p = 0.261) and increasing severity of angiographic evidences of coronary artery disease were observed. Conclusively the significant association of the G894T with the narrowing of two or three coronary vessels of this patients in an Iranian population have been detected.
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Affiliation(s)
- Seyed Masoud Seyedian
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Cardiology, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahdi Bijanzadeh
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medical genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Farzaneh Ahmadi
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Cardiology, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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21
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Cheng CF, Lin YJ, Lin MC, Liang WM, Chen CC, Chen CH, Wu JY, Lin TH, Liao CC, Huang SM, Hsieh AR, Tsai FJ. Genetic risk score constructed from common genetic variants is associated with cardiovascular disease risk in type 2 diabetes mellitus. J Gene Med 2020; 23:e3305. [PMID: 33350037 DOI: 10.1002/jgm.3305] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/21/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) experience a two-fold increased risk of cardiovascular diseases. Genome-wide association studies (GWAS) have identified T2DM susceptibility genetic variants. Interestingly, the genetic variants associated with cardiovascular disease risk in T2DM Han Chinese remain to be elucidated. The present study aimed to investigate the genetic variants associated with cardiovascular disease risk in T2DM. METHODS We performed bootstrapping, GWAS and an investigation of genetic variants associated with cardiovascular disease risk in a discovery T2DM cohort and in a replication cohort. The discovery cohort included 326 cardiovascular disease patients and 1209 noncardiovascular disease patients. The replication cohort included 68 cardiovascular disease patients and 317 noncardiovascular disease patients. The main outcome measures were genetic variants for genetic risk score (GRS) in cardiovascular disease risk in T2DM. RESULTS In total, 35 genetic variants were associated with cardiovascular disease risk. A GRS was generated by combining risk alleles from these variants weighted by their estimated effect sizes (log odds ratio [OR]). T2DM patients with weighted GRS ≥ 12.63 had an approximately 15-fold increase in cardiovascular disease risk (odds ratio = 15.67, 95% confidence interval [CI] = 10.33-24.00) compared to patients with weighted GRS < 10.39. With the addition of weighted GRS, receiver-operating characteristic curves showed that area under the curve with conventional risk factors was improved from 0.719 (95% CI = 0.689-0.750) to 0.888 (95% CI = 0.866-0.910). CONCLUSIONS These 35 genetic variants are associated with cardiovascular disease risk in T2DM, alone and cumulatively. T2DM patients with higher levels of weighted genetic risk score have higher cardiovascular disease risks.
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Affiliation(s)
- Chi-Fung Cheng
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan.,Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Ying-Ju Lin
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Mei-Chen Lin
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan
| | - Wen-Miin Liang
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan
| | - Ching-Chu Chen
- Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hsiun Chen
- School of Chinese Medicine, China Medical University, Taichung, Taiwan.,Institute of Biomedical Sciences, Taipei, Taiwan
| | - Jer-Yuarn Wu
- School of Chinese Medicine, China Medical University, Taichung, Taiwan.,Institute of Biomedical Sciences, Taipei, Taiwan
| | - Ting-Hsu Lin
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Chiu-Chu Liao
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Shao-Mei Huang
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Ai-Ru Hsieh
- Department of Statistics, Tamkang University, New Taipei, Taiwan
| | - Fuu-Jen Tsai
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan.,Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan
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22
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Shou W, Zhang C, Shi J, Wu H, Huang W. Fine genetic mapping of the chromosome 11q23.3 region in a Han Chinese population: insights into the apolipoprotein genes underlying the blood lipid-lipoprotein variances. J Genet Genomics 2020; 47:756-769. [PMID: 33753020 DOI: 10.1016/j.jgg.2020.11.010] [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: 07/03/2020] [Revised: 11/09/2020] [Accepted: 11/20/2020] [Indexed: 12/01/2022]
Abstract
The unusual chromosome 11q23.3 harboring the apolipoprotein (APO) gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases. However, its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed. We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing, association analyses, genetic fine mapping, and functional interpretation. The present study identified new meaningful genetic associations that were not simply determined by statistical significance. In addition to the APOA5 gene, we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids. Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses. rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediate APOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility. Similarly, multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol. Our findings provided novel insights into this genomic locus in the Chinese population.
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Affiliation(s)
- Weihua Shou
- Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai 200025, China.
| | - Chenhui Zhang
- Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai 200025, China
| | - Jinxiu Shi
- Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai 200025, China
| | - Hong Wu
- Department of Cardiology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Wei Huang
- Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai 200025, China.
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Circulating Levels of CILP2 Are Elevated in Coronary Heart Disease and Associated with Atherosclerosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1871984. [PMID: 33204392 PMCID: PMC7652603 DOI: 10.1155/2020/1871984] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 08/23/2020] [Accepted: 10/01/2020] [Indexed: 01/18/2023]
Abstract
Methods and Results Circulating CILP2 levels (measured by ELISA) were compared to various insulin resistance- and atherosclerosis-related parameters in normal subjects and newly diagnosed CHD patients. THP-1 cells were cultured and treated with indicated stimulators. Western blots and RT-PCR were performed to examine protein and mRNA expressions. The results showed that there were significantly higher circulating CILP2 levels in CHD patients relative to healthy controls. Circulating CILP2 correlated positively with waist-hip ratio (WHR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HbA1c, homeostasis model assessment of insulin resistance (HOMA-IR), and Gensini scores. In an in vitro study, we found that CILP2 increased oxidatively modified LDL-stimulated lipid accumulation in THP-1 macrophages via the upregulation of CD36 expression. Inhibition of PPARγ signaling eliminated the CILP2 regulation of CD36 expression in THP-1 macrophages. CILP2 positively regulated CD36 transcription through PPARγ-mediated action on two peroxisome-proliferator-responsive elements (PPREs) binding sites of CD36 promoter, PPRE-G, and PPRE-J. Conclusions Our findings have uncovered a novel role for CILP2 in lipid uptake and foam cell formation. This role is mediated by CD36 through the activation of PPARγ pathway.
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24
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Qin Y, Li L, Luo E, Hou J, Yan G, Wang D, Qiao Y, Tang C. Role of m6A RNA methylation in cardiovascular disease (Review). Int J Mol Med 2020; 46:1958-1972. [PMID: 33125109 PMCID: PMC7595665 DOI: 10.3892/ijmm.2020.4746] [Citation(s) in RCA: 183] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 09/29/2020] [Indexed: 02/07/2023] Open
Abstract
N6-methyladenosine (m6A) is the most prevalent and abundant type of internal post-transcriptional RNA modification in eukaryotic cells. Multiple types of RNA, including mRNAs, rRNAs, tRNAs, long non-coding RNAs and microRNAs, are involved in m6A methylation. The biological function of m6A modification is dynamically and reversibly mediated by methyltransferases (writers), demethylases (erasers) and m6A binding proteins (readers). The methyltransferase complex is responsible for the catalyzation of m6A modification and is typically made up of methyltransferase-like (METTL)3, METTL14 and Wilms tumor 1-associated protein. Erasers remove methylation by fat mass and obesity-associated protein and ALKB homolog 5. Readers play a role through the recognition of m6A-modified targeted RNA. The YT521-B homology domain family, heterogeneous nuclear ribonucleoprotein and insulin-like growth factor 2 mRNA-binding protein serve as m6A readers. The m6A methylation on transcripts plays a pivotal role in the regulation of downstream molecular events and biological functions, such as RNA splicing, transport, stability and translatability at the post-transcriptional level. The dysregulation of m6A modification is associated with cancer, drug resistance, virus replication and the pluripotency of embryonic stem cells. Recently, a number of studies have identified aberrant m6A methylation in cardiovascular diseases (CVDs), including cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification and pulmonary hypertension. The aim of the present review article was to summarize the recent research progress on the role of m6A modification in CVD and give a brief perspective on its prospective applications in CVD.
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Affiliation(s)
- Yuhan Qin
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Linqing Li
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Erfei Luo
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Jiantong Hou
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Gaoliang Yan
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Dong Wang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Yong Qiao
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Chengchun Tang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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25
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Mo XB, Zhang H, Wang AL, Xu T, Zhang YH. Integrative analysis identifies the association between CASZ1 methylation and ischemic stroke. Neurol Genet 2020; 6:e509. [PMID: 33134510 PMCID: PMC7577558 DOI: 10.1212/nxg.0000000000000509] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/27/2020] [Indexed: 01/11/2023]
Abstract
Objective To highlight potential epigenetic risk factors for blood pressure (BP) and ischemic stroke (IS) in loci identified by genome-wide association studies (GWASs). Methods We detected DNA methylation for BP (317,756 individuals from UK Biobank) and IS (521,612 individuals from MEGASTROKE) in Europeans by using the summary data–based mendelian randomization (SMR) method. We selected the most relevant gene to validate the association in 1,207 patients with hypertensive IS and 1,269 controls from the Chinese populations. Results We first identified 173 CpG sites in 90 genes, 337 CpG sites in 142 genes, and 9 CpG sites in 7 genes that were significantly associated with systolic, diastolic BP, and IS, respectively. The methylation level of cg12760995 in CASZ1 was associated with systolic (PSMR = 1.74 × 10−12), diastolic BP (PSMR = 2.48 × 10−10), and IS (odds ratio [OR] = 0.92 [95% confidence interval [CI]: 0.91–0.94]; PSMR = 2.28 × 10−8) in Europeans. The methylation levels of 17 sites in the promoter of CASZ1 were measured in the Chinese individuals, and 10 of them were significantly associated with IS. The higher methylation level of CASZ1 was associated with a lower risk of IS (adjusted OR = 0.97 [95% CI: 0.96–0.99]). CASZ1 seemed to be hypomethylated in hypertensive cases, and the level was negatively correlated with BP. Systolic and diastolic BP mediated approximately 61.2% (p = 3.49 × 10−6) and 45.0% (p = 0.0029) of the association between CASZ1 methylation and IS, respectively. Conclusions This study identified DNA methylations that were associated with BP and IS. CASZ1 was hypomethylated in Chinese patients with hypertensive IS.
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Affiliation(s)
- Xing-Bo Mo
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (X.-B.M., H.Z., A.-L.W., T.X., Y-.H.Z.); Center for Genetic Epidemiology and Genomics (X.-B.M.); and Department of Epidemiology (X.-B.M., H.Z., A.-L.W., T.X., Y.-H.Z.), School of Public Health, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Huan Zhang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (X.-B.M., H.Z., A.-L.W., T.X., Y-.H.Z.); Center for Genetic Epidemiology and Genomics (X.-B.M.); and Department of Epidemiology (X.-B.M., H.Z., A.-L.W., T.X., Y.-H.Z.), School of Public Health, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Ai-Li Wang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (X.-B.M., H.Z., A.-L.W., T.X., Y-.H.Z.); Center for Genetic Epidemiology and Genomics (X.-B.M.); and Department of Epidemiology (X.-B.M., H.Z., A.-L.W., T.X., Y.-H.Z.), School of Public Health, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Tan Xu
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (X.-B.M., H.Z., A.-L.W., T.X., Y-.H.Z.); Center for Genetic Epidemiology and Genomics (X.-B.M.); and Department of Epidemiology (X.-B.M., H.Z., A.-L.W., T.X., Y.-H.Z.), School of Public Health, Soochow University, Suzhou, Jiangsu, P. R. China
| | - Yong-Hong Zhang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases (X.-B.M., H.Z., A.-L.W., T.X., Y-.H.Z.); Center for Genetic Epidemiology and Genomics (X.-B.M.); and Department of Epidemiology (X.-B.M., H.Z., A.-L.W., T.X., Y.-H.Z.), School of Public Health, Soochow University, Suzhou, Jiangsu, P. R. China
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26
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Cui NH, Yang JM, Liu X, Wang XB. Poly(ADP-Ribose) Polymerase Activity and Coronary Artery Disease in Type 2 Diabetes Mellitus: An Observational and Bidirectional Mendelian Randomization Study. Arterioscler Thromb Vasc Biol 2020; 40:2516-2526. [PMID: 32757651 DOI: 10.1161/atvbaha.120.314712] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Experimental evidence suggests a close link between PARP (poly[ADP-ribose] polymerase) activation and diabetic endothelial dysfunction. Here, we tested whether PARP activity in circulating leukocytes was associated with coronary artery disease (CAD) among patients with type 2 diabetes mellitus (T2DM). Approach and Results: We performed observational and bidirectional Mendelian randomization studies of 3149 Chinese individuals with T2DM who underwent coronary angiography, with leukocyte PARP activity, 16 tag single-nucleotide polymorphisms in PARP1 and PARP2, and 17 CAD risk single-nucleotide polymorphisms analyzed. Of 3149 participants, 1180 who further received percutaneous coronary intervention were prospectively followed for 1 year to track major adverse cardiovascular and cerebrovascular events. Overall, greater PARP activity was cross-sectionally associated with an odds ratio of 1.23 for obstructive CAD, and prospectively with a hazard ratio of 1.34 for 1-year major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention (both P<0.001). Using a genetic score of 5 screened single-nucleotide polymorphisms in PARP1 and PARP2 as the instrumental variable, genetically predicted elevation in PARP activity showed a causal association with obstructive CAD (odds ratio=1.35, P<0.001). In contrast, the genetic risk of CAD had no significant effect on PARP activity. Ex vivo and in vitro cultures of human monocytes showed that rs747657, as the lead single-nucleotide polymorphism strongly associated with PARP activity, caused the differential binding of transcription factor GATA2 (GATA-binding protein 2) to an intronic regulatory region in PARP1, thus modulating PARP1 expression and PARP activity. CONCLUSIONS Greater PARP activity may have causal roles in the development of obstructive CAD among patients with diabetes mellitus.
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Affiliation(s)
- Ning-Hua Cui
- Zhengzhou Key Laboratory of Children's Infection and Immunity, Children's Hospital Affiliated to Zhengzhou University, Henan, China (N.-h.C., J.-m.Y.)
| | - Jun-Mei Yang
- Zhengzhou Key Laboratory of Children's Infection and Immunity, Children's Hospital Affiliated to Zhengzhou University, Henan, China (N.-h.C., J.-m.Y.)
| | - Xia'nan Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Henan, China (X.L., X.-b.W.)
| | - Xue-Bin Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Henan, China (X.L., X.-b.W.)
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Huang S, Yu X, Wang H, Zheng J. Elevated serum sortilin is related to carotid plaque concomitant with calcification. Biomark Med 2020; 14:381-389. [PMID: 32077308 DOI: 10.2217/bmm-2019-0472] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Aim: To explore whether elevated serum sortilin was associated with calcified carotid plaque and ischemic stroke. Methods: A total of 171 patients with cardiovascular risk factors were enrolled. Ultrasonography was performed to evaluate calcified plaques and noncalcified plaques. Serum sortilin concentration was measured by ELISA. Results: Serum sortilin level was higher in patients with calcified carotid plaque and positively related to carotid plaque burden, but not with ischemic stroke during the follow-up. Multivariable logistic regression analysis revealed serum sortilin level was an independent determinant for calcified carotid plaque (p = 0.001). Receiving operating characteristic analysis showed an area under the curve of sortilin for carotid calcification was 0.759. Conclusion: Higher serum sortilin level was associated with carotid calcification and severe carotid plaque score.
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Affiliation(s)
- Shanshan Huang
- Department of Ultrasound, Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, Guangdong, PR China
| | - Xingxing Yu
- Department of Internal Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China
| | - Haiqing Wang
- Department of Cardiology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China
| | - Jianlei Zheng
- Department of Cardiology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China
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Wang L, Xu F, Brickell A, Sun N, Mao X, Zhang Q, Wang G, Zhou Q, Yang B, Li F, Yue L, Zhang W, Hao Y, Sun C. Additional common loci associated with stroke and obesity identified using pleiotropic analytical approach. Mol Genet Genomics 2019; 295:439-451. [PMID: 31813042 DOI: 10.1007/s00438-019-01630-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/25/2019] [Indexed: 12/11/2022]
Abstract
Stroke is a complex disease with multiple etiologies. Numerous studies suggest an established association between obesity and stroke, which may partly arise from the shared genetic components between the two phenotypes. Despite genome-wide association studies (GWASs) have identified some loci associated with stroke and obesity individually, the estimated genetic variability explained by these loci is limited (especially for stroke) and the pleiotropic loci between them are largely unknown. In this study, we jointly applied the pleiotropy-informed conditional false discovery rate (cFDR) method and the genetic analysis incorporating pleiotropy and annotation (GPA) method on summary statistics of two large GWASs to detect the genetic overlap between stroke (n = 446,696) and obesity (n = 681,275). Stratified Q-Q and fold-enrichment plots showed strong pleiotropic enrichment between the two phenotypes. With cFDR < 0.05 and fdr.GPA < 0.2, we identified 24 (16 novel) stroke-associated SNPs and 12 (10 novel) of them to be potentially pleiotropic SNPs for both phenotypes. The corresponding genes were enriched in trait-associated gene ontology (GO) terms "brain development" and "negative regulation of transport". In conclusion, our study demonstrated the feasibility and effectivity of the two pleiotropic methods which successfully improved the genetic discovery by incorporating related GWAS datasets and validated the genetic intercommunity between stroke and obesity. The identification of pleiotropic loci may provide us any new insights into potential genetic and etiology mechanism between them for the further studies.
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Affiliation(s)
- Lianke Wang
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Fei Xu
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Anna Brickell
- College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Nan Sun
- Department of Management Information Systems, Terry College of Business, University of Georgia, Athens, GA, 30602, USA
| | - Xiangjie Mao
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Qiang Zhang
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Ganyi Wang
- Center for Food and Drug Reevaluation of Henan, No. 79 Xiongerhe Road, Jinshui District, Zhengzhou, 450000, Henan, People's Republic of China
| | - Qianyu Zhou
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Bin Yang
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Fangwei Li
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Limin Yue
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Weidong Zhang
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China
| | - Yibin Hao
- People's Hospital of Zhengzhou, No. 33 Huanghe Road, Jinshui District, Zhengzhou, 450000, Henan, People's Republic of China
| | - Changqing Sun
- Department of Social Medicine and Health Management, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, High-Tech Development Zone of States, Zhengzhou, 450001, Henan, People's Republic of China.
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Lasek-Bal A, Kula D, Urbanek T, Puz P, Szymszal J, Jarzab M, Halczok M, Cyplinska R, Bal W, Łabuz-Roszak B, Cieślik A, Jasnos I, Jarzab B, Ziaja D. The Association of SNPs Located in the CDKN2B-AS1 and LPA Genes With Carotid Artery Stenosis and Atherogenic Stroke. Front Neurol 2019; 10:1170. [PMID: 31824394 PMCID: PMC6883000 DOI: 10.3389/fneur.2019.01170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 10/21/2019] [Indexed: 11/13/2022] Open
Abstract
Introduction: The aim of this project was to assess the prevalence of four selected SNPs rs4977574 and rs7857345 (CDKN2B-AS1 gene) and rs3798220 and rs10455872 polymorphisms (the LPA gene) in the subpopulation of patients with symptomatic and asymptomatic carotid stenosis. Material and Methods: This study included 623 individuals (244 patients with symptomatic carotid artery stenosis, 176 patients with asymptomatic carotid artery stenosis and 203 healthy people. All the participants underwent neurological examination, duplex Doppler ultrasound examination and molecular procedures. Results: In the first part of the analysis the assiociation of SNPs with stroke/TIA was investigated. The association was seen in symptomatic vs. control group for two SNPs: rs4977574 and rs7857345 (CDKN2B-AS1 gene); genotype distributions for rs4977574 and rs7857345 showed the statistically significant differences between patients and controls (p = 0.043 and 0.017, respectively). No association was observed for rs3798220 and rs10455872 located in the LPA gene. There were statistically significant differences between asymptomatic patients vs. control group in genotype distribution for the SNPs located in CDKN2B-AS1: rs4977574 and rs7857345 (p = 0.031 and 0.0099, respectively); and for the rs3798220 (LPA gene; p = 0.003); however, statistically significant differences did not occur for the rs10455872 polymorphism located in the LPA gene. In the next part of the evaluation, a comparison between symptomatic and asymptomatic patients was performed. Significant differences in genotype distribution were seen only for the rs3798220 polymorphism located in the LPA gene (p = 0.0015). The analysis of the prevalence of the polymorphisms in the total group (symptomatic and asymptomatic) patients in comparison with the control group showed significant differences for three polymorphisms: rs4977574 and rs7857345 (CDKN2B-AS1 gene; p = 0.015 and 0.0046, respectively) and rs3798220 (LPA gene, p = 0.044). Conclusions: The present research on the carotid artery stenosis patient cohort suggests the significant association between the rs4977574, rs7857345 and rs3798220 polymorphisms and carotid artery stenosis as well as between the rs4977574 and rs7857345 polymorphisms and atherogenic stroke. The rs4977574 and rs7857345 polymorphisms in patients with carotid artery stenosis appear to affect a person's susceptibility to atherogenic brain ischemia. Our results need to be replicated in future studies.
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Affiliation(s)
- Anetta Lasek-Bal
- Department of Neurology, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Dorota Kula
- Maria Skłodowska-Curie, Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Tomasz Urbanek
- Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland
| | - Przemysław Puz
- Department of Neurology, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Jan Szymszal
- Faculty of Technical Sciences, University of Occupational Safety Management in Katowice, Katowice, Poland
| | - Michał Jarzab
- 3rd Department of Radiotherapy and Chemotherapy, Maria Sklodowska-Curie Institute-Oncology Center, Gliwice, Poland
| | - Monika Halczok
- Maria Skłodowska-Curie, Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Renata Cyplinska
- Maria Skłodowska-Curie, Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Wiesław Bal
- Department of Outpatient Chemotherapy, Maria Skłodowska-Curie, Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Beata Łabuz-Roszak
- Department of Basic Medical Sciences, Faculty of Public Health, Medical University of Silesia, Katowice, Poland
| | - Aleksandra Cieślik
- Department of Neurology, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Ilona Jasnos
- Department of Neurology, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Barbara Jarzab
- Maria Skłodowska-Curie, Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Damian Ziaja
- Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland
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Li HW, Shen M, Gao PY, Li ZR, Cao JL, Zhang WL, Sui BB, Wang YX, Wang YJ. Association between ADAMTS7 polymorphism and carotid artery plaque vulnerability. Medicine (Baltimore) 2019; 98:e17438. [PMID: 31651847 PMCID: PMC6824807 DOI: 10.1097/md.0000000000017438] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 09/06/2019] [Accepted: 09/11/2019] [Indexed: 12/22/2022] Open
Abstract
Recent genome-wide association studies (GWAS) indicated that polymorphisms in ADAMTS7 were associated with artery disease caused by atherosclerosis. However, the correlation between the ADAMTS7 polymorphism and plaque stability remains unclear. The objective of this study was to evaluate the association between 2 ADAMTS7 variants rs3825807 and rs7173743 and ischemic stroke or atherosclerotic plaque vulnerability.This research is an observational study. Patients with ischemic stroke and normal control individuals admitted to Beijing Tiantan Hospital from May 2014 to October 2017 were enrolled. High-resolution magnetic resonance imaging was used to distinguish vulnerable and stable carotid plaques. The ADAMTS7 SNPs were genotyped using TaqMan assays on real-time PCR system. The multivariate logistic regression analyses were used to adjust for multiple risk factors between groups.Three hundred twenty-six patients with ischemic stroke (189 patients with vulnerable plaque and 81 patients with stable plaque) and 432 normal controls were included. ADAMTS7 polymorphisms of both rs7173743 and rs3825807 were associated with carotid plaque vulnerability but not the prevalence of ischemic stroke. The T/T genotype of rs7173743 [odds ratio (OR) = 1.885, 95% confidence interval (CI) = 1.067-3.328, P = .028] and A/A genotype of rs3825807 (OR = 2.146, 95% CI = 1.163-3.961, P = .013) were considered as risk genotypes for vulnerable plaque susceptibility.In conclusion, ADAMTS7 variants rs3825807 and rs7173743 are associated with the risk for carotid plaque vulnerability.
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Affiliation(s)
- Hao-wen Li
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital
- Advanced Innovation Center for Human Brain Protection, Capital Medical University
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Mi Shen
- Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University
| | - Pei-yi Gao
- Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University
- Beijing Neurosurgical Institute
| | - Zi-rui Li
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital
- Advanced Innovation Center for Human Brain Protection, Capital Medical University
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Jing-li Cao
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital
- Advanced Innovation Center for Human Brain Protection, Capital Medical University
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Wen-li Zhang
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital
| | - Bin-bin Sui
- Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University
| | - Yu-xin Wang
- Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University
| | - Ya-jie Wang
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Gai L, Eskin E. Finding associated variants in genome-wide association studies on multiple traits. Bioinformatics 2019; 34:i467-i474. [PMID: 29949991 PMCID: PMC6022769 DOI: 10.1093/bioinformatics/bty249] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Motivation Many variants identified by genome-wide association studies (GWAS) have been found to affect multiple traits, either directly or through shared pathways. There is currently a wealth of GWAS data collected in numerous phenotypes, and analyzing multiple traits at once can increase power to detect shared variant effects. However, traditional meta-analysis methods are not suitable for combining studies on different traits. When applied to dissimilar studies, these meta-analysis methods can be underpowered compared to univariate analysis. The degree to which traits share variant effects is often not known, and the vast majority of GWAS meta-analysis only consider one trait at a time. Results Here, we present a flexible method for finding associated variants from GWAS summary statistics for multiple traits. Our method estimates the degree of shared effects between traits from the data. Using simulations, we show that our method properly controls the false positive rate and increases power when an effect is present in a subset of traits. We then apply our method to the North Finland Birth Cohort and UK Biobank datasets using a variety of metabolic traits and discover novel loci. Availability and implementation Our source code is available at https://github.com/lgai/CONFIT. Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Lisa Gai
- Department of Computer Science, University of California, Los Angeles, CA, USA
| | - Eleazar Eskin
- Department of Computer Science, University of California, Los Angeles, CA, USA.,Department of Human Genetics, University of California, Los Angeles, CA, USA
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Improved detection of common variants in coronary artery disease and blood pressure using a pleiotropy cFDR method. Sci Rep 2019; 9:10340. [PMID: 31316127 PMCID: PMC6637206 DOI: 10.1038/s41598-019-46808-2] [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: 09/07/2018] [Accepted: 07/04/2019] [Indexed: 11/24/2022] Open
Abstract
Plenty of genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms (SNPs) for coronary artery disease (CAD) and blood pressure (BP). However, these SNPs only explain a small proportion of the heritability of two traits/diseases. Although high BP is a major risk factor for CAD, the genetic intercommunity between them remain largely unknown. To recognize novel loci associated with CAD and BP, a genetic-pleiotropy-informed conditional false discovery rate (cFDR) method was applied on two summary statistics of CAD and BP from existing GWASs. Stratified Q-Q and fold enrichment plots showed a high pleiotropic enrichment of SNPs associated with two traits. Adopting a cFDR of 0.05 as a threshold, 55 CAD-associated loci (25 variants being novel) and 47 BP loci (18 variants being novel) were identified, 25 of which were pleiotropic loci (13 variants being novel) for both traits. Among the 32 genes these 25 SNPs were annotated to, 20 genes were newly detected compared to previous GWASs. This study showed the cFDR approach could improve gene discovery by incorporating GWAS datasets of two related traits. These findings may provide novel understanding of etiology relationships between CAD and BP.
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The association between the chromosome 9p21 CDKN2B-AS1 gene variants and the lipid metabolism: A pre-diagnostic biomarker for coronary artery disease. Anatol J Cardiol 2019; 21:31-38. [PMID: 30587704 PMCID: PMC6382903 DOI: 10.14744/anatoljcardiol.2018.90907] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Objective: Recent genome-wide association studies have established that polymorphisms within CDKN2B-AS1 of chr9p21.3 locus increased susceptibility to coronary artery disease (CAD) or myocardial infarction. Common variants of CDKN2B-AS1 (including rs4977574 A>G and rs1333040 C>T) are determined to be directly associated with CADs in many populations worldwide and suggested biomarkers for the early detection of CAD. There is a lack of investigation for the association between CDKN2B-AS1 rs4977574 A>G and rs1333040 C>T genetic modifiers and CAD in a Turkish Cypriot population. The aim of the present study was to investigate the potential effects of these variants on susceptibility to developing CAD in a Turkish Cypriot population and their contribution to lipid metabolism. Methods: Seventy-one patients with angiography-confirmed CAD were recruited to the CAD group, whereas 153 voluntary subjects without CAD symptoms were enrolled to the control group. Genotyping for the CDKN2B-AS1 gene polymorphisms was performed by polymerase chain reaction, followed by restriction fragment length polymorphism analysis. Results: There is no statistical significant association observed between rs4977574 and rs1333040 single-nucleotide polymorphisms and two studied groups [odds ratio (OR): 0.763, p=0.185, 95% confidence interval (CI): 0.511–1.139 and OR: 1.060, p=0.802, 95% CI 0.672–1.671, respectively]. However, rs2977574 G and rs1333040 T alleles–the risk alleles–were found to be associated with higher level of serum total cholesterol and lower level of high-density lipoprotein-cholesterol in the CAD group (p=0.019, p=0.006 and p=0.022, p=0.031, respectively). To our knowledge, this is the first study that establishes the effect of rs1333040 on lipid metabolism. Conclusion: The presence of rs4977574 G and rs1333040 T alleles and interaction may exist as environmental factors associated with lipid metabolism and might be responsible for the development of CAD in a Turkish Cypriot population.
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Examination of the associations between m6A-associated single-nucleotide polymorphisms and blood pressure. Hypertens Res 2019; 42:1582-1589. [DOI: 10.1038/s41440-019-0277-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 04/25/2019] [Accepted: 05/06/2019] [Indexed: 01/10/2023]
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Wang Y, Wang JG. Genome-Wide Association Studies of Hypertension and Several Other Cardiovascular Diseases. Pulse (Basel) 2019; 6:169-186. [PMID: 31049317 PMCID: PMC6489084 DOI: 10.1159/000496150] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 12/07/2018] [Indexed: 12/30/2022] Open
Abstract
Genome-wide association studies (GWAS) have greatly expanded our understanding of the genetic architecture of cardiovascular diseases in the past decade. They have revealed hundreds of suggestive genetic loci that replicate known biological candidate genes and indicate the existence of a previously unsuspected new biology relevant to cardiovascular disorders. These data have been used successfully to create genetic risk scores that may improve risk prediction and the identification of susceptive individuals. Furthermore, these GWAS-identified novel pathways may herald a new era of novel drug development and stratification of patients. In this review, we will briefly summarize the literature on the candidate genes and signals discovered by GWAS on hypertension and coronary artery disease and discuss their implications on clinical medicine.
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Affiliation(s)
| | - Ji-Guang Wang
- Shanghai Key Laboratory of Hypertension, The Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Moon S, Lee Y, Won S, Lee J. Multiple genotype-phenotype association study reveals intronic variant pair on SIDT2 associated with metabolic syndrome in a Korean population. Hum Genomics 2018; 12:48. [PMID: 30382898 PMCID: PMC6211397 DOI: 10.1186/s40246-018-0180-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 10/08/2018] [Indexed: 12/14/2022] Open
Abstract
Background Metabolic syndrome is a risk factor for type 2 diabetes and cardiovascular disease. We identified common genetic variants that alter the risk for metabolic syndrome in the Korean population. To isolate these variants, we conducted a multiple-genotype and multiple-phenotype genome-wide association analysis using the family-based quasi-likelihood score (MFQLS) test. For this analysis, we used 7211 and 2838 genotyped study subjects for discovery and replication, respectively. We also performed a multiple-genotype and multiple-phenotype analysis of a gene-based single-nucleotide polymorphism (SNP) set. Results We found an association between metabolic syndrome and an intronic SNP pair, rs7107152 and rs1242229, in SIDT2 gene at 11q23.3. Both SNPs correlate with the expression of SIDT2 and TAGLN, whose products promote insulin secretion and lipid metabolism, respectively. This SNP pair showed statistical significance at the replication stage. Conclusions Our findings provide insight into an underlying mechanism that contributes to metabolic syndrome. Electronic supplementary material The online version of this article (10.1186/s40246-018-0180-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sanghoon Moon
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Cheongju, Chungcheongbuk-do, 28159, South Korea
| | - Young Lee
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Cheongju, Chungcheongbuk-do, 28159, South Korea.,Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, 05368, South Korea
| | - Sungho Won
- Department of Public Health Science, Seoul National University, Seoul, 08826, South Korea
| | - Juyoung Lee
- Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Cheongju, Chungcheongbuk-do, 28159, South Korea.
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Xu B, Fang Z, He S, Wang J, Yang X. ANRIL polymorphism rs4977574 is associated with increased risk of coronary artery disease in Asian populations: A meta-analysis of 12,005 subjects. Medicine (Baltimore) 2018; 97:e12641. [PMID: 30278588 PMCID: PMC6181537 DOI: 10.1097/md.0000000000012641] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Several studies have shown that ANRIL polymorphism may be associated with the risk of coronary artery disease (CAD). However, these studies do not provide a clear consensus in Asian population. Thus, this meta-analysis was aimed to evaluate the relationship between the common variant rs4977574 in ANRIL and CAD risk in Asian population. METHODS We conducted a systematic literature search of PubMed, Embase and the Cochrane Library and 2 Chinese databases. A total of 12,005 subjects from 6 independent studies were included. The pooled odds ratio (OR) and their corresponding 95% confidence intervals (CIs) were used to assess the association between rs4977574 and CAD using random effects model. RESULTS A significant association was observed between rs4977574 and CAD risk under the allelic (OR: 1.18, 95% CI: 1.04-1.34, P = .010), recessive (OR: 1.27, 95% CI: 1.01-1.60, P = .04), dominant (OR: 1.28, 95% CI: 1.13-1.44, P = .002), homozygous (OR: 1.46, 95% CI: 1.15-1.86, P = .002), and heterozygous model (OR: 1.17, 95% CI: 1.07-1.28, P = .0004), especially in the Chinese subgroup and the myocardial infarction (MI) subgroup (P < .05). CONCLUSION The ANRIL polymorphism rs4977574 is associated with CAD risk in Asian population. The rs4977574 with G allele may confer to a higher risk of CAD, especially MI.
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Affiliation(s)
- Bing Xu
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou
- Department of Cardiology, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou
| | - Zhen Fang
- Department of Cardiology, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou
| | - Shenghu He
- Department of Cardiology, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou
| | - Junhong Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiangjun Yang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou
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Qin J, Tian J, Liu G, Zhang Y, Tian L, Zhen Y, Zhang H, Xu J, Sun X, Fang H. Association between 1p13 polymorphisms and peripheral arterial disease in a Chinese population with diabetes. J Diabetes Investig 2018; 9:1189-1195. [PMID: 29356453 PMCID: PMC6123029 DOI: 10.1111/jdi.12804] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 01/09/2018] [Accepted: 01/10/2018] [Indexed: 01/06/2023] Open
Abstract
AIMS/INTRODUCTION Variants on chromosome 1p13 have been associated with coronary artery disease and acute myocardial infarction risk in different ethnic groups. The present study aimed to investigate the association between 1p13 polymorphisms and the development of peripheral artery disease (PAD) in a Chinese population with type 2 diabetes mellitus. MATERIALS AND METHODS 1p13 polymorphisms, rs599839, rs646776 and rs12740374, were assessed in a cohort of 882 type 2 diabetes mellitus patients including 440 type 2 diabetes mellitus patients with PAD (DM + PAD group) and 442 patients without PAD (DM group). Genotyping was carried out using TaqMan assay. RESULTS Compared with the DM group, the frequencies of the minor G allele of both rs599839 and rs646776 and the minor T allele of rs12740374 decreased (P = 0.013, P = 0.019 and P = 0.005, respectively), and the frequencies of rs599839 AG + GG, rs646776 AG + GG and rs12740374 CT+TT genotypes were statistically significantly decreased as well (P = 0.017, P = 0.011 and P = 0.007, respectively) in the dominant model in the DM + PAD group than in the DM group. Multivariate unconditional logistic regression analyses adjusted for age, glycated hemoglobin, triglyceride, low-density lipoprotein cholesterol, smoking, hypertension, diabetes duration, coronary heart disease and cerebral infarction showed that the genotypic distribution of rs599839 AG + GG, rs646776 AG + GG and rs12740374 CT + TT remained statistically different between the DM and DM + PAD group (P = 0.014, P = 0.003 and P = 0.004, respectively). The frequencies of haplotype GGT were statistically significantly different between groups (P = 0.08). CONCLUSIONS The present study strongly supports that genotypes of rs599839, rs646776 and rs12740374 on 1p13 are protective factors for diabetic PAD in a Chinese population. Haplotype GGT generated by rs599839, rs646776 and rs12740374 might also decrease the risk of the disease.
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Affiliation(s)
- Jiangyuan Qin
- Department of Internal MedicineHebei Medical UniversityShijiazhuangHebeiChina
| | - Jinli Tian
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Guanhua Liu
- Department of OrthopedicsTangshan Gongren HospitalTangshanHebeiChina
| | - Yazhong Zhang
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Luobing Tian
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Yanfeng Zhen
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Hewei Zhang
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Jing Xu
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Xueling Sun
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
| | - Hui Fang
- Department of Internal MedicineHebei Medical UniversityShijiazhuangHebeiChina
- Second Department of EndocrinologyTangshan Gongren HospitalTangshanHebeiChina
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Fernández-Rhodes L, Malinowski JR, Wang Y, Tao R, Pankratz N, Jeff JM, Yoneyama S, Carty CL, Setiawan VW, Le Marchand L, Haiman C, Corbett S, Demerath E, Heiss G, Gross M, Buzkova P, Crawford DC, Hunt SC, Rao DC, Schwander K, Chakravarti A, Gottesman O, Abul-Husn NS, Bottinger EP, Loos RJF, Raffel LJ, Yao J, Guo X, Bielinski SJ, Rotter JI, Vaidya D, Chen YDI, Castañeda SF, Daviglus M, Kaplan R, Talavera GA, Ryckman KK, Peters U, Ambite JL, Buyske S, Hindorff L, Kooperberg C, Matise T, Franceschini N, North KE. The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis. PLoS One 2018; 13:e0200486. [PMID: 30044860 PMCID: PMC6059436 DOI: 10.1371/journal.pone.0200486] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 06/27/2018] [Indexed: 11/18/2022] Open
Abstract
Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.
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Affiliation(s)
- Lindsay Fernández-Rhodes
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail:
| | | | - Yujie Wang
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Ran Tao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Nathan Pankratz
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Janina M. Jeff
- Genotyping Arrays Division, Illumina, Inc., San Diego, California, United States of America
| | - Sachiko Yoneyama
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Cara L. Carty
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - V. Wendy Setiawan
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Loic Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America
| | - Christopher Haiman
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Steven Corbett
- Kansas Health Institute, Topeka, Kansas, United States of America
| | - Ellen Demerath
- Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Gerardo Heiss
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Myron Gross
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Petra Buzkova
- Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington, United States of America
| | - Dana C. Crawford
- Institute for Computational Biology, Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Steven C. Hunt
- Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Doha, Qatar
| | - D. C. Rao
- Division of Biostatistics, Washington University in St. Louis, St. Louis, Michigan, United States of America
| | - Karen Schwander
- Division of Biostatistics, Washington University in St. Louis, St. Louis, Michigan, United States of America
| | - Aravinda Chakravarti
- Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Omri Gottesman
- Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Noura S. Abul-Husn
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Erwin P. Bottinger
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Ruth J. F. Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Leslie J. Raffel
- Division of Genetic and Genomic Medicine, University of California—Irvine, Irvine, California, United States of America
| | - Jie Yao
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Xiuqing Guo
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Suzette J. Bielinski
- College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Jerome I. Rotter
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Dhananjay Vaidya
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Yii-Der Ida Chen
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Sheila F. Castañeda
- South Bay Latino Research Center, Graduate School of Public Health, San Diego State University, San Diego, California, United States of America
| | - Martha Daviglus
- Institute of Minority Health Research, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Robert Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Gregory A. Talavera
- South Bay Latino Research Center, Graduate School of Public Health, San Diego State University, San Diego, California, United States of America
| | - Kelli K. Ryckman
- Departments of Epidemiology and Pediatrics, University of Iowa, Iowa City, Iowa, United States of America
| | - Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Jose Luis Ambite
- Information Sciences Institute, University of Southern California, Marina del Rey, California, United States of America
| | - Steven Buyske
- Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America
| | - Lucia Hindorff
- Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Tara Matise
- Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America
| | - Nora Franceschini
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Kari E. North
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
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40
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Hernandez-Pacheco N, Guillen-Guio B, Acosta-Herrera M, Pino-Yanes M, Corrales A, Ambrós A, Nogales L, Muriel A, González-Higueras E, Diaz-Dominguez FJ, Zavala E, Belda J, Ma SF, Villar J, Flores C. A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome. Intensive Care Med Exp 2018; 6:16. [PMID: 29987654 PMCID: PMC6037659 DOI: 10.1186/s40635-018-0181-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 06/20/2018] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The acute respiratory distress syndrome (ARDS) is one of the main causes of mortality in adults admitted to intensive care units. Previous studies have demonstrated the existence of genetic variants involved in the susceptibility and outcomes of this syndrome. We aimed to identify novel genes implicated in sepsis-induced ARDS susceptibility. METHODS We first performed a prioritization of candidate genes by integrating our own genomic data from a transcriptomic study in an animal model of ARDS and from the only published genome-wide association study of ARDS study in humans. Then, we selected single nucleotide polymorphisms (SNPs) from prioritized genes to conduct a case-control discovery association study in patients with sepsis-induced ARDS (n = 225) and population-based controls (n = 899). Finally, we validated our findings in an independent sample of 661 sepsis-induced ARDS cases and 234 at-risk controls. RESULTS Three candidate genes were prioritized: dynein cytoplasmic-2 heavy chain-1, fms-related tyrosine kinase 1 (FLT1), and integrin alpha-1. Of those, a SNP from FLT1 gene (rs9513106) was associated with ARDS in the discovery study, with an odds ratio (OR) for the C allele of 0.76, 95% confidence interval (CI) 0.58-0.98 (p = 0.037). This result was replicated in an independent study (OR = 0.78, 95% CI = 0.62-0.98, p = 0.039), showing consistent direction of effects in a meta-analysis (OR = 0.77, 95% CI = 0.65-0.92, p = 0.003). CONCLUSIONS We identified FLT1 as a novel ARDS susceptibility gene and demonstrated that integration of genomic data can be a valid procedure to identify novel susceptibility genes. These results contribute to previous firm associations and functional evidences implicating FLT1 gene in other complex traits that are mechanistically linked, through the key role of endothelium, to the pathophysiology of ARDS.
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Affiliation(s)
- Natalia Hernandez-Pacheco
- Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
| | - Beatriz Guillen-Guio
- Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
| | - Marialbert Acosta-Herrera
- Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
- Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain
- Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, P.T.S, Granada, Spain
| | - Maria Pino-Yanes
- Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Tenerife Spain
| | - Almudena Corrales
- Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - Alfonso Ambrós
- Intensive Care Unit, Hospital General de Ciudad Real, Ciudad Real, Spain
| | - Leonor Nogales
- Intensive Care Unit, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | - Arturo Muriel
- Intensive Care Unit, Hospital Universitario Rio Hortega, Valladolid, Spain
| | | | | | - Elizabeth Zavala
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Intensive Care Unit, Hospital Clinic Barcelona, Barcelona, Spain
| | - Javier Belda
- Department of Anesthesiology, Hospital Clínico Universitario, Universidad de Valencia, Valencia, Spain
| | - Shwu-Fan Ma
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, USA
| | - Jesús Villar
- Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - Carlos Flores
- Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
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41
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Yamada Y, Kato K, Oguri M, Horibe H, Fujimaki T, Yasukochi Y, Takeuchi I, Sakuma J. Identification of nine genes as novel susceptibility loci for early-onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Biomed Rep 2018; 9:8-20. [PMID: 29930801 PMCID: PMC6006761 DOI: 10.3892/br.2018.1104] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 05/23/2018] [Indexed: 02/07/2023] Open
Abstract
Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies (GWASs) have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders remain to be identified definitively. We performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in early-onset subjects with these conditions. A total of 6,649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6,224 individuals (450 subjects with ischemic stroke, 5,774 controls) or 6,179 individuals (261 subjects with ICH, 176 subjects with SAH, 5,742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. The association of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR <0.05) associated with ischemic stroke. The association of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P<0.0004 (0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P<0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous GWASs, we identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Therefore, to the best of our knowledge, we have newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.
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Affiliation(s)
- Yoshiji Yamada
- Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.,CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
| | - Kimihiko Kato
- Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.,Department of Internal Medicine, Meitoh Hospital, Nagoya, Aichi 465-0025, Japan
| | - Mitsutoshi Oguri
- Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.,Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Aichi 486-8510, Japan
| | - Hideki Horibe
- Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Gifu 507-8522, Japan
| | - Tetsuo Fujimaki
- Department of Cardiovascular Medicine, Northern Mie Medical Center Inabe General Hospital, Inabe, Mie 511-0428, Japan
| | - Yoshiki Yasukochi
- Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.,CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
| | - Ichiro Takeuchi
- CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.,Department of Computer Science, Nagoya Institute of Technology, Nagoya, Aichi 466-8555, Japan.,RIKEN Center for Advanced Intelligence Project, Tokyo 103-0027, Japan
| | - Jun Sakuma
- CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.,RIKEN Center for Advanced Intelligence Project, Tokyo 103-0027, Japan.,Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Ibaraki 305-8573, Japan
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42
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Yamada Y, Sakuma J, Takeuchi I, Yasukochi Y, Kato K, Oguri M, Fujimaki T, Horibe H, Muramatsu M, Sawabe M, Fujiwara Y, Taniguchi Y, Obuchi S, Kawai H, Shinkai S, Mori S, Arai T, Tanaka M. Identification of polymorphisms in 12q24.1, ACAD10, and BRAP as novel genetic determinants of blood pressure in Japanese by exome-wide association studies. Oncotarget 2018; 8:43068-43079. [PMID: 28562329 PMCID: PMC5522128 DOI: 10.18632/oncotarget.17474] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 04/05/2017] [Indexed: 12/29/2022] Open
Abstract
We performed exome-wide association studies to identify genetic variants that influence systolic or diastolic blood pressure or confer susceptibility to hypertension in Japanese. The exome-wide association studies were performed with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays and with 14,678 subjects, including 8215 individuals with hypertension and 6463 controls. The relation of genotypes of 41,843 single nucleotide polymorphisms to systolic or diastolic blood pressure was examined by linear regression analysis. After Bonferroni's correction, 44 and eight polymorphisms were significantly (P < 1.19 × 10−6) associated with systolic or diastolic blood pressure, respectively, with six polymorphisms (rs12229654, rs671, rs11066015, rs2074356, rs3782886, rs11066280) being associated with both systolic and diastolic blood pressure. Examination of the relation of allele frequencies to hypertension with Fisher's exact test revealed that 100 of the 41,843 single nucleotide polymorphisms were significantly (P < 1.19 × 10−6) associated with hypertension. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that five polymorphisms (rs150854849, rs202069030, rs139012426, rs12229654, rs76974938) were significantly (P < 1.25 × 10−4) associated with hypertension. The polymorphism rs12229654 was thus associated with both systolic and diastolic blood pressure and with hypertension. Six polymorphisms (rs12229654 at 12q24.1, rs671 of ALDH2, rs11066015 of ACAD10, rs2074356 and rs11066280 of HECTD4, and rs3782886 of BRAP) were found to be associated with both systolic and diastolic blood pressure, with those at 12q24.1 or in ACAD10 or BRAP being novel determinants of blood pressure in Japanese.
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Affiliation(s)
- Yoshiji Yamada
- Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan.,CREST, Japan Science and Technology Agency, Kawaguchi, Japan
| | - Jun Sakuma
- CREST, Japan Science and Technology Agency, Kawaguchi, Japan.,Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan.,RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Ichiro Takeuchi
- CREST, Japan Science and Technology Agency, Kawaguchi, Japan.,RIKEN Center for Advanced Intelligence Project, Tokyo, Japan.,Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan
| | - Yoshiki Yasukochi
- Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan.,CREST, Japan Science and Technology Agency, Kawaguchi, Japan
| | - Kimihiko Kato
- Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan.,Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan
| | - Mitsutoshi Oguri
- Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan.,Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Tetsuo Fujimaki
- Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan
| | - Hideki Horibe
- Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
| | - Masaaki Muramatsu
- Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Motoji Sawabe
- Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshinori Fujiwara
- Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Yu Taniguchi
- Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Shuichi Obuchi
- Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Hisashi Kawai
- Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Shoji Shinkai
- Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Seijiro Mori
- Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
| | - Masashi Tanaka
- Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
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Sánchez Muñoz-Torrero JF, Rivas MD, Zamorano J, Joya-Vázquez PP, de Isla LP, Padro T, Mata P, The Safeheart Investigators. Multivariate analysis for coronary heart disease in heterozygote familial hypercholesterolemia patients. Per Med 2018; 15:87-92. [PMID: 29714125 DOI: 10.2217/pme-2017-0075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
AIM rs599839 polymorphism has been related with low levels of cholesterol and reduced coronary heart disease (CHD). METHODS We investigated the frequency of this polymorphism in patients with heterozygous familial hypercholesterolemia (HeFH) in the Spanish familial hypercholesterolemia cohort, 230 with and 202 without CHD. Results & discussion: A lower G-allele prevalence was observed in HeFH patients with CHD with respect to controls, 35 versus 45%, respectively (p = 0.029), suggesting a protective effect. However, it was found that there was no association between rs599839 alleles and CHD in the multivariate analysis. CONCLUSION The frequency of the protective G-allele of the rs599839 polymorphism was lower in HeFH patients with CHD compared with those HeFH patients without CHD. However, its role in HeFH may be masked by very high levels of cholesterol.
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Affiliation(s)
| | - Maria D Rivas
- Research Unit, Hospital San Pedro de Alcantara, Caceres, Spain
| | - Jose Zamorano
- Research Unit, Hospital San Pedro de Alcantara, Caceres, Spain
| | | | | | - Teresa Padro
- Centro de Investigacion Cardiovascular CSIC-ICCC, Hospital Sant Pau & IIB-Sant Pau, & CIBEROBN, ISC III, Barcelona, Spain
| | - Pedro Mata
- Fundacion Hipercolesterolemia Familial, Madrid, Spain
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44
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You L, Li C, Zhao J, Wang DW, Cui W. Associations of common variants at ALDH2 gene and the risk of stroke in patients with coronary artery diseases undergoing percutaneous coronary intervention. Medicine (Baltimore) 2018; 97:e0711. [PMID: 29742731 PMCID: PMC5959384 DOI: 10.1097/md.0000000000010711] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Limited data are available about the role of common variants at the aldehyde dehydrogenase 2 gene (ALDH2) on the clinical outcome in Chinese patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI). In the present study, a total of 1089 patients were consecutively enrolled from January 2012 and July 2013. Six common variants at ALDH2 gene, including rs2339840, rs4648328, rs4767939, rs11066028, rs16941669, and rs671, were selected to test the associations of those polymorphisms with the cardiovascular outcome in patients with CHD after PCI. The clinical endpoints included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The composite of clinical endpoints was defined as the primary endpoint, and every endpoint alone was considered as the secondary endpoints. The median follow-up time was 38.27 months. Our results showed that the common variant rs2339840 was independently associated with a lower risk of stroke in patients with CHD after PCI (codominant model, HR = 0.32, 95% CI, 0.11-0.91, P = .074 for heterozygotes; HR = 0.25, 95% CI, 0.06-1.14, P = .033 for homozygotes; dominant model, HR = 0.32, 95% CI, 0.14-0.74, P = .007). However, no significant associations were found between other 5 single nucleotide polymorphisms (SNPs) and the clinical endpoints. For the first time, the common variant rs2339840 was reported to be a protective factor against stroke in CHD patients with PCI.
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Affiliation(s)
- Ling You
- Division of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province
| | - Chenze Li
- Departments of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Jinzhao Zhao
- Departments of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Dao Wen Wang
- Departments of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Wei Cui
- Division of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province
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45
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Lee HS, Kim Y, Park T. New Common and Rare Variants Influencing Metabolic Syndrome and Its Individual Components in a Korean Population. Sci Rep 2018; 8:5701. [PMID: 29632305 PMCID: PMC5890262 DOI: 10.1038/s41598-018-23074-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 03/01/2018] [Indexed: 12/25/2022] Open
Abstract
To identify novel loci for susceptibility to MetS, we conducted genome-wide association and exome wide association studies consisting of a discovery stage cohort (KARE, 1946 cases and 6427 controls), and a replication stage cohort (HEXA, 430 cases and 3,264 controls). For finding genetic variants for MetS, with its components, we performed multivariate analysis for common and rare associations, using a standard logistic regression analysis for MetS. From the discovery and replication GWA studies, we confirmed 21 genome-wide signals significantly associated with MetS. Of these 21, four were previously unreported to associate with any MetS components: rs765547 near LPL; rs3782889 in MYL2; and rs11065756 and rs10849915 in CCDC63. Using exome chip variants, gene-based analysis of rare variants revealed three genes, CETP, SH2B1, and ZFP2, in the discovery stage, among which only CETP was confirmed in the replication stage. Finally, CETP D442G (rs2303790) associated, as a less common variant, with decreased risk of MetS. In conclusion, we discovered a total of five new MetS-associated loci, and their overlap with other disease-related components, suggest roles in the various etiologies of MetS, and its possible preventive strategies.
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Affiliation(s)
- Ho-Sun Lee
- Department of Statistics, Seoul National University, Seoul, 08826, Republic of Korea.,Daegu Institution, National Forensic Service, 33-14, Hogukro, Waegwon-eup, Chilgok-gun, Gyeomgsamgbuk-do, Republic of Korea
| | - Yongkang Kim
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, 08826, Republic of Korea
| | - Taesung Park
- Department of Statistics, Seoul National University, Seoul, 08826, Republic of Korea. .,Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, 08826, Republic of Korea.
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46
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Abstract
Heart failure is a growing cardiovascular disease with significant epidemiological, clinical, and societal implications and represents a high unmet need. Strong efforts are currently underway by academic and industrial researchers to develop novel treatments for heart failure. Biomarkers play an important role in patient selection and monitoring in drug trials and in clinical management. The present review gives an overview of the role of available molecular, imaging, and device-derived digital biomarkers in heart failure drug development and highlights capabilities and limitations of biomarker use in this context.
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47
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Ke W, Rand KA, Conti DV, Setiawan VW, Stram DO, Wilkens L, Le Marchand L, Assimes TL, Haiman CA. Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort. Front Cardiovasc Med 2018; 5:19. [PMID: 29740590 PMCID: PMC5931137 DOI: 10.3389/fcvm.2018.00019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 02/21/2018] [Indexed: 01/07/2023] Open
Abstract
Background Coronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear. Methods and Results We examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10−6), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10−5) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual’s aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10−5) and Latinos (OR = 1.03; p = 2.2 × 10−8), but not in Japanese (OR = 1.01; p = 0.11). Conclusions While a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.
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Affiliation(s)
- Wangjing Ke
- Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, United States
| | | | - David V Conti
- Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, United States
| | - Veronica W Setiawan
- Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, United States
| | - Daniel O Stram
- Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, United States
| | - Lynne Wilkens
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States
| | - Loic Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States
| | - Themistocles L Assimes
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.,Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
| | - Christopher A Haiman
- Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, United States
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48
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Franzén O, Ermel R, Sukhavasi K, Jain R, Jain A, Betsholtz C, Giannarelli C, Kovacic JC, Ruusalepp A, Skogsberg J, Hao K, Schadt EE, Björkegren JL. Global analysis of A-to-I RNA editing reveals association with common disease variants. PeerJ 2018; 6:e4466. [PMID: 29527417 PMCID: PMC5844249 DOI: 10.7717/peerj.4466] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 02/15/2018] [Indexed: 01/04/2023] Open
Abstract
RNA editing modifies transcripts and may alter their regulation or function. In humans, the most common modification is adenosine to inosine (A-to-I). We examined the global characteristics of RNA editing in 4,301 human tissue samples. More than 1.6 million A-to-I edits were identified in 62% of all protein-coding transcripts. mRNA recoding was extremely rare; only 11 novel recoding sites were uncovered. Thirty single nucleotide polymorphisms from genome-wide association studies were associated with RNA editing; one that influences type 2 diabetes (rs2028299) was associated with editing in ARPIN. Twenty-five genes, including LRP11 and PLIN5, had editing sites that were associated with plasma lipid levels. Our findings provide new insights into the genetic regulation of RNA editing and establish a rich catalogue for further exploration of this process.
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Affiliation(s)
- Oscar Franzén
- Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
| | - Raili Ermel
- Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia
| | - Katyayani Sukhavasi
- Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Rajeev Jain
- Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Anamika Jain
- Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Christer Betsholtz
- Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
- Department of Immunology, Genetics and Pathology, Uppsala Universitet, Uppsala, Sweden
| | - Chiara Giannarelli
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Institute of Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Jason C. Kovacic
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Arno Ruusalepp
- Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia
- Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
- Clinical Gene Networks AB, Stockholm, Sweden
| | - Josefin Skogsberg
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
| | - Ke Hao
- Institute of Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Eric E. Schadt
- Institute of Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Clinical Gene Networks AB, Stockholm, Sweden
| | - Johan L.M. Björkegren
- Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
- Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
- Institute of Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Clinical Gene Networks AB, Stockholm, Sweden
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Andersson CH, Hansson O, Minthon L, Andreasen N, Blennow K, Zetterberg H, Skoog I, Wallin A, Nilsson S, Kettunen P. A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease. J Alzheimers Dis 2018; 53:1353-63. [PMID: 27392867 PMCID: PMC5147507 DOI: 10.3233/jad-160319] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.
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Affiliation(s)
- Carl-Henrik Andersson
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Oskar Hansson
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Sweden.,Memory Clinic, Skåne University Hospital, Malmö, Sweden
| | - Lennart Minthon
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Sweden.,Memory Clinic, Skåne University Hospital, Malmö, Sweden
| | - Niels Andreasen
- Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Kaj Blennow
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Henrik Zetterberg
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,UCL Institute of Neurology, Queen Square, London, United Kingdom
| | - Ingmar Skoog
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Wallin
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Staffan Nilsson
- Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Sweden
| | - Petronella Kettunen
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
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50
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Han Y, Dorajoo R, Chang X, Wang L, Khor CC, Sim X, Cheng CY, Shi Y, Tham YC, Zhao W, Chee ML, Sabanayagam C, Chee ML, Tan N, Wong TY, Tai ES, Liu J, Goh DYT, Yuan JM, Koh WP, van Dam RM, Low AF, Chan MYY, Friedlander Y, Heng CK. Genome-wide association study identifies a missense variant at APOA5 for coronary artery disease in Multi-Ethnic Cohorts from Southeast Asia. Sci Rep 2017; 7:17921. [PMID: 29263402 PMCID: PMC5738399 DOI: 10.1038/s41598-017-18214-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 12/01/2017] [Indexed: 12/19/2022] Open
Abstract
Recent genome-wide association studies (GWAS) have identified multiple loci associated with coronary artery disease (CAD) among predominantly Europeans. However, their relevance to multi-ethnic populations from Southeast Asia is largely unknown. We performed a meta-analysis of four GWAS comprising three Chinese studies and one Malay study (Total N = 2,169 CAD cases and 7,376 controls). Top hits (P < 5 × 10-8) were further evaluated in 291 CAD cases and 1,848 controls of Asian Indians. Using all datasets, we validated recently identified loci associated with CAD. The involvement of known canonical pathways in CAD was tested by Ingenuity Pathway Analysis. We identified a missense SNP (rs2075291, G > T, G185C) in APOA5 for CAD that reached robust genome-wide significance (Meta P = 7.09 × 10-10, OR = 1.636). Conditional probability analysis indicated that the association at rs2075291 was independent of previously reported index SNP rs964184 in APOA5. We further replicated 10 loci previously identified among predominantly Europeans (P: 1.33 × 10-7-0.047). Seven pathways (P: 1.10 × 10-5-0.019) were identified. We identified a missense SNP, rs2075291, in APOA5 associated with CAD at a genome-wide significance level and provided new insights into pathways contributing to the susceptibility to CAD in the multi-ethnic populations from Southeast Asia.
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Affiliation(s)
- Yi Han
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, Singapore
| | - Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Xuling Chang
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, Singapore
| | - Ling Wang
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Chiea-Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Xueling Sim
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
| | - Ching-Yu Cheng
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yuan Shi
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
| | - Yih Chung Tham
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
| | - Wanting Zhao
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
| | - Miao Ling Chee
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
| | - Charumathi Sabanayagam
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
- Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Miao Li Chee
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
| | - Nicholas Tan
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
- Department of Ophthalmology, National University Hospital, Singapore, Singapore
| | - Tien Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - E-Shyong Tai
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
| | - Jianjun Liu
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
| | - Daniel Y T Goh
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, Singapore
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health; and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Woon-Puay Koh
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
- Duke-NUS Graduate Medical School Singapore, Singapore, Singapore
| | - Rob M van Dam
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
| | - Adrian F Low
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Heart Centre, National University Health System, Singapore, Singapore
| | - Mark Yan-Yee Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yechiel Friedlander
- School of Public Health and Community Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
| | - Chew-Kiat Heng
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, Singapore.
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