Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population

Wang, Fan; Xu, Chengqi; He, Qing; Cai, Jian Ping; Li, Xiu Chun; Wang, Dan; Xiong, Xin; Liao, Yuan; Zeng, Qingtao; Yang, Yan; Cheng, Xiang; Liu, Cong; Yang, Rong; Wang, Chu Chu; Wu, Gang; Lu, Qiu Lun; Bai, Ying; Huang, Yu Feng; Yin, Dan; Yang, Qing; Wang, Xiao Jing; Dai, Da Peng; Zhang, Rong Feng; Wan, Jing; Ren, Jiangbo; Li, Si Si; Zhao, Yuan; Fu, Fen; Huang, Yuan; Li, Qing Xian; Sheng, Shi; Lin, Nan; Pan, Zhen Wei; Li, Yue; Yu, Bo; Wu, Yan; Ke, Yu He; Lei, Jian; Wang, Nan; Luo, Chengzhi; Li, Ji; Gao, Lian Jun; Li, Lei; Liu, Hui; Huang, Er Wen; Cui, Jin; Jia, Na; Ren, Xiang; Li, Hui; Ke, Tie; Zhang, Xian Qin; Liu, Jingyu; Liu, Mu Gen; Xia, Hao; Yang, Bo; Shi, Liming; Xia, Yun; Tu, Xin; Wang, Qing Kenneth

doi:10.1038/ng.783

Cited by 236 publications

(204 citation statements)

References 27 publications

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“…In the first years of GWAS discoveries, identification of further loci came from individual genome‐wide association studies (Erdmann et al , 2009; Myocardial Infarction Genetics Consortium et al , 2009; Tregouet et al , 2009; IBC 50K CAD Consortium, 2011; Wang et al , 2011), whereas more recently the formation of large, international consortia has accumulated a sufficient statistical power for new discoveries. The joint forces of the CARDIoGRAM (Schunkert et al , 2011), C4D (Coronary Artery Disease C4D Genetics Consortium, 2011) and finally the CARDIoGRAMplusC4D (CARDIoGRAMplusC4D Consortium et al , 2013; Nikpay et al , 2015) consortium allowed the analysis of up to 180,000 individuals, about half of which had CAD.…”

Section: Genome‐wide Association Studies In Coronary Artery Disease Amentioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

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Section: Genome‐wide Association Studies In Coronary Artery Disease Amentioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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“…H9C2 cells were cultured in DMEM supplemented with 15% fetal bovine serum and transfected with siRNA using Lipofectamine 2000 according to the manufacturer's instructions (Invitrogen). After 48 h of transfection, cells were harvested for assaying siRNA knockdown efficiency using quantitative real-time RT-PCR and Western blotting analysis as described (4,(22)(23)(24)(25). Sequences of primers used for quantitative real-time PCR analysis are listed in Table 1.…”

Section: Methodsmentioning

confidence: 99%

αB-Crystallin Interacts with Nav1.5 and Regulates Ubiquitination and Internalization of Cell Surface Nav1.5

Huang

Wang

Liu

et al. 2016

Journal of Biological Chemistry

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Na v 1.5, the pore-forming ␣ subunit of the cardiac voltagegated Na ؉ channel complex, is required for the initiation and propagation of the cardiac action potential. Mutations in Na v 1.5 cause cardiac arrhythmias and sudden death. The cardiac Na ؉ channel functions as a protein complex; however, its complete components remain to be fully elucidated. A yeast two-hybrid screen identified a new candidate Na v 1.5-interacting protein, ␣B-crystallin. GST pull-down, co-immunoprecipitation, and immunostaining analyses validated the interaction between Na v 1.5 and ␣B-crystallin. Whole-cell patch clamping showed that overexpression of ␣B-crystallin significantly increased peak sodium current (I Na ) density, and the underlying molecular mechanism is the increased cell surface expression level of Na v 1.5 via reduced internalization of cell surface Na v 1.5 and ubiquitination of Na v 1.5. Knock-out of ␣B-crystallin expression significantly decreased the cell surface expression level of Na v 1.5. Co-immunoprecipitation analysis showed that ␣B-crystallin interacted with Nedd4-2; however, a catalytically inactive Nedd4-2-C801S mutant impaired the interaction and abolished the up-regulation of I Na by ␣B-crystallin. Na v 1.5 mutation V1980A at the interaction site for Nedd4-2 eliminated the effect of ␣B-crystallin on reduction of Na v 1.5 ubiquitination and increases of I Na density. Two disease-causing mutations in ␣B-crystallin, R109H and R151X (nonsense mutation), eliminated the effect of ␣B-crystallin on I Na . This study identifies ␣B-crystallin as a new binding partner for Na v 1.5. ␣B-Crystallin interacts with Na v 1.5 and increases I Na by modulating the expression level and internalization of cell surface Na v 1.5 and ubiquitination of Na v 1.5, which requires the protein-protein interactions between ␣B-crystallin and Na v 1.5 and between ␣B-crystallin and functionally active Nedd4-2.Na v 1.5 is the pore-forming ␣ subunit of the major cardiac voltage-gated Na ϩ channel complex. It generates the sodium current (I Na ) 4 that plays an essential role in the initiation and propagation of the cardiac action potential (1-3). Mutations in the SCN5A gene (encoding Na v 1.5) cause several inherited arrhythmias, including atrial fibrillation, Brugada syndrome, long QT syndrome, progressive cardiac conduction defect disease, sick sinus syndrome, and dilated cardiomyopathy (4). Na v 1.5 exists in vivo in a multiprotein complex, which interacts with the actin cytoskeleton and the extracellular matrix to provide an important functional link between channel complexes, cardiac structure, and electrical functioning (5, 6). Several proteins have been reported to bind to Na v 1.5 (5-7). We have previously reported a small protein, MOG1, with a function in nucleocytoplasmic protein transport that interacts directly with Na v 1.5, promotes trafficking of Na v 1.5 to the cell surface, and increases peak I Na density (4, 6). Specifically, MOG1 facilitates export of Na v 1.5 from the endoplasmic reticulum as well as targeting of Na v 1.5...

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“…3 Even after large-scale genome-wide association studies (GWAS) in European populations, GWAS in Asian populations have identified novel loci. [4][5][6][7] More additional loci are certainly left unidentified, and in such a situation, it remains elusive in total how many susceptibility loci exist. Here, to potently identify as many susceptibility loci as possible, GWAS and replication studies in a total of 44 673 Japanese participants were performed.…”

Section: Introductionmentioning

confidence: 99%

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

et al. 2014

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Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210:A4G, P ¼ 2.60 Â 10 À9 , odds ratio (OR) ¼ 0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915:A4C, P ¼ 3.84 Â 10 À9 , OR ¼ 0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886:A4G: P ¼ 1.14 Â 10 À14 , OR ¼ 1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci. INTRODUCTIONMyocardial infarction (MI), the severest form of coronary artery disease (CAD), is characterized by the occlusion of the coronary artery, resulting in ischemic damage of the myocardium. The occlusion of the coronary artery is characterized by abrupt plaque rupture with thrombogenesis 1 following the atherosclerotic process, which has recently been regarded as a chronic inflammatory condition involving lipid accumulation, abnormal extracellular matrix metabolism, innate immunity with macrophages, and the adaptive immune response with T and B lymphocytes. 2 Despite recent dramatic advances in preventive and/or therapeutic strategies, MI is still one of the leading causes of death in Asian populations as well as European populations.The pathogenesis of MI is considered to be the cumulative effect of multiple genetic and environmental factors. For the genetic aspect, a

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Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population

Cited by 236 publications

References 27 publications

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

αB-Crystallin Interacts with Nav1.5 and Regulates Ubiquitination and Internalization of Cell Surface Nav1.5

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

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