Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Q Medicine

Circulation-Cardiovascular Genetics Pub Date : 2016-12-01 DOI:10.1161/CIRCGENETICS.116.001572

P. Natarajan, J. Bis, L. Bielak, A. Cox, M. Dörr, M. Feitosa, N. Franceschini, Xiuqing Guo, Shih-Jen Hwang, A. Isaacs, Min A. Jhun, M. Kavousi, R. Li-Gao, L. Lyytikäinen, R. Marioni, U. Schminke, N. Stitziel, H. Tada, J. van Setten, A. Smith, D. Vojinović, L. Yanek, J. Yao, L. Yerges-Armstrong, N. Amin, U. Baber, I. Borecki, J. Carr, Y. Chen, L. Cupples, P. D. de Jong, H. D. de Koning, B. D. de Vos, A. Demirkan, V. Fuster, O. Franco, M. Goodarzi, T. Harris, S. Heckbert, G. Heiss, U. Hoffmann, A. Hofman, I. Išgum, J. Jukema, M. Kähönen, S. Kardia, B. Kral, L. Launer, J. Massaro, R. Mehran, B. Mitchell, T. Mosley, R. de Mutsert, A. Newman, Khanh-dung Nguyen, K. North, J. O’Connell, M. Oudkerk, J. Pankow, G. Peloso, W. Post, M. Province, L. Raffield, Olli T. Raitakari, Dermot F. Reilly, F. Rivadeneira, F. Rosendaal, S. Sartori, K. Taylor, A. Teumer, S. Trompet, S. Turner, A. Uitterlinden, Dhananjay Vaidya, A. van der Lugt, U. Völker, Joanna M. Wardlaw, C. Wassel, S. Weiss, M. Wojczynski, D. Becker, L. Becker

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引用次数: 38

Abstract

Background—The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results—We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10−10). The APOE &egr;2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10−12) and 1.4% reduced carotid intima–media thickness (P=4×10−14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the &egr;2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of &egr;2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10−11). Conclusions—Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE &egr;2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

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亚临床动脉粥样硬化的多种族外显子组关联研究

背景:无症状个体的亚临床动脉粥样硬化负担是遗传性的，并与临床冠心病发生风险升高相关。我们试图确定与亚临床动脉粥样硬化和随后冠心病风险相关的蛋白质编码区域的遗传变异。方法和结果:在CHARGE联盟(基因组流行病学心脏与衰老研究队列)中，我们研究了25109名欧洲血统和非洲血统的冠状动脉钙化(CAC)患者和52869名颈总动脉内膜-中膜厚度的患者。参与者在整个基因组中对244870个DNA序列变异(231 539个外显子)进行了基因分型。对CAC和颈动脉内膜-中膜厚度的全外显子组相关性研究进行了荟萃分析。APOB p.a g3527gln与4倍的CAC过量相关(P=3×10−10)。与非携带者相比，APOE &egr;2等位基因(p.a g176cys)与携带者CAC降低22.3% (P=1×10−12)和颈动脉内膜-中膜厚度降低1.4% (P=4×10−14)相关。在低密度脂蛋白胆固醇浓度条件下的二次分析中，&egr;2与CAC的保护关联虽然减弱，但仍然非常显著。此外，&egr;2的存在与冠心病风险降低相关(优势比0.77;P = 1×10−11)。结论:外显子组关联荟萃分析表明，APOB和APOE蛋白编码变异与亚临床动脉粥样硬化相关。APOE &egr;2代表了多个亚临床动脉粥样硬化特征和临床冠心病之间的第一个显著关联。

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来源期刊

Circulation-Cardiovascular Genetics CARDIAC & CARDIOVASCULAR SYSTEMS-GENETICS & HEREDITY

CiteScore

3.95

自引率

0.00%

发文量

期刊介绍： Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease. Manuscripts are examined by the editorial staff and usually evaluated by expert reviewers assigned by the editors. Both clinical and basic articles will also be subject to statistical review, when appropriate. Provisional or final acceptance is based on originality, scientific content, and topical balance of the journal. Decisions are communicated by email, generally within six weeks. The editors will not discuss a decision about a manuscript over the phone. All rebuttals must be submitted in writing to the editorial office.