Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.
Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.
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DOI：
10.1016/j.jacc.2016.11.056
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发表时间：
2017-02-21
影响因子：
24
通讯作者：
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
中科院分区：
文献类型：
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作者：
Webb TR;Erdmann J;Stirrups KE;Stitziel NO;Masca NG;Jansen H;Kanoni S;Nelson CP;Ferrario PG;König IR;Eicher JD;Johnson AD;Hamby SE;Betsholtz C;Ruusalepp A;Franzén O;Schadt EE;Björkegren JL;Weeke PE;Auer PL;Schick UM;Lu Y;Zhang H;Dube MP;Goel A;Farrall M;Peloso GM;Won HH;Do R;van Iperen E;Kruppa J;Mahajan A;Scott RA;Willenborg C;Braund PS;van Capelleveen JC;Doney AS;Donnelly LA;Asselta R;Merlini PA;Duga S;Marziliano N;Denny JC;Shaffer C;El-Mokhtari NE;Franke A;Heilmann S;Hengstenberg C;Hoffmann P;Holmen OL;Hveem K;Jansson JH;Jöckel KH;Kessler T;Kriebel J;Laugwitz KL;Marouli E;Martinelli N;McCarthy MI;Van Zuydam NR;Meisinger C;Esko T;Mihailov E;Escher SA;Alver M;Moebus S;Morris AD;Virtamo J;Nikpay M;Olivieri O;Provost S;AlQarawi A;Robertson NR;Akinsansya KO;Reilly DF;Vogt TF;Yin W;Asselbergs FW;Kooperberg C;Jackson RD;Stahl E;Müller-Nurasyid M;Strauch K;Varga TV;Waldenberger M;Wellcome Trust Case Control Consortium;Zeng L;Chowdhury R;Salomaa V;Ford I;Jukema JW;Amouyel P;Kontto J;MORGAM Investigators;Nordestgaard BG;Ferrières J;Saleheen D;Sattar N;Surendran P;Wagner A;Young R;Howson JM;Butterworth AS;Danesh J;Ardissino D;Bottinger EP;Erbel R;Franks PW;Girelli D;Hall AS;Hovingh GK;Kastrati A;Lieb W;Meitinger T;Kraus WE;Shah SH;McPherson R;Orho-Melander M;Melander O;Metspalu A;Palmer CN;Peters A;Rader DJ;Reilly MP;Loos RJ;Reiner AP;Roden DM;Tardif JC;Thompson JR;Wareham NJ;Watkins H;Willer CJ;Samani NJ;Schunkert H;Deloukas P;Kathiresan S;Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
全基因组关联研究迄今已确定了56个与冠状动脉疾病（CAD）风险相关的基因座。许多CAD基因座显示多效性;也就是说，它们也与其他疾病或性状相关。本研究试图系统地测试非CAD疾病/性状的遗传变异是否也与CAD相关，并对所有CAD基因座的多效性程度进行全面分析。在涉及42，335例CAD病例和78，240例对照受试者的发现分析中，我们测试了外显子组阵列上可用的29，383个常见（次要等位基因频率>5%）单核苷酸多态性的关联，其中包括截至2011年与常见疾病或性状相关的大部分已知或疑似单核苷酸多态性。在另外30，533例病例和42，530例对照受试者中复制了暗示性关联信号。为了评估多效性，我们通过询问当前可用的全基因组关联来测试CAD基因座与心血管危险因素（血脂特征、血压表型、体重指数、糖尿病和吸烟行为）以及与其他疾病/特征的关联性研究目录。我们在全基因组范围内发现了6个与CAD相关的新位点：2 q37（KCNJ 13-GIGYF 2），6p 21（C2），11 p15（MRVI 1-CTR 9），12 q13（LRP 1），12 q24（SCARB 1）和16 q13（CETP）。危险等位基因频率范围为0.15至0.86，每拷贝危险等位基因的比值比范围为1.04至1.09。在62个新的和已知的CAD位点中，24个（38.7%）与传统的心血管危险因素有统计学关联，其中一些显示出多种关联，29个（47%）与一系列其他疾病/特征的关联p < 1 × 10−4。我们确定了6个基因座与CAD在全基因组意义。几个CAD基因座显示出显著的多效性，这可能有助于我们了解这些基因座影响CAD风险的机制。
Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.