对基因多效性的系统评估确定了另外6个与冠状动脉疾病相关的基因座。
Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.
作者信息
Webb Thomas R, Erdmann Jeanette, Stirrups Kathleen E, Stitziel Nathan O, Masca Nicholas G D, Jansen Henning, Kanoni Stavroula, Nelson Christopher P, Ferrario Paola G, König Inke R, Eicher John D, Johnson Andrew D, Hamby Stephen E, Betsholtz Christer, Ruusalepp Arno, Franzén Oscar, Schadt Eric E, Björkegren Johan L M, Weeke Peter E, Auer Paul L, Schick Ursula M, Lu Yingchang, Zhang He, Dube Marie-Pierre, Goel Anuj, Farrall Martin, Peloso Gina M, Won Hong-Hee, Do Ron, van Iperen Erik, Kruppa Jochen, Mahajan Anubha, Scott Robert A, Willenborg Christina, Braund Peter S, van Capelleveen Julian C, Doney Alex S F, Donnelly Louise A, Asselta Rosanna, Merlini Pier A, Duga Stefano, Marziliano Nicola, Denny Josh C, Shaffer Christian, El-Mokhtari Nour Eddine, Franke Andre, Heilmann Stefanie, Hengstenberg Christian, Hoffmann Per, Holmen Oddgeir L, Hveem Kristian, Jansson Jan-Håkan, Jöckel Karl-Heinz, Kessler Thorsten, Kriebel Jennifer, Laugwitz Karl L, Marouli Eirini, Martinelli Nicola, McCarthy Mark I, Van Zuydam Natalie R, Meisinger Christa, Esko Tõnu, Mihailov Evelin, Escher Stefan A, Alver Maris, Moebus Susanne, Morris Andrew D, Virtamo Jarma, Nikpay Majid, Olivieri Oliviero, Provost Sylvie, AlQarawi Alaa, Robertson Neil R, Akinsansya Karen O, Reilly Dermot F, Vogt Thomas F, Yin Wu, Asselbergs Folkert W, Kooperberg Charles, Jackson Rebecca D, Stahl Eli, Müller-Nurasyid Martina, Strauch Konstantin, Varga Tibor V, Waldenberger Melanie, Zeng Lingyao, Chowdhury Rajiv, Salomaa Veikko, Ford Ian, Jukema J Wouter, Amouyel Philippe, Kontto Jukka, Nordestgaard Børge G, Ferrières Jean, Saleheen Danish, Sattar Naveed, Surendran Praveen, Wagner Aline, Young Robin, Howson Joanna M M, Butterworth Adam S, Danesh John, Ardissino Diego, Bottinger Erwin P, Erbel Raimund, Franks Paul W, Girelli Domenico, Hall Alistair S, Hovingh G Kees, Kastrati Adnan, Lieb Wolfgang, Meitinger Thomas, Kraus William E, Shah Svati H, McPherson Ruth, Orho-Melander Marju, Melander Olle, Metspalu Andres, Palmer Colin N A, Peters Annette, Rader Daniel J, Reilly Muredach P, Loos Ruth J F, Reiner Alex P, Roden Dan M, Tardif Jean-Claude, Thompson John R, Wareham Nicholas J, Watkins Hugh, Willer Cristen J, Samani Nilesh J, Schunkert Heribert, Deloukas Panos, Kathiresan Sekar
机构信息
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; University Heart Center Luebeck, Lübeck, Germany.
出版信息
J Am Coll Cardiol. 2017 Feb 21;69(7):823-836. doi: 10.1016/j.jacc.2016.11.056.
BACKGROUND
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.
OBJECTIVES
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.
METHODS
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.
RESULTS
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 with a range of other diseases/traits.
CONCLUSIONS
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.
背景
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基因座表现出多效性；也就是说，它们也与其他疾病或性状相关。
目的
本研究旨在系统测试为非CAD疾病/性状鉴定的基因变异是否也与CAD相关，并对所有CAD基因座的多效性程度进行全面分析。
方法
在涉及42335例CAD病例和78240例对照受试者的发现性分析中，我们测试了外显子阵列上29383个常见（次要等位基因频率>5%）单核苷酸多态性的关联性，其中包括截至2011年与常见疾病或性状相关的已知或疑似单核苷酸多态性的很大一部分。在另外30533例病例和42530例对照受试者中对提示性关联信号进行了重复验证。为了评估多效性，我们通过查询当前可用的全基因组关联研究目录，测试CAD基因座与心血管危险因素（血脂性状、血压表型、体重指数、糖尿病和吸烟行为）以及其他疾病/性状的关联性。
结果
我们在全基因组显著性水平上鉴定出6个与CAD相关的新基因座：位于2q37（KCNJ13 - GIGYF2）、6p21（C2）、11p15（MRVI1 - CTR9）、12q13（LRP1）、12q24（SCARB1）和16q13（CETP）。风险等位基因频率范围为0.15至0.86，每个风险等位基因拷贝的比值比范围为1.04至1.09。在62个新的和已知的CAD基因座中，24个（38.7%）与传统心血管危险因素存在统计学关联，有些表现出多种关联，29个（47%）在p < 1×10时与一系列其他疾病/性状存在关联。
结论
我们在全基因组显著性水平上鉴定出6个与CAD相关的基因座。几个CAD基因座表现出显著的多效性，这可能有助于我们理解这些基因座影响CAD风险的机制。
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