Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.
Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.
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DOI：
10.1371/journal.pgen.1001167
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发表时间：
2010-10-21
期刊：
影响因子：
4.5
通讯作者：
Hengstenberg C
中科院分区：
文献类型：
--
作者：
Stark K;Esslinger UB;Reinhard W;Petrov G;Winkler T;Komajda M;Isnard R;Charron P;Villard E;Cambien F;Tiret L;Aumont MC;Dubourg O;Trochu JN;Fauchier L;Degroote P;Richter A;Maisch B;Wichter T;Zollbrecht C;Grassl M;Schunkert H;Linsel-Nitschke P;Erdmann J;Baumert J;Illig T;Klopp N;Wichmann HE;Meisinger C;Koenig W;Lichtner P;Meitinger T;Schillert A;König IR;Hetzer R;Heid IM;Regitz-Zagrosek V;Hengstenberg C
扩张型心肌病(DCM)是一种遗传背景较强的结构性心脏病。DCM的单基因形式见于突变主要位于编码结构蛋白和肌瘤蛋白的基因中的家族。然而，强有力的证据表明，遗传因素也影响特发性扩张型心肌病的易感性。为了确定非家族性DCM的风险等位基因，我们开展了一项病例对照关联研究，使用50K人类心血管疾病珠芯片对来自德国的664例DCM病例和1874名基于人群的健康对照进行了基因分型，该芯片涵盖了预先选择的2000多个与心血管相关的基因。在质量控制后，对30,920个单核苷酸多态(SNP)进行了性别校正的Logistic回归分析，并对结果进行了基因组对照校正。分析发现，HSPB7基因的单核苷酸多态(rs1739843，小等位基因频率为39%)与特发性扩张型心肌病(p = 1.06×10−6，或小等位基因T的 = 为0.67[95%CI为0.57~0.79])显著相关。另有3个SNPs显示P<；2.21×10−5。这4个SNPs在3个独立的特发性扩张性心肌病病例对照研究中进行了重新基因分型。在所有复制样本中，SNP rs1739843与扩张型心肌病显著相关：德国(n = 564，n = 981对照，p = 2.07×10−3，OR = 0.79[95%CI 0.67-0.92])，法国1(n = 433例，n = 395对照，p = 3.73×10−3，OR = 0.74[95%CI 0.60-0.91])，法国2(n = 249例，n = 380对照，P = 2.2 6×10−4，OR = 0.6 3[95%CI 0.5 0~0.81]。对所有四项研究，包括n = 1,910例和n = 3,630例的联合分析表明，rs1739843与特发性扩张型心肌梗死有非常显著的相关性(p = 5.28×10−13，OR = 0.72[95%CI 0.65-0.78])。在复制阶段，其他三个SNP均未显示出显著效果。利用一个大型SNP小组对特发性扩张型心肌病进行遗传搜索的HSPB7基因的这一发现强调了常见的多态对扩张型心肌病易感性的影响。扩张型心肌病是一种严重的心肌疾病，通常会导致慢性心力衰竭，最终导致心脏移植的后果。在高危人群中识别遗传病标记物在预防保健中可能发挥重要作用。描述了这种疾病的几种家族形式的突变。在这里，我们研究了常见的基因变异在散发性扩张型心肌病中的作用。通过在1900多名患者和3600名对照中筛选约2000个以前与心血管疾病相关的候选基因，我们发现HSPB7基因(Rs1739843)的多态性与扩张型心肌病的易感性密切相关。我们还表明，这种对疾病风险的影响在德国和法国的队列中都存在。因此，这项研究是揭示散发性扩张型心肌病遗传背景的重要一步。
Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility. Dilated cardiomyopathy is a severe disease of the heart muscle and often leads to chronic heart failure, eventually with the consequence of cardiac transplantation. Identification of genetic disease markers in at-risk persons could play an important role in preventive health care. Several mutations in familial forms of the disease are described. Here, we examine the role of common genetic variants on the sporadic form of dilated cardiomyopathy. By screening about 2,000 candidate genes previously related to cardiovascular disease in more than 1,900 cases and 3,600 controls, we show that a polymorphism in the HSPB7 gene (rs1739843) is strongly associated with susceptibility to dilated cardiomyopathy. We also show that the effect on disease risk is present in both German and French cohorts. Therefore, this study is an important step towards revealing insight in the genetic background of the sporadic form of dilated cardiomyopathy.
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影响因子：
37.8
作者：
CODD, MB;SUGRUE, DD;MELTON, LJ
通讯作者：
MELTON, LJ
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
30.8
作者：
Bione, S;DAdamo, P;Toniolo, D
通讯作者：
Toniolo, D
影响因子：
5.8
作者：
Johnson, Andrew D.;Handsaker, Robert E.;de Bakker, Paul I. W.
通讯作者：
de Bakker, Paul I. W.
影响因子：
15.8
作者：
Ioannidis, JPA
通讯作者：
Ioannidis, JPA