Genomewide association analysis of coronary artery disease.
Genomewide association analysis of coronary artery disease.
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DOI：
10.1056/nejmoa072366
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发表时间：
2007-08-02
期刊：
影响因子：
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通讯作者：
WTCCC and the Cardiogenics Consortium
中科院分区：
文献类型：
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作者：
Samani NJ;Erdmann J;Hall AS;Hengstenberg C;Mangino M;Mayer B;Dixon RJ;Meitinger T;Braund P;Wichmann HE;Barrett JH;König IR;Stevens SE;Szymczak S;Tregouet DA;Iles MM;Pahlke F;Pollard H;Lieb W;Cambien F;Fischer M;Ouwehand W;Blankenberg S;Balmforth AJ;Baessler A;Ball SG;Strom TM;Braenne I;Gieger C;Deloukas P;Tobin MD;Ziegler A;Thompson JR;Schunkert H;WTCCC and the Cardiogenics Consortium
现代基因分型平台允许系统地搜索复杂疾病的遗传成分。我们对冠状动脉疾病的两项全基因组关联研究进行了联合分析。我们首先在威康信托病例对照联盟（WTCCC）研究中（涉及1926例冠心病患者和2938例对照）确定了与冠状动脉疾病密切相关的染色体位点，并在德国心肌梗死家族研究（涉及875例心肌梗死患者和1644例对照）中寻找重复的染色体位点。然后结合两项研究中与冠状动脉疾病显著相关的其他单核苷酸多态性（snp）的数据（P<0.001），以确定具有高概率真实关联的其他位点。两项研究均使用GeneChip Human Mapping 500K Array Set （Affymetrix）进行基因分型。在研究的数千个染色体位点中，在WTCCC和德国的研究中，同一位点与冠状动脉疾病的相关性最强：染色体9p21.3 (SNP, rs1333049) （P=1.80×10−14和P=3.40×10−6）。总的来说，WTCCC研究揭示了9个与冠状动脉疾病密切相关的基因座（P<1.2×10 - 5，假阳性的几率小于50%）。在德国的研究中，除了染色体9p21.3之外，还有两个位点成功复制（调整P<0.05）：染色体6q25.1 （rs6922269）和染色体2q36.3 （rs2943634）。两项研究的综合分析确定了另外四个与冠状动脉疾病显著相关的位点（P<1.3×10−6）和高概率（bbb80 %）的真正关联：染色体1p13.3 (rss599839), 1q41 (rs17465637), 10q11.21 （rs501120）和15q22.33 （rs17228212）。我们确定了几个基因位点，它们单独或总体上对冠状动脉疾病的发生风险有重大影响。
Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80×10−14 and P=3.40×10−6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2×10−5 and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3×10−6) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.