Samani Nilesh J, Erdmann Jeanette, Hall Alistair S, Hengstenberg Christian, Mangino Massimo, Mayer Bjoern, Dixon Richard J, Meitinger Thomas, Braund Peter, Wichmann H-Erich, Barrett Jennifer H, König Inke R, Stevens Suzanne E, Szymczak Silke, Tregouet David-Alexandre, Iles Mark M, Pahlke Friedrich, Pollard Helen, Lieb Wolfgang, Cambien Francois, Fischer Marcus, Ouwehand Willem, Blankenberg Stefan, Balmforth Anthony J, Baessler Andrea, Ball Stephen G, Strom Tim M, Braenne Ingrid, Gieger Christian, Deloukas Panos, Tobin Martin D, Ziegler Andreas, Thompson John R, Schunkert Heribert
University of Leicester, Leicester, United Kingdom.
N Engl J Med. 2007 Aug 2;357(5):443-53. doi: 10.1056/NEJMoa072366. Epub 2007 Jul 18.
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=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-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<1.3x10(-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.
现代基因分型平台允许对复杂疾病的遗传成分进行系统搜索。我们对两项冠状动脉疾病的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研究联盟（WTCCC）研究中（该研究涉及1926例冠状动脉疾病病例和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中（该研究涉及875例心肌梗死病例和1644例对照）寻找其重复性。然后将两项研究中任何一项与冠状动脉疾病显著相关（P<0.001）的其他单核苷酸多态性（SNP）数据合并，以确定具有高真实关联可能性的其他位点。两项研究均使用基因芯片人类图谱500K阵列集（Affymetrix）进行基因分型。
在研究的数千个染色体位点中，WTCCC研究和德国研究中与冠状动脉疾病关联最强的是同一位点：9号染色体p21.3区域（SNP，rs1333049）（P值分别为1.80×10⁻¹⁴和3.40×10⁻⁶）。总体而言，WTCCC研究发现了9个与冠状动脉疾病密切相关的位点（P<1.2×10⁻⁵且假阳性概率小于50%）。除9号染色体p21.3区域外，其中两个位点在德国研究中成功得到重复验证（校正P<0.05）：6号染色体q25.1区域（rs6922269）和2号染色体q36.3区域（rs2943634）。两项研究的联合分析确定了另外四个与冠状动脉疾病显著相关（P<1.3×10⁻⁶）且具有高真实关联可能性（>80%）的位点：1号染色体p13.3区域（rs599839）、1号染色体q41区域（rs17465637）、10号染色体q11.21区域（rs501120）和15号染色体q22.33区域（rs17228212）。
我们确定了几个遗传位点，这些位点单独或共同对冠状动脉疾病的发生风险有重大影响。
