Large scale association analysis of novel genetic loci for coronary artery disease.
Large scale association analysis of novel genetic loci for coronary artery disease.
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冠状动脉疾病的新遗传基因座的大规模关联分析。
DOI：
10.1161/atvbaha.108.181388
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发表时间：
2009-05
期刊：
影响因子：
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通讯作者：
Ziegler A
中科院分区：
文献类型：
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作者：
Coronary Artery Disease Consortium;Samani NJ;Deloukas P;Erdmann J;Hengstenberg C;Kuulasmaa K;McGinnis R;Schunkert H;Soranzo N;Thompson J;Tiret L;Ziegler A
最近对家族史丰富病例中的 2 项全基因组关联研究进行了综合分析，发现了 7 个可能影响冠状动脉疾病 (CAD) 风险的位点（位于 1p13.3、1q41、2q36.3、6q25.1、9p21、10q11.21 和 15q22.33）。除了9p21位点外，其他位点等待实质性复制。此外，这些位点对更广泛个体的 CAD 风险的影响仍有待确定。我们对来自 9 项欧洲研究的 11 550 例病例和 11 205 例对照的每个基因座的单核苷酸多态性与 CAD 风险进行了关联分析。 9p21.3 位点显示出明确的关联（rs1333049，组合优势比 [OR]=1.20，95% CI [1.16 至 1.25]，概率值=2.81×10−21）。我们还确认了 1p13.3（rs599839，OR=1.13 [1.08 至 1.19]，P=1.44×10−7）、1q41（rs3008621，OR=1.10 [1.04 至 1.17]，P=1.02×10−3）和 10q11.21 处的关联信号（rs501120，OR=1.11 [1.05 至 1.18]， P=4.34×10−4).与6q25.1（rs6922269，P = 0.020）和2q36.3（rs2943634，P = 0.032）的关联处于临界状态，并且在多次测试校正后没有统计学意义。 15q22.33 基因座没有复制。 10q11.21位点显示出可能的性别相互作用（P = 0.015），对女性有显着影响（OR = 1.29 [1.15至1.45]，P = 1.86×10−5），但对男性则没有显着影响（OR = 1.03 [0.96至1.11]，P = 0.387）。任何基因座与其他传统风险因素没有其他强烈的相互作用。 9p21、1p13.3、2q36.3 和 10q11.21 的基因座独立发挥作用，每增加一个风险等位基因，CAD 风险累计增加 15%（12% 至 18%）。这些发现为至少 4 个基因位点与 CAD 风险之间的关联提供了强有力的证据。总的来说，这些新基因座至少对欧洲人群的 CAD 风险具有重大影响。
Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81×10−21). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44×10−7), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02×10−3), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34×10−4). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P=0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86×10−5) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.