Musunuru Kiran, Post Wendy S, Herzog William, Shen Haiqing, O'Connell Jeffrey R, McArdle Patrick F, Ryan Kathleen A, Gibson Quince, Cheng Yu-Ching, Clearfield Elizabeth, Johnson Andrew D, Tofler Geoffrey, Yang Qiong, O'Donnell Christopher J, Becker Diane M, Yanek Lisa R, Becker Lewis C, Faraday Nauder, Bielak Lawrence F, Peyser Patricia A, Shuldiner Alan R, Mitchell Braxton D
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Circ Cardiovasc Genet. 2010 Oct;3(5):445-53. doi: 10.1161/CIRCGENETICS.109.923508. Epub 2010 Sep 21.
Genome-wide association studies have identified a locus on chromosome 9p21.3 to be strongly associated with myocardial infarction/coronary artery disease and ischemic stroke. To gain insights into the mechanisms underlying these associations, we hypothesized that single nucleotide polymorphisms (SNPs) in this region would be associated with platelet reactivity across multiple populations.
Subjects in the initial population included 1402 asymptomatic Amish adults in whom we measured platelet reactivity (n=788) and coronary artery calcification (CAC) (n=939). Platelet reactivity on agonist stimulation was measured by impedance aggregometry, and CAC was measured by electron beam CT. Twenty-nine SNPs at the 9p21.3 locus were genotyped using the Affymetrix 500K array. Twelve correlated SNPs in the locus were significantly associated with platelet reactivity (all P≤0.001). The SNP most strongly associated with platelet reactivity, rs10965219 (P=0.0002), also was associated with CAC (P=0.002) along with 9 other SNPs (all P<0.004). Association of rs10965219 with platelet reactivity persisted after adjustment for CAC, a measure of underlying atherosclerotic burden known to affect platelet reactivity. We then tested rs10965219 for association with platelet function in 2364 subjects from the Framingham Heart Study and 1169 subjects from the Genetic Study of Aspirin Responsiveness. The rs10965219 G allele (frequency ≈51% across all 3 populations) was significantly associated with higher platelet reactivity in the Framingham Heart Study (P=0.001) and trended toward higher reactivity in the Genetic Study of Aspirin Responsiveness (P=0.087); the combined P value for metaanalysis was 0.0002.
These results suggest that risk alleles at 9p21.3 locus may have pleiotropic effects on myocardial infarction/coronary artery disease and stroke risk, possibly through their influence on platelet reactivity.
全基因组关联研究已确定9号染色体p21.3上的一个基因座与心肌梗死/冠状动脉疾病和缺血性中风密切相关。为深入了解这些关联背后的机制，我们推测该区域的单核苷酸多态性（SNP）与多人群的血小板反应性相关。
初始人群中的受试者包括1402名无症状阿米什成年人，我们测量了他们的血小板反应性（n = 788）和冠状动脉钙化（CAC）（n = 939）。通过阻抗聚集法测量激动剂刺激后的血小板反应性，通过电子束CT测量CAC。使用Affymetrix 500K芯片对9p21.3基因座上的29个SNP进行基因分型。该基因座上的12个相关SNP与血小板反应性显著相关（所有P≤0.001）。与血小板反应性最密切相关的SNP，rs10965219（P = 0.0002），也与CAC相关（P = 0.002），以及其他9个SNP（所有P<0.004）。在校正了CAC（一种已知会影响血小板反应性的潜在动脉粥样硬化负担指标）后，rs10965219与血小板反应性的关联仍然存在。然后，我们在来自弗雷明汉心脏研究的2364名受试者和来自阿司匹林反应性基因研究的1169名受试者中测试了rs10965219与血小板功能的关联。rs10965219 G等位基因（在所有3个人群中的频率约为51%）在弗雷明汉心脏研究中与较高的血小板反应性显著相关（P = 0.001），在阿司匹林反应性基因研究中倾向于较高的反应性（P = 0.087）；荟萃分析的合并P值为0.0002。
这些结果表明，9p21.3基因座上的风险等位基因可能对心肌梗死/冠状动脉疾病和中风风险具有多效性影响，可能是通过它们对血小板反应性的影响。
