Ding Hu, Xu Yujun, Wang Xiaojing, Wang Qi, Zhang Lan, Tu Yuanchao, Yan Jiangtao, Wang Wei, Hui Rutai, Wang Cong-Yi, Wang Dao Wen
Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Circ Cardiovasc Genet. 2009 Aug;2(4):338-46. doi: 10.1161/CIRCGENETICS.108.810226. Epub 2009 May 28.
Recent studies on genome-wide association have identified common variants on chromosome 9p21 associated with coronary artery disease (CAD). Given that ischemic stroke and CAD share several aspects of etiology and pathogenesis, we investigated the association of variants on chromosome 9p21 with ischemic stroke and CAD in the Chinese Han population by capturing the majority of diversity in this locus using haplotype-tagging single-nucleotide polymorphisms.
We performed a shared control-cases study using 15 tagging single-nucleotide polymorphisms and 2 previously reported susceptibility single-nucleotide polymorphisms spanning 58 kb of the chromosome of 9p21 in a set of 558 patients with ischemic stroke, 510 patients with CAD, and 557 unaffected participants (controls) in the Chinese Han population. The association analyses were performed at both SNP and haplotype levels. We further verified our findings in an independent cohort of 442 ischemic stroke cases and 502 control subjects. In the first study, rs2383206, rs1004638, and rs10757278 in block 3 were significantly associated with CAD but not with ischemic stroke independent of traditional cardiovascular risk factors in additive model (P = 0.002 to 0.0001, q = 0.026 to 0.004). Analysis from all blocks revealed that haplotype profiles of block 3 on 9p21 were significantly different between shared control and cases of CAD (P = 1.3 x 10(-10), q = 1.2 x 10(-9)) and ischemic stroke (P = 1.7 x 10(-6), q = 7.7 x 10(-6)). In the expanded second case-control study, block 3 on 9p21 remained associated with ischemic stroke (P = 2.6 x 10(-4), q = 6.3 x 10(-4)).
Our results suggest for the first time that 9p21 is a shared susceptibility locus, strongly for CAD and weakly for ischemic stroke, in a Chinese Han population.
近期全基因组关联研究已确定9号染色体短臂2区1带（9p21）上的常见变异与冠状动脉疾病（CAD）相关。鉴于缺血性卒中和CAD在病因和发病机制方面有若干共同之处，我们通过使用单倍型标签单核苷酸多态性捕获该位点的大部分多样性，在中国汉族人群中研究了9p21上的变异与缺血性卒中和CAD的关联。
我们在中国汉族人群的558例缺血性卒中患者、510例CAD患者和557名未受影响的参与者（对照）中，使用15个标签单核苷酸多态性和2个先前报道的易感单核苷酸多态性进行了一项共享对照-病例研究，这些多态性跨越9p21染色体的58 kb。关联分析在单核苷酸多态性（SNP）和单倍型水平上进行。我们在一个由442例缺血性卒中病例和502名对照受试者组成的独立队列中进一步验证了我们的发现。在第一项研究中，3号区域的rs2383206、rs1004638和rs10757278在加性模型中与CAD显著相关，但与缺血性卒中无关，且独立于传统心血管危险因素（P = 0.002至0.0001，q = 0.026至0.004）。对所有区域的分析显示，9p21上3号区域的单倍型图谱在共享对照与CAD病例（P = 1.3×10⁻¹⁰，q = 1.2×10⁻⁹）和缺血性卒中病例（P = 1.7×10⁻⁶，q = 7.7×10⁻⁶）之间存在显著差异。在扩大的第二项病例对照研究中，9p21上的3号区域仍与缺血性卒中相关（P = 2.6×10⁻⁴，q = 6.3×10⁻⁴）。
我们的结果首次表明，在汉族人群中，9p21是一个共享的易感位点，对CAD影响较强，对缺血性卒中影响较弱。
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