Genome-wide association study of coronary artery disease in the Japanese
Genome-wide association study of coronary artery disease in the Japanese
复制标题
DOI：
10.1038/ejhg.2011.184
复制
发表时间：
2012-03-01
影响因子：
5.2
通讯作者：
Kato, Norihiro
中科院分区：
文献类型：
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作者：
Takeuchi, Fumihiko;Yokota, Mitsuhiro;Kato, Norihiro
最近，对常见单核苷酸多态性（SNP）的全基因组关联（GWA）研究得出了对冠状动脉疾病（CAD）遗传基础的新认识，迄今为止，这些研究主要在欧洲血统人群中进行。为了识别 CAD 的新易感基因变异并确认之前主要在欧洲血统人群中发现的变异，在日本人中进行了一项多阶段 GWA 研究。在发现阶段，我们首先使用 451 382 个 SNP 标记对 806 个病例和 1337 个对照进行基因分型，随后通过直接基因分型（另外 541 个病例）和计算机比较（964 个健康对照）评估了 34 个选定的 SNP。在复制阶段，涉及3052个病例和6335个对照，测试了12个SNP；对来自 3 个位点的 4 个（共 12 个）SNP 复制和/或验证了 CAD 关联：12q24 上的 BRAP 和 ALDH2 附近 (P=1.6x10(-34))、6p21 上的 HLA-DQB1 (P=4.7x10(-7)) 和 9p21 上的 CDKN2A/B (P=6.1 x 10（-16））。在 12q24 上，我们确定了最强的关联信号，其关联强度对于心肌梗塞病例亚组而言非常明显 (P=1.4x10(-40))。在 6p21，HLA 等位基因 DQB1*0604 可以在包含 LTA 基因的类似于 8 Mb 间隔中显示出最显着的关联信号之一，另一项日本研究报告了该信号与心肌梗塞的关联。正如之前在欧洲血统和亚洲人的不同人群中报道的那样，CDKN2A/B 也发现了 CAD 关联。因此，日本 GWA 研究中确认的三个位点强调了可能存在风险等位基因，这些基因对 CAD 易感性具有两种类型的遗传效应（人群特异性和常见）。欧洲人类遗传学杂志 (2012) 20, 333-340; doi：10.1038/ejhg.2011.184； 2011 年 10 月 5 日在线发布
A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6x10(-34)), HLA-DQB1 on 6p21 (P=4.7x10(-7)), and CDKN2A/B on 9p21 (P=6.1 x 10(-16)). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4x10(-40)). On 6p21, an HLA allele, DQB1*0604, could show one of the most prominent association signals in an similar to 8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects - population specific and common - on susceptibility to CAD. European Journal of Human Genetics (2012) 20, 333-340; doi:10.1038/ejhg.2011.184; published online 5 October 2011