Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Eur J Hum Genet. 2012 Mar;20(3):333-40. doi: 10.1038/ejhg.2011.184. Epub 2011 Oct 5.
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=1.6 × 10(-34)), HLA-DQB1 on 6p21 (P=4.7 × 10(-7)), and CDKN2A/B on 9p21 (P=6.1 × 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=1.4 × 10(-40)). On 6p21, an HLA allele, DQB1(*)0604, could show one of the most prominent association signals in an ∼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.
冠心病（CAD）的遗传基础的新认识最近已经从常见单核苷酸多态性（SNPs）的全基因组关联（GWA）研究中出现，迄今为止，这些研究主要在欧洲裔人群中进行。为了确定 CAD 的新的易感基因变异，并确认那些主要在欧洲裔人群中发现的变异，在日本人中进行了多阶段 GWA 研究。在发现阶段，我们首先对 806 例病例和 1337 例对照进行了 451382 个 SNP 标记的基因分型，随后对 34 个选定的 SNP 进行了直接基因分型（541 例额外病例）和基于计算机的比较（964 例健康对照）。在涉及 3052 例病例和 6335 例对照的复制阶段，测试了 12 个 SNP；有 4 个（12 个中的 4 个）来自 3 个位点的 SNP 得到了 CAD 关联的复制和/或验证：12q24 上的 BRAP 和 ALDH2 附近（P=1.6×10(-34)），6p21 上的 HLA-DQB1（P=4.7×10(-7)）和 9p21 上的 CDKN2A/B（P=6.1×10(-16)）。在 12q24 上，我们发现了与心肌梗死病例亚组关联强度明显增强的最强关联信号（P=1.4×10(-40)）。在 6p21 上，一个 HLA 等位基因 DQB1(*)0604，可能在一个包含 LTA 基因的约 8-Mb 间隔内显示出最显著的关联信号，在另一项日本研究中，该基因与心肌梗死有关。在 CDKN2A/B 上也发现了 CAD 关联，这在不同的欧洲裔和亚洲人群中已有报道。因此，在日本 GWA 研究中证实的三个位点突出了在 CAD 易感性中存在两种遗传效应的风险等位基因 - 人群特异性和常见 - 的可能性。
