Yamada Yoshiji, Sakuma Jun, Takeuchi Ichiro, Yasukochi Yoshiki, Kato Kimihiko, Oguri Mitsutoshi, Fujimaki Tetsuo, Horibe Hideki, Muramatsu Masaaki, Sawabe Motoji, Fujiwara Yoshinori, Taniguchi Yu, Obuchi Shuichi, Kawai Hisashi, Shinkai Shoji, Mori Seijiro, Arai Tomio, Tanaka Masashi
Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan.
CREST, Japan Science and Technology Agency, Kawaguchi, Japan.
Oncotarget. 2017 May 16;8(20):33527-33535. doi: 10.18632/oncotarget.16536.
We performed exome-wide association studies to identify genetic variants-in particular, low-frequency variants with a large effect size-that confer susceptibility to coronary artery disease or myocardial infarction in Japanese. The exome-wide association studies were performed with 12,698 individuals (3488 subjects with coronary artery disease including 2438 with myocardial infarction, 9210 controls) and with the use of the Illumina HumanExome-12 DNA Analysis or Infinium Exome-24 BeadChip. The relation of allele frequencies for 41,339 single nucleotide polymorphisms that passed quality control to coronary artery disease or myocardial infarction was examined with Fisher's exact test. The exome-wide association study for coronary artery disease revealed that 126 single nucleotide polymorphisms were significantly (P <1.21 × 10-6) associated with this condition. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus, and dyslipidemia showed that six of these polymorphisms were related (P < 0.01) to coronary artery disease, but none was significantly (P < 9.92 × 10-5) associated with this condition. The exome-wide association study for myocardial infarction revealed that 114 single nucleotide polymorphisms were significantly (P <1.21 × 10-6) associated with this condition. Multivariable logistic regression analysis with adjustment for covariates revealed that nine of these polymorphisms were related (P < 0.01) to myocardial infarction. Among these nine polymorphisms, rs188212047 [G/T (L212F)] of STXBP2 was significantly (dominant model; P = 4.84 × 10-8; odds ratio, 2.94) associated with myocardial infarction. STXBP2 may thus be a novel susceptibility locus for myocardial infarction in Japanese.
我们开展了全外显子组关联研究，以识别在日本人中导致冠状动脉疾病或心肌梗死易感性的基因变异，尤其是那些效应大小较大的低频变异。全外显子组关联研究纳入了12,698名个体（3488例冠状动脉疾病患者，其中包括2438例心肌梗死患者，9210例对照），并使用了Illumina HumanExome-12 DNA分析芯片或Infinium Exome-24 BeadChip芯片。采用Fisher精确检验分析了41,339个通过质量控制的单核苷酸多态性的等位基因频率与冠状动脉疾病或心肌梗死之间的关系。冠状动脉疾病的全外显子组关联研究显示，126个单核苷酸多态性与该疾病显著相关（P <1.21×10-6）。在对年龄、性别以及高血压、糖尿病和血脂异常患病率进行校正的多变量逻辑回归分析中，这些多态性中有6个与冠状动脉疾病相关（P < 0.01），但均未与该疾病显著相关（P < 9.92×10-5）。心肌梗死的全外显子组关联研究显示，114个单核苷酸多态性与该疾病显著相关（P <1.21×10-6）。对协变量进行校正的多变量逻辑回归分析显示，这些多态性中有9个与心肌梗死相关（P < 0.01）。在这9个多态性中，STXBP2基因的rs188212047 [G/T (L212F)]与心肌梗死显著相关（显性模型；P = 4.84×10-8；比值比，2.94）。因此，STXBP2可能是日本人中一个新的心肌梗死易感基因座。
