久山町研究を基盤とした脳梗塞のゲノムワイド関連遺伝子研究

抄録

Ischemic stroke is a major cause of death and disability, and occurs owing to a combination of multiple environmental and genetic risk factors. Although twin studies and family-based studies have suggested the existence of genetic risk factors for ischemic stroke, few candidate genes have been discovered. To identify genes for susceptibility to ischemic stroke, we performed a genome-wide association study using 52,608 single nucleotide polymorphism (SNP) markers. After comparison of allele frequencies between 1,112 patients with ischemic stroke and the same number of age- and sex-matched control subjects, who were selected from among the residents of the town of Hisayama, Japan, we identified three novel candidate genes for ischemic stroke: PRKCH (protein kinase C eta (PKCη)), AGTRL1 (apelin receptor), and ARHGEF10 (Rho guanine nucleotide exchange factor 10). In the functional analyses, we found that PKCη was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and that the kinase activity of PKCη was modified by a nonsynonymous SNP in PRKCH (rs2230500). We also clarified that functional SNPs in AGTRL1 (rs9943582) and ARHGEF10 (rs4376531) affected transcriptional activities owing to the different Sp1-binding affinities. In a 14-year follow-up cohort study of Hisayama residents, all of these SNPs were significantly associated with the development of ischemic stroke. Although the mechanisms of these genes in the pathogenesis of ischemic stroke are still to be elucidated, our findings might contribute to a better understanding of ischemic stroke in the future.