Ebana Yusuke, Ozaki Kouichi, Inoue Katsumi, Sato Hiroshi, Iida Aritoshi, Lwin Htay, Saito Susumu, Mizuno Hiroya, Takahashi Atsushi, Nakamura Takahiro, Miyamoto Yoshinari, Ikegawa Shiro, Odashiro Keita, Nobuyoshi Masakiyo, Kamatani Naoyuki, Hori Masatsugu, Isobe Mitsuaki, Nakamura Yusuke, Tanaka Toshihiro
Laboratory for Cardiovascular Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
J Hum Genet. 2007;52(3):220-229. doi: 10.1007/s10038-006-0102-5. Epub 2007 Jan 9.
Myocardial infarction (MI) results from complex interactions of multiple genetic and environmental factors. To disclose genetic backgrounds of MI, we performed a large-scale, case-control association study using 52,608 gene-based single-nucleotide polymorphism (SNP) markers, and identified a candidate SNP located on chromosome 3p21.2-p21.1. Subsequent linkage-disequilibrium mapping indicated very significant association between MI and a SNP in exon 2 of the inter-alpha (globulin) inhibitor 3 gene (ITIH3; chi(2) = 24.88, P = 6.1 x 10(-7), 3,353 affected individuals versus 3,807 controls). In vitro functional analyses showed that this SNP enhanced the transcriptional level of the ITIH3 gene. Furthermore, we found expression of the ITIH3 protein in the vascular smooth muscle cells and macrophages in the human atherosclerotic lesions, suggesting ITIH3 SNP to be a novel genetic risk factor of MI.
心肌梗死（MI）是多种遗传和环境因素复杂相互作用的结果。为了揭示MI的遗传背景，我们使用52,608个基于基因的单核苷酸多态性（SNP）标记进行了一项大规模病例对照关联研究，并鉴定出一个位于3号染色体p21.2 - p21.1上的候选SNP。随后的连锁不平衡图谱分析表明，MI与α-（球蛋白）抑制剂3基因（ITIH3）第2外显子中的一个SNP之间存在非常显著的关联（卡方 = 24.88，P = 6.1×10⁻⁷，3353例患者与3807例对照）。体外功能分析表明，该SNP提高了ITIH3基因的转录水平。此外，我们发现ITIH3蛋白在人类动脉粥样硬化病变的血管平滑肌细胞和巨噬细胞中表达，提示ITIH3 SNP是MI的一个新的遗传危险因素。
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