A functional SNP in ITIH3 is associated with susceptibility to myocardial infarction.
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.
Ebana
Yusuke
Y
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.
Ozaki
Kouichi
K
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.
Inoue
Katsumi
K
Department of Cardiology, Kokura Memorial Hospital, Kitakyushu, 802-8555, Japan.
Sato
Hiroshi
H
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
Iida
Aritoshi
A
Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Lwin
Htay
H
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.
Saito
Susumu
S
Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Mizuno
Hiroya
H
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
Takahashi
Atsushi
A
Laboratory for Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Nakamura
Takahiro
T
Laboratory for Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Miyamoto
Yoshinari
Y
Laboratory for Bone and Joint Disease, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Ikegawa
Shiro
S
Laboratory for Bone and Joint Disease, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Odashiro
Keita
K
Department of Cardiology, Kokura Memorial Hospital, Kitakyushu, 802-8555, Japan.
Nobuyoshi
Masakiyo
M
Department of Cardiology, Kokura Memorial Hospital, Kitakyushu, 802-8555, Japan.
Kamatani
Naoyuki
N
Laboratory for Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Hori
Masatsugu
M
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
Isobe
Mitsuaki
M
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Nakamura
Yusuke
Y
Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Tanaka
Toshihiro
T
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. toshitan@ims.u-tokyo.ac.jp.
D000510:Alpha-Globulins / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000473:pathology; D016022:Case-Control Studies; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D000510:Alpha-Globulins; C011877:inter-alpha-inhibitor