title: A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population.
abstract: Inflammation is now considered critical in the pathogenesis of myocardial infarction. One of the mechanisms regulating the inflammatory process is the ubiquitin-proteasome system. We investigated whether variants of the 20S proteasome are associated with susceptibility to myocardial infarction and found a common SNP (minor allele frequency of 0.35) in the proteasome subunit alpha type 6 gene (PSMA6) conferring risk of myocardial infarction in the Japanese population (chi(2) = 21.1, P = 0.0000044, 2,592 affected individuals versus 2,851 controls). We replicated this association in another panel of myocardial infarction and control subjects, although its relevance to other ethnic groups remains to be clarified. The SNP, located in the 5' untranslated region of exon 1 in this gene, enhanced the transcription of PSMA6. Moreover, suppression of PSMA6 expression using short interfering RNA in cultured cells reduced activation of the transcription factor NF-kappaB by stabilizing phosphorylated IkappaB. Our results implicate this PSMA6 SNP as a previously unknown genetic risk factor for myocardial infarction.
authors.affiliation: 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.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.forename: Hiroya
authors.initials: H
authors.lastname: Mizuno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000483:Alleles; D001402:B-Lymphocytes / Q000201:enzymology; D016022:Case-Control Studies; D002460:Cell Line; D005091:Exons; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics*; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012307:Risk Factors
chemical_list: D009097:Multienzyme Complexes; D034741:RNA, Small Interfering; C465641:PSMA6 protein, human; D046988:Proteasome Endopeptidase Complex