Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction.
Through a large-scale case-control association study using 52,608 haplotype-based single nucleotide polymorphism (SNP) markers, we identified a susceptible locus for myocardial infarction (MI) on chromosome 22q12.1. Following linkage disequilibrium (LD) mapping, haplotype analyses revealed that six SNPs in this locus, all of which were in complete LD, showed markedly significant association with MI (chi2=25.27, P=0.0000005; comparison of allele frequency, 3,435 affected individuals versus 3,774 controls, in the case of intron 1 5,338 C>T; rs2331291). Within this locus, we isolated a complete cDNA of a novel gene, designated myocardial infarction associated transcript (MIAT). MIAT has five exons, and in vitro translation assay showed that MIAT did not encode any translational product, indicating that this is likely to be a functional RNA. In vitro functional analyses revealed that the minor variant of one SNP in exon 5 increased transcriptional level of the novel gene. Moreover, unidentified nuclear protein(s) bound more intensely to risk allele than non-risk allele. These results indicate that the altered expression of MIAT by the SNP may play some role in the pathogenesis of MI.
Ishii
Nobuaki
N
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.|Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 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.
Sato
Hiroshi
H
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Mizuno
Hiroya
H
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Susumu Saito
Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Takahashi
Atsushi
A
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.
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 Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Satoshi Saito
Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
Nakamura
Yusuke
Y
Laboratory for Genotyping, 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.
D000483:Alleles; D016022:Case-Control Studies; D002892:Chromosomes, Human, Pair 22; D024202:Electrophoretic Mobility Shift Assay; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D009203:Myocardial Infarction / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020871:RNA Stability / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D012307:Risk Factors; D014158:Transcription, Genetic
D005819:Genetic Markers; C517383:Miat long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated