1. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction.
- Author
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Ozaki, Kouichi, Ohnishi, Yozo, Iida, Aritoshi, Sekine, Akihiko, Yamada, Ryo, Tsunoda, Tatsuhiko, Sato, Hiroshi, Sato, Hideyuki, Hori, Masatsugu, Nakamura, Yusuke, and Tanaka, Toshihiro
- Subjects
GENETIC polymorphisms ,TUMOR necrosis factors ,MYOCARDIAL infarction - Abstract
By means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on chromosome 6p21 associated with susceptibility to myocardial infarction. Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-α), NFKBIL1 (encoding nuclear factor of κ light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1). Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, χ
2 = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls). In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery. Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA. These results indicate that variants in the LTA are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder. [ABSTRACT FROM AUTHOR]- Published
- 2002
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