Nature Genetics
32, 650 - 654 (2002)
Published online: 11 November 2002; | doi:10.1038/ng1047
There is an Erratum (January 2003) associated with this Letter.
Functional SNPs in the lymphotoxin- gene that are associated with susceptibility to myocardial infarctionKouichi Ozaki1, Yozo Ohnishi1, Aritoshi Iida2, Akihiko Sekine2, Ryo Yamada3, Tatsuhiko Tsunoda4, Hiroshi Sato5, Hideyuki Sato5, Masatsugu Hori5, Yusuke Nakamura2, 6
& Toshihiro Tanaka11
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. 2
Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. 3
Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. 4
Laboratory for Medical Informatics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. 5
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan. 6
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Correspondence should be addressed to Toshihiro Tanaka toshitan@ims.u-tokyo.ac.jpBy 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- ), NFKBIL1 (encoding nuclear factor of  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,  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.
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by activated B cell factor-1
