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Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction

  • An Erratum to this article was published on 01 January 2003

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, χ2 = 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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Acknowledgements

We thank Y. Ariji, M. Yoshii, M. Omotezako, S. Abiko and K. Tabei for their assistance; H. Kawakami, A. Takahashi and M. Yamaguchi for their expertise in computer programming; M. Takahashi for her excellent technical expertise; and all the other members of SNP Research Center, The Institute of Physical and Chemical Research and Osaka Acute Coronary Insufficiency Study for their contribution to the completion of our study. This work was supported by a grant from the Japanese Millennium Project.

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The authors declare no competing financial interests.

Correspondence to Toshihiro Tanaka.

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Figure 1: Linkage disequilibrium and haplotype block in the genomic region including the LTA locus.
Figure 2: Transcriptional regulatory activity affected by SNPs.
Figure 3: Differing abilities of 26Asn-LTA and 26Thr-LTA to induce mRNA expression of adhesion molecules.