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

Nat Genet. 2002 Dec;32(4):650-4. doi: 10.1038/ng1047. Epub 2002 Nov 11.

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-alpha), NFKBIL1 (encoding nuclear factor of kappa 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, chi(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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Substitution
  • Case-Control Studies
  • Cells, Cultured
  • Chromosome Mapping
  • Chromosomes, Human, Pair 6
  • Coronary Vessels / metabolism
  • Databases, Genetic
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Genotype
  • Haplotypes
  • Homozygote
  • Humans
  • Introns
  • Jurkat Cells
  • Linkage Disequilibrium
  • Lymphotoxin-alpha / genetics*
  • Middle Aged
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / physiology
  • Myocardial Infarction / genetics*
  • Polymorphism, Single Nucleotide*
  • Recombinant Fusion Proteins / metabolism
  • Sequence Analysis, DNA
  • Transcription, Genetic
  • Vascular Cell Adhesion Molecule-1 / biosynthesis

Substances

  • Lymphotoxin-alpha
  • Recombinant Fusion Proteins
  • Vascular Cell Adhesion Molecule-1