RRC ID 41722
Author Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, Tsunoda T, Sato H, Sato H, Hori M, Nakamura Y, Tanaka T.
Title Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.
Journal Nat Genet
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.
Volume 32(4)
Pages 650-4
Published 2002-12-1
DOI 10.1038/ng1047
PII ng1047
PMID 12426569
MeSH 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
IF 27.605
Times Cited 613
Human and Animal Cells Jurkat(RCB0806)