Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction
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- 11 November 2002
- journal article
- Published by Springer Nature in Nature Genetics
- Vol. 32 (4) , 650-654
- https://doi.org/10.1038/ng1047
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.Keywords
This publication has 26 references indexed in Scilit:
- Loss of Lymphotoxin-α but Not Tumor Necrosis Factor-α Reduces Atherosclerosis in MicePublished by Elsevier ,2002
- Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion-transporting polypeptides, and three NADH:ubiquinone oxidoreductase flavoproteinsJournal of Human Genetics, 2001
- A high-throughput SNP typing system for genome-wide association studiesJournal of Human Genetics, 2001
- Association between a Single-Nucleotide Polymorphism in the Promoter of the Human Interleukin-3 Gene and Rheumatoid Arthritis in Japanese Patients, and Maximum-Likelihood Estimation of Combinatorial Effect That Two Genetic Loci Have on Susceptibility to the DiseaseAmerican Journal of Human Genetics, 2001
- Atherosclerosis — An Inflammatory DiseaseNew England Journal of Medicine, 1999
- New indices of ischemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischemic heart diseaseAtherosclerosis, 1997
- The New Genomics: Global Views of BiologyScience, 1996
- The pathogenesis of atherosclerosis: a perspective for the 1990sNature, 1993
- Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque.Arteriosclerosis: An Official Journal of the American Heart Association, Inc., 1986
- Plaque fissuring--the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina.Heart, 1985