Document Detail


Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.
MedLine Citation:
PMID:  12426569     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Kouichi Ozaki; Yozo Ohnishi; Aritoshi Iida; Akihiko Sekine; Ryo Yamada; Tatsuhiko Tsunoda; Hiroshi Sato; Hideyuki Sato; Masatsugu Hori; Yusuke Nakamura; Toshihiro Tanaka
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-11-11
Journal Detail:
Title:  Nature genetics     Volume:  32     ISSN:  1061-4036     ISO Abbreviation:  Nat. Genet.     Publication Date:  2002 Dec 
Date Detail:
Created Date:  2002-11-28     Completed Date:  2003-01-17     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  650-4     Citation Subset:  IM    
Affiliation:
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.
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MeSH Terms
Descriptor/Qualifier:
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,  physiology
Myocardial Infarction / genetics*
Polymorphism, Single Nucleotide*
Recombinant Fusion Proteins / metabolism
Sequence Analysis, DNA
Transcription, Genetic
Vascular Cell Adhesion Molecule-1 / biosynthesis
Chemical
Reg. No./Substance:
0/Lymphotoxin-alpha; 0/Recombinant Fusion Proteins; 0/Vascular Cell Adhesion Molecule-1
Comments/Corrections
Erratum In:
Nat Genet. 2003 Jan;33(1):107.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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