title: Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.
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.
authors.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.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Yozo
authors.initials: Y
authors.lastname: Ohnishi
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sekine
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sato
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D003331:Coronary Vessels / Q000378:metabolism; D030541:Databases, Genetic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007438:Introns; D019169:Jurkat Cells; D015810:Linkage Disequilibrium; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D008233:Lymphotoxin-alpha; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1