Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.
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.
Ozaki
Kouichi
K
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.
Ohnishi
Yozo
Y
Iida
Aritoshi
A
Sekine
Akihiko
A
Yamada
Ryo
R
Tsunoda
Tatsuhiko
T
Sato
Hiroshi
H
Sato
Hideyuki
H
Hori
Masatsugu
M
Nakamura
Yusuke
Y
Tanaka
Toshihiro
T
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
D008233:Lymphotoxin-alpha; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1