Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction
Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction
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DOI：
10.1038/ng1047
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发表时间：
2002-12-01
期刊：
影响因子：
30.8
通讯作者：
Tanaka, T
中科院分区：
文献类型：
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作者：
Ozaki, K;Ohnishi, Y;Tanaka, T
通过使用92，788个基于基因的单核苷酸多态性（SNP）标记的大规模病例对照关联研究，我们确定了染色体6p 21上与心肌梗死易感性相关的候选位点。随后的连锁不平衡（LD）作图和单倍型结构分析显示心肌梗死与单个50 kb单倍型之间存在显著相关性，该单倍型由LTA（编码α-光敏素）、NFKBIL 1（编码B细胞中κ轻链多肽基因增强子的核因子，类似于1）和BAT 1（编码HLA-B相关转录本1）中的5个SNP组成。LTA中两个SNPs的纯合性与心肌梗死风险增加显著相关（比值比=1.78，chi（2）=21.6，P=0.00000033; 1，133例受影响个体与1，006例对照）。体外功能分析表明，一个SNP的LTA编码区，改变了一个氨基酸残基从苏氨酸天冬酰胺（Thr 26 Asn），影响了一些细胞粘附分子，包括VCAM 1，在人冠状动脉血管平滑肌细胞的诱导增加了一倍。此外，LTA内含子1的SNP增强了LTA的转录水平。这些结果表明，在LTA的变异是心肌梗死的危险因素，并牵连LTA在疾病的发病机制。
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.