Multiple less common genetic variants explain the association of the cholesteryl ester transfer protein gene with coronary artery disease
Multiple less common genetic variants explain the association of the cholesteryl ester transfer protein gene with coronary artery disease
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DOI：
10.1016/j.jacc.2007.02.039
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发表时间：
2007-05-22
影响因子：
24
通讯作者：
Carlquist, John F.
中科院分区：
文献类型：
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作者：
Horne, Benjamin D.;Camp, Nicola J.;Carlquist, John F.
本研究的目的是通过标记(t)单核苷酸多态性（snp）来确定胆固醇酯转移蛋白（CETP）基因与冠状动脉疾病（CAD）的关联，以最佳地解释基因内变异。CETP基因在脂蛋白代谢中起关键作用，但常见且研究充分的TaqIB变异对CAD的预测并不一致。方法从10020例非糖尿病非吸烟患者（n = 4811）中选取血管造影明确、临床明显冠心病（>= 70%狭窄）或冠状动脉正常的11个CETP tSNPs进行基因分型。心肌梗死（MI）和血脂水平作为次要终点进行评估。结果对单个tssnp进行分析，经多重比较校正（p < 0.00485），鉴定出等位基因+1086A与CAD相关（p = 0.0034）。与-631AA（比值比[OR] = 3.95, p = 0.004 vs. CC）和+2389GA（比值比[OR] = 1.21, p = 0.003 vs. GG）存在提示性等位基因和显著基因型关联。链接不平衡（LD）组的单倍型分析显示，LID组B与CAD有密切关联（T+1086A、C+878T、C+408T间p = 0.0025）， LD组a与CAD有密切关联（C- 631a、Mspl、G + 2389A间p = 0.013）。TaqIB的弱保护倾向被其他tsps的调整所消除，单倍型分析表明TaqIB只是其他tsps或单倍型的标记。未发现与心肌梗死相关的tssnp或单倍型。结论：多个不常见的snp和单倍型变异是cetp相关CAD风险的基础，其中常见的TaqIB变异只是一个较差的标记。风险相关变异在单独单倍型上的出现表明遗传风险复杂性和等位基因异质性。
Objectives The objective of this study was to identify associations of the cholesteryl ester transfer protein (CETP) gene with coronary artery disease (CAD) with tagging (t) single nucleotide polymorphisms (SNPs) chosen to optimally account for intra-genic variation.Background The CETP gene plays a critical role in lipoprotein metabolism, but the common and well-studied TaqIB variant is inconsistently predictive of CAD.Methods From a deoxyribonucleic acid bank of 10,020 individuals, nondiabetic nonsmoking patients (n = 4,811) with angiographically defined, clinically significant CAD (>= 70% stenosis) or normal coronaries were genotyped for 11 CETP tSNPs. Myocardial infarction (MI) and lipid levels were evaluated as secondary end points.Results Analysis of single tSNPs, corrected for multiple comparisons (p < 0.00485), identified allele +1086A to be associated with CAD (p = 0.0034). Suggestive allelic and significant genotypic associations were found for -631AA (odds ratio [OR] = 3.95, p = 0.004 vs. CC) and +2389GA (OR = 1.21, p = 0.003 vs. GG). Haplotype analysis by linkage disequilibrium (LD) group revealed a CAD association for LID group B (p = 0.0025 across T+1086A, C+878T, C+408T) and near significance for LD group A (p = 0.013 across C-631A, Mspl, G + 2389A). A weak protective trend for TaqIB was eliminated by adjustment for other tSNPs, and haplotype analyses suggested that TaqIB was simply a marker for other tSNPs or haplotypes. No tSNPs or haplotype associations with MI were found.Conclusions Multiple, less common SNPs and haplotype variants underlie CETP-related CAD risk, for which the common TaqIB variant is simply a poor marker. The occurrence of risk-related variants on separate haplotypes suggests genetic-risk complexity and allelic heterogeneity.