多种较罕见的基因变异解释了胆固醇酯转运蛋白基因与冠状动脉疾病之间的关联。

Multiple less common genetic variants explain the association of the cholesteryl ester transfer protein gene with coronary artery disease.

作者信息

Horne Benjamin D, Camp Nicola J, Anderson Jeffrey L, Mower Chrissa P, Clarke Jessica L, Kolek Matthew J, Carlquist John F

机构信息

Cardiovascular Department, LDS Hospital, Intermountain Medical Center, University of Utah, Salt Lake City, Utah 84143, USA.

出版信息

J Am Coll Cardiol. 2007 May 22;49(20):2053-60. doi: 10.1016/j.jacc.2007.02.039. Epub 2007 May 4.

DOI:10.1016/j.jacc.2007.02.039

PMID:17512363

Abstract

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 (> or =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 LD 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, MspI, 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 tSNP 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. (Database Registry of the Intermountain Heart Collaborative Study; http://clinicaltrials.gov/ct/show/NCT00406185?order=1; NCT00406185).

摘要

目的

本研究的目的是通过选择能最佳解释基因内变异的标签（t）单核苷酸多态性（SNP）来确定胆固醇酯转运蛋白（CETP）基因与冠状动脉疾病（CAD）之间的关联。

背景

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10,020名个体的脱氧核糖核酸库中，对血管造影定义的、临床上有意义的CAD（狭窄≥70%）或冠状动脉正常的非糖尿病、不吸烟患者（n = 4,811）进行11个CETP tSNP的基因分型。将心肌梗死（MI）和血脂水平作为次要终点进行评估。

结果

对单tSNP进行分析，并校正多重比较（p < 0.00485），发现等位基因+1086A与CAD相关（p = 0.0034）。发现-631AA（优势比[OR]=3.95，与CC相比，p = 0.004）和+2389GA（OR = 1.21，与GG相比，p = 0.003）存在提示性等位基因关联和显著的基因型关联。通过连锁不平衡（LD）组进行单倍型分析，发现LD组B与CAD相关（在T + 1086A、C + 878T、C + 408T上p = 0.0025），LD组A接近显著（在C - 631A、MspI、G + 2389A上p = 0.013）。通过对其他tSNP进行校正，TaqIB的微弱保护趋势消失，单倍型分析表明TaqIB只是其他tSNP或单倍型的一个标记。未发现tSNP或单倍型与MI有关联。

结论

多个较不常见的SNP和单倍型变异是与CETP相关的CAD风险的基础，而常见的TaqIB变异只是一个较差的标记。不同单倍型上出现与风险相关的变异表明遗传风险的复杂性和等位基因异质性。（山间心脏协作研究数据库登记号；http://clinicaltrials.gov/ct/show/NCT00406185?order=1；NCT00406185）