The class
Rare CETP variants, not the common TaqIB marker, best explain the link of the gene to coronary artery disease in 4,811 patients (J Am Coll Cardiol 2007)
Original title: Multiple less common genetic variants explain the association of the cholesteryl ester transfer protein gene with coronary artery disease
From a DNA bank of 10,020 individuals, researchers genotyped 4,811 nondiabetic, nonsmoking patients with angiographically defined significant coronary artery disease (CAD) or normal coronaries for 11 CETP tagging SNPs, chosen to capture the full variation of the gene. After correction for multiple comparisons, allele +1086A was significantly associated with CAD (p=0.0034), with suggestive associations for -631AA (odds ratio 3.95, p=0.004 versus CC) and +2389GA (odds ratio 1.21, p=0.003 versus GG). Haplotype analysis found a significant CAD association for one linkage disequilibrium group spanning T+1086A, C+878T, and C+408T (p=0.0025), and near-significance for a second group spanning C-631A, MspI, and G+2389A (p=0.013); a weak protective trend for the common TaqIB variant disappeared after adjusting for these other SNPs, suggesting TaqIB was merely a marker for the true risk variants. No SNP or haplotype was associated with myocardial infarction. The authors conclude multiple, less common CETP SNPs and haplotypes, not the well-studied TaqIB variant, underlie the CETP-CAD association, reflecting genetic-risk complexity and allelic heterogeneity.
Original 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).
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.