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CLINICAL RESEARCH: GENETICS AND HEART DISEASE

Multiple Less Common Genetic Variants Explain the Association of the Cholesteryl Ester Transfer Protein Gene With Coronary Artery Disease

Benjamin D. Horne, PhD, MPH^_*,,_*, Nicola J. Camp, PhD^,, Jeffrey L. Anderson, MD, FACC^_*,, Chrissa P. Mower^_*, Jessica L. Clarke, BS^_*, Matthew J. Kolek, BS^_*, John F. Carlquist, PhD^_*, Intermountain Heart Collaborative Study Group

^_* Cardiovascular Department, LDS Hospital, Intermountain Medical Center
Genetic Epidemiology Division, Department of Biomedical Informatics
Cardiology Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah
Genetic Research, Intermountain Healthcare, Salt Lake City, Utah

Manuscript received December 1, 2006; revised manuscript received January 29, 2007, accepted February 5, 2007.

^_* Reprint requests and correspondence: Dr. Benjamin D. Horne, Cardiovascular Department, LDS Hospital, Intermountain Medical Center, 8th Avenue and C Street, Salt Lake City, Utah 84143. (Email: benjamin.horne{at}intermountainmail.org).

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 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 [ClinicalTrials.gov] ).

Abbreviations and Acronyms   CAD = coronary artery disease   CETP = cholesteryl ester transfer protein   CI = confidence interval   CK-MB = creatine kinase-myocardial band   HDL-C = high-density lipoprotein cholesterol   LD = linkage disequilibrium   LDL-C = low-density lipoprotein cholesterol   MAF = minor allele frequency   MI = myocardial infarction   OR = odds ratio   SNP = single nucleotide polymorphism   TC = total cholesterol   TG = triglyceride   tSNP = tagging single nucleotide polymorphism

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