Polymorphism in the CETP Gene Region, HDL Cholesterol, and Risk of Future Myocardial Infarction: Genomewide Analysis Among 18 245 Initially Healthy Women From the Women’s Genome Health Study

Background—Recent trial data have challenged the hypothesis that cholesteryl ester transfer protein (CETP) and high-density lipoprotein cholesterol (HDL-C) have causal roles in atherothrombosis. One method to evaluate this issue is to examine whether polymorphisms in the CETP gene that impact on HDL-C levels also impact on the future development of myocardial infarction. Methods and Results—In a prospective cohort of 18 245 initially healthy American women, we examined over 350 000 singe-nucleotide polymorphisms (SNPs) first to identify loci associated with HDL-C and then to evaluate whether significant SNPs within these loci also impact on rates of incident myocardial infarction during an average 10-year follow-up period. Nine loci on 9 chromosomes had 1 or more SNPs associated with HDL-C at genome-wide statistical significance (P<5×10−8). However, only SNPs near or in the CETP gene at 16q13 were associated with both HDL-C and risk of incident myocardial infarction (198 events). For example, SNP rs708272 in the CETP gene was associated with a per-allele increase in HDL-C levels of 3.1 mg/dL and a concordant 24% lower risk of future myocardial infarction (age-adjusted hazard ratio, 0.76; 95% CI, 0.62 to 0.94), consistent with recent meta-analysis. Independent and again concordant effects on HDL-C and incident myocardial infarction were also observed at the CETP locus for rs4329913 and rs7202364. Adjustment for HDL-C attenuated but did not eliminate these effects. Conclusion—In this prospective cohort of initially healthy women, SNPs at the CETP locus impact on future risk of myocardial infarction, supporting a causal role for CETP in atherothrombosis, possibly through an HDL-C mediated pathway.

[1]  A. Tall,et al.  Separation of a plasma phospholipid transfer protein from cholesterol ester/phospholipid exchange protein. , 1983, The Journal of biological chemistry.

[2]  A. Tall,et al.  Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins , 1989, Nature.

[3]  A. Tall,et al.  Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. , 1990, The New England journal of medicine.

[4]  G M Sanderson,et al.  Cloning and Characterization of GRB14, a Novel Member of the GRB7 Gene Family (*) , 1996, The Journal of Biological Chemistry.

[5]  A. Tall,et al.  Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. , 1996, The Journal of clinical investigation.

[6]  L Tiret,et al.  Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene‐environment interaction , 2000, Genetic epidemiology.

[7]  N Rifai,et al.  Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. , 2001, JAMA.

[8]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[9]  P. Ridker,et al.  A prospective study of TaqIB polymorphism in the gene coding for cholesteryl ester transfer protein and risk of myocardial infarction in middle-aged men. , 2002, Atherosclerosis.

[10]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[11]  N. Laird,et al.  Estimation and Tests of Haplotype-Environment Interaction when Linkage Phase Is Ambiguous , 2003, Human Heredity.

[12]  A. Zwinderman,et al.  Haplotype analysis of the CETP gene: not TaqIB, but the closely linked -629C-->A polymorphism and a novel promoter variant are independently associated with CETP concentration. , 2003, Human molecular genetics.

[13]  David E James,et al.  Improved glucose homeostasis and enhanced insulin signalling in Grb14‐deficient mice , 2004, The EMBO journal.

[14]  A. Gotto,et al.  Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update. , 2004, Journal of the American College of Cardiology.

[15]  M. Laville,et al.  Increased adipose tissue expression of Grb14 in several models of insulin resistance , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  A. Tall,et al.  A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly Published, JLR Papers in Press, February 16, 2004. DOI 10.1194/jlr.M300520-JLR200 , 2004, Journal of Lipid Research.

[17]  S. Ebrahim,et al.  Mendelian randomization: prospects, potentials, and limitations. , 2004, International journal of epidemiology.

[18]  J. Danesh,et al.  Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk. , 2004, International journal of epidemiology.

[19]  P J Talmud,et al.  Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment: Individual Patient Meta-Analysis of 13 677 Subjects , 2005, Circulation.

[20]  J. Manson,et al.  A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women , 2005, The New England journal of medicine.

[21]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[22]  Jonathan C. Cohen,et al.  Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. , 2006, The New England journal of medicine.

[23]  A. Tall,et al.  The failure of torcetrapib: was it the molecule or the mechanism? , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[24]  M. Caulfield,et al.  Effects of torcetrapib in patients at high risk for coronary events. , 2007, The New England journal of medicine.

[25]  R. Collins,et al.  Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths , 2007, The Lancet.

[26]  D. Rader Illuminating HDL--is it still a viable therapeutic target? , 2007, The New England journal of medicine.

[27]  Jonathan C. Cohen,et al.  Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol. , 2007, American journal of human genetics.

[28]  M. Rieder,et al.  Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication , 2008, Circulation. Cardiovascular genetics.

[29]  Olle Melander,et al.  Polymorphisms associated with cholesterol and risk of cardiovascular events. , 2008, The New England journal of medicine.

[30]  N. Cook,et al.  Rationale, design, and methodology of the Women's Genome Health Study: a genome-wide association study of more than 25,000 initially healthy american women. , 2008, Clinical chemistry.

[31]  N. Cook,et al.  Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. , 2008, American journal of human genetics.

[32]  R. Collins,et al.  Newly identified loci that influence lipid concentrations and risk of coronary artery disease , 2008, Nature Genetics.

[33]  D. Strachan,et al.  LDL-cholesterol concentrations: a genome-wide association study , 2008, The Lancet.

[34]  M. Rieder,et al.  Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. , 2008, American journal of human genetics.

[35]  J. Danesh,et al.  Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. , 2008, JAMA.