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Original Articles

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

Paul M. Ridker, MD, MPH; Guillaume Paré, MD, MSc; Alex N. Parker, PhD; Robert Y.L. Zee, PhD, MPH; Joseph P. Miletich, MD and Daniel I. Chasman, PhD

From the Center for Cardiovascular Disease Prevention (P.M.R., G.P., R.Y.L.Z., D.I.C.) and The Donald W Reynolds Center for Cardiovascular Research (P.M.R., R.Y.L.Z., D.I.C.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.; and Amgen, Inc (A.N.P., J.P.M.), Cambridge Mass.

Correspondence to Daniel I. Chasman, PhD or Paul M Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail dchasman{at}rics.bwh.harvard.edu

Received August 25, 2008; accepted December 3, 2008.

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<5x10^–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.

Key Words: HDL-cholesterol • myocardial infarction • atherosclerosis • genetic association

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CLINICAL PERSPECTIVE

Guest Editor for this article was Donna K. Arnett, PhD.

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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

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