Published Online
on January 23, 2009

A more recent version of this article appeared on February 1, 2009

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Original Article

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. Ridker¹; Guillaume Paré¹; Alex N. Parker²; Robert Y.L. Zee¹; Joseph P. Miletich² and Daniel I. Chasman^1,3

¹ Brigham and Women's Hospital, Boston, MA;
² Amgen, Inc., Cambridge, MA

³ E-mail: dchasman{at}rics.bwh.harvard.edu

Background—Recent trial data have challenged the hypothesis that cholesteryl ester transfer protein (CETP) and high-density lipoprotein cholesterol (HDLC) have causal roles in atherothrombosis. One method to evaluate this issue is to examine whether polymorphisms in the CETP gene that impact on HDLC 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 HDLC and then to evaluate whether significant SNPs within these loci also impact upon rates of incident myocardial infarction during an average 10-year follow-up period. Nine loci on 9 chromosomes had one or more SNPs associated with HDLC at genomewide statistical significance (P<5x10-8). However, only SNPs near or in the CETP gene at 16q13 were associated with both HDLC and risk of incident myocardial infarction (198 events). For example, SNP rs708272 in the CETP gene was associated with a per-allele increase in HDLC levels of 3.1 mg/dL and a concordant 24 percent lower risk of future myocardial infarction (age-adjusted HR 0.76, 95%CI 0.62-0.94), consistent with recent meta-analysis. Independent and again concordant effects on HDLC and incident myocardial infarction were also observed at the CETP locus for rs4329913 and rs7202364. Adjustment for HDLC attenuated did not eliminate these effects.

Conclusion—In this prospective cohort of initially healthy women, SNPs at the CETP locus impact upon future risk of myocardial infarction, supporting a causal role for CETP in atherothrombosis, possibly through an HDLC mediated pathway.

Key Words: atherosclerosis • cholesterol • genetics • lipoproteins • myocardial infarction

Related Article

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, Guillaume Paré, Alex N. Parker, Robert Y.L. Zee, Joseph P. Miletich, and Daniel I. Chasman
Circ Cardiovasc Genet 2009 2: 26-33. [Abstract] [Full Text] [PDF]