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
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 (
). However, only SNPs near or in the
gene at 16q13 were associated with both HDL-C and risk of incident myocardial infarction (198 events). For example, SNP rs708272 in the
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
locus for rs4329913 and rs7202364. Adjustment for HDL-C attenuated but did not eliminate these effects.
In this prospective cohort of initially healthy women, SNPs at the
locus impact on future risk of myocardial infarction, supporting a causal role for CETP in atherothrombosis, possibly through an HDL-C mediated pathway.