CETP enhancer variant rs3764261 boosts statin-associated HDL-C rise but reduces statin protection against myocardial infarction (Clin Pharmacol Ther 2013)

Original title: Cholesteryl ester transfer protein polymorphisms, statin use, and their impact on cholesterol levels and cardiovascular events

Clin Pharmacol Ther · 30 September 2013 · 7

Leusink M, Onland-Moret NC, Asselbergs FW, Ding B, Kotti S, van Zuydam NR, Papp AC, Danchin N, Donnelly L, Morris AD, Chasman DI, Doevendans PA et al.

Meta-analyzing three studies totaling 11,021 individuals for the effect of CETP genotype on statin-achieved lipid levels, and five studies totaling 16,570 individuals for statin-by-SNP interactions on myocardial infarction protection, researchers found the CETP enhancer variant rs3764261 significantly increased HDL cholesterol by 0.02 mmol/L per T allele (P=6x10-5) during statin treatment. The same T allele reduced statin protection against myocardial infarction (interaction odds ratio 1.19 per T allele, P=0.04), meaning carriers who gained more HDL-C from statins paradoxically had less cardiovascular benefit, a genetic dissociation between statin-induced HDL-C rise and clinical protection specifically tied to CETP genotype.

Original abstract

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta-analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single-nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin × SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 × 10(-5)) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.