Cholesteryl ester transfer protein (CETP) polymorphisms, statin use, and their impact on cholesterol levels and cardiovascular events

Background: The association of variants in the CETP gene with efficacy of statins has been subject of debate, but most studies investigated a common non-functional variant. Three CETP variants were found to directly influence mRNA expression and RNA splicing, and to affect HDL-cholesterol (HDLc) levels and the risk of myocardial infarction (MI). Objectives: To determine whether three functional CETP variants influence statin efficacy in modifying cholesterol levels and preventing MI. Methods: For all analyses, only participants of European ancestry were selected. Three studies (population study Go-DARTS and randomized controlled trials PREVEND-IT and JUPITER, totaling 11,021 individuals) were included in a meta-analysis to investigate the variants' effect on achieved cholesterol levels. Linear regression was used to investigate the relation between CETP genotypes and achieved HDLc, LDLcholesterol (LDLc) and total cholesterol levels during statin treatment. Results were pooled assuming random effects and using inverse variance weighting. Five studies, totaling 16,570 individuals, were included in a meta-analysis to assess the interaction between CETP genotypes and statin response in protecting against MI: GoDARTS, PREVEND, PREVEND-IT, MI-registry FAST-MI and population based case-control study UCP. Results from logistic regression models with statin∗SNP interaction terms were pooled, assuming random effects and using inverse variance weighting. Results: The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/L per T allele (95% CI 0.02-0.03, p = 6E-05) during statin use, and had no effect on achieved LDLc. Rs3764261 also showed an interaction with statin use on MI outcome (interaction- OR = 1.19 per T allele; 95% CI 1.01-1.40, p = 0.04). The SNPs influencing splicing (rs5883 and rs9930761) did not modify statin efficacy on treated cholesterol levels or MI. Conclusions: Focusing on functional CETP variants, we showed that, during statin treatment, HDLc increased more in carriers of the rs3764261 T variant. This effect was accompanied by a reduced protection against MI by statins when compared to non-carriers.