Large meta-analysis shows unique association between CETP locus and HDL-c response to statins

Postmus I, Warren HR, Trompet S, et al.
J Med Genet 2016;published online ahead of print

Background

Statins reduce LDL-c and moderately increase HDL-c by 4-10% [1,2]. The variation of HDL-c increase after statins may be partially explained by genetic variation, since CETP gene variants influence HDL-c levels and coronary artery disease (CAD) risk [3,4].

In this meta-analysis of genome-wide association studies (GWAS), datasets from randomised controlled trials and cohort studies in the large Genomic Investigation of Statin Therapy (GIST) consortium were analysed to investigate whether additional loci have an effect on statin-induced changes of HDL-c levels.

Main results

• First-stage meta-analysis (16.769 patients): genome-wide 3 SNPs at the CETP locus (Chr. 16) were significant (P<5*10⁻⁸) for their relationship with HDL-c response to statins. The most significant association was for SNP rs247616 (MAF=0.324; β=0.011; SE=0.002; P=5.95*10⁻¹⁰). This finding suggests that carriers of the minor allele of this SNP, respond to statins with a 1.1% (≈0.046 mmol/L) greater increase per allele in HDL-c, compared with non-carriers.
• The second-stage meta-analysis (10.951 patients) included a selection of 123 SNPs and confirmed the first-stage meta-analysis (rs247616: MAF=0.327; β=0.005; SE=0.001; P=1.59*10⁻⁵).
• Interaction analysis to exclude confounding suggests that the genetic effects of CETP on baseline HDL-c contribute only partially to genetic effects on HDL-c response: an interaction analysis of the rs247616 SNP with statin or placebo allocation showed that statin treatment modified the genetic effect (P-interaction= −3.52*10⁻³; β=0.007; SE=0.002).
• 78 variants previously known to be associated with HDL-c levels were assessed for their association with statin-induced HDL-c response: rs3764261 (CETP) was the only genetic variant with a significant association.
• These 78 variants had been used in a joint analysis, which revealed that predisposition to high HDL-c was associated with increased statin-induced HDL-c response: a 2.9% fractional increase (β=0.029, SE=0.003, p=1*10^-19).
• Conditional analysis of Chr. 16 to assess whether the CETP region contains more than one independent signal of association, showed only one remaining SNP in the model: the lead SNP rs247616 within the CETP locus (joint P value = 9.96*10⁻¹⁰; joint β=0.0104).
• Variance explained: from genome-wide data of the ASCOT-UK datasets, the trait heritability for HDL-c response to statins was: h²=17.8%, SE=0.154, P=0.125. The trait variance explained by the lead CETP SNP rs247616 alone was 0.04% in ASCOT-UK (P=0.38) and 0.01% in CARDS (P=0.54).

Conclusion

In a large meta-analysis of genome-wide association studies (GWAS) for HDL-c response to statins, CETP was found to be the only locus, in which common genetic variants are significantly associated with a substantial HDL-c response to statin treatment. This pharmacogenetics effect is independent of the CETP association with baseline HDL-c levels.

Find this article online at BMJ

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