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CETP inhibition and ADCY9 genotype: evidence of a qualitative pharmacogenetic interaction in cardiovascular disease?

By Michael V Holmes, George Davey Smith

Posted 06 Jun 2018
bioRxiv DOI: 10.1101/336875

Background: CETP inhibitors raise circulating concentrations of HDL-cholesterol, and potent inhibitors also lower non-HDL-cholesterol and risk of vascular disease. Previous genome-wide pharmacogenetic analysis of a phase III randomized controlled trial (RCT) of the CETP inhibitor, dalcetrapib, found variants in ADCY9 to associate with response to treatment. More recently, findings from a pharmacogenetic analysis of the CETP inhibitor evacetrapib reported a lack of such an association. Aims: To clarify the totality of evidence on whether ADCY9 genotype modifies the treatment response to CETP inhibition on risk of major adverse cardiac events through systematic review and meta-analysis. Methods: We searched PubMed on 22nd May 2018 to identify RCTs of CETP inhibition that reported vascular disease effect estimates stratified by ADCY9 genotype. Stratum-specific estimates were pooled using fixed effect meta-analysis. Tests of heterogeneity between, and trend across, genotypic strata were assessed using Chi2. Results: Nine studies were identified from PubMed, of which two (dal-OUTCOMES and ACCELERATE) were RCTs reporting the treatment response to CETP inhibition by ADCY9 genotype, and fulfilled the inclusion criteria. In meta-analysis of dal-OUTCOMES and ACCELERATE, treatment with a CETP inhibitor was associated with a relative risk (RR) for major adverse cardiac events of RR 0.80 (95%CI, 0.65-0.99) in carriers of ADCY9 rs1967309 AA. For carriers of AG, the corresponding estimate was a RR of 1.01 (95%CI, 0.89-1.13), and for GG carriers, it was RR 1.21 (95%CI, 1.06-1.40). We identified evidence of heterogeneity (P=0.004) and a trend (P=0.0009) across genotypic groups. Conclusions: In contrast to the interpretation provided by authors of the analysis based in the ACCELERATE trial, the available evidence lends weak support to a potential interaction of CETP treatment by ADCY9 genotype on risk of major adverse cardiac events. Additional data, e.g. from the ongoing dal-GenE trial focused explicitly on this interaction, should provide further clarity regarding the robustness of this pharmacogenetic effect.

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