A sex-specific evolutionary interaction betweenADCY9andCETP

Abstract

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of natural selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3400 Peruvians. We further detected interaction effects of these two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues. We propose that ADCY9 and CETP coevolved during recent human evolution, which points towards a biological link between dalcetrapib's pharmacogene ADCY9 and its therapeutic target CETP.

Study of effect modifiers of genetically predicted CETP reduction

“…Human genetics can also inform on subgroup effects in the context of precision medicine, for clinical trial design, or to estimate external validity of drug effects to other patient populations. Genetic studies of CETP variants have highlighted possible effect modi cation by sex on HDL-c levels, carotid intima-media thickness, the HDL-c / apoAI ratio and on the dynamics of postprandial triglyceride levels [31][32][33][34][35] . Sex differences were also observed in many traits thought to be involved in the atheroprotective effect of CETP such as the apoAI and apoA-II composition of HDL and CETP mediated cholesterol e ux 36,37 .…”

Study of effect modifiers of genetically predicted CETP reduction

“…Human genetics can also inform on subgroup effects in the context of precision medicine, for clinical trial design, or to estimate external validity of drug effects to other patient populations. Genetic studies of CETP variants have highlighted possible effect modification by sex on HDL-c levels, carotid intima-media thickness, the HDL-c / apoAI ratio and on the dynamics of postprandial triglyceride levels [31][32][33][34][35] . Sex differences were also observed in many traits thought to be involved in the atheroprotective effect of CETP such as the apoAI and apoA-II composition of HDL and CETP mediated cholesterol efflux 36,37 .…”