Dalcetrapib
ADCY9 and CETP show signs of having coevolved under sex-specific selection, offering a biological explanation for the pharmacogenomic signal of dalcetrapib (eLife 2021)
Original title: A sex-specific evolutionary interaction between ADCY9 and CETP
Pharmacogenomic studies had linked rs1967309 in ADCY9 to clinical response to the CETP modulator dalcetrapib, but the mechanism was unknown. This study found the rs1967309 region shows signatures of positive selection across several human populations, and identified a CETP variant, rs158477, in long-range linkage disequilibrium with rs1967309 specifically in the Peruvian population, a signal seen mainly in males and replicated in the LIMAA cohort of over 3,400 Peruvians. RNA sequencing data suggested an epistatic interaction between the two SNPs on CETP expression across multiple tissues, differing between males and females, and the two SNPs interacted with sex on cardiovascular phenotypes in the UK Biobank, consistent with the Peruvian findings. The authors propose ADCY9 and CETP coevolved during recent human evolution through sex-specific selection, offering a biological link between ADCY9, the pharmacogene of dalcetrapib, and its drug target, CETP, that helps explain why the benefit of the drug appeared confined to a genetic subgroup.
Original 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 positive 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. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the 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. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points toward a biological link between dalcetrapib's pharmacogene ADCY9 and its therapeutic target CETP.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.