A sex-specific evolutionary interaction between ADCY9 and CETP

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 3,400 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 towards a biological link between dalcetrapib’s pharmacogene ADCY9 and its therapeutic target CETP.

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial

“… 8 , 9 In addition, the CETP target gene for dalcetrapib and the ADCY9 effect modifier gene, both residing on chromosome 16, have shown evidence of co-evolution through human history, possibly through a selection pressure. 11 Further evidence of an interplay between these two gene products was obtained from genetically modified mice, with ADCY9 inactivation clearly protecting from atherosclerosis and improving endothelial function only in the absence of CETP. 10 In contrast to the effect on cholesterol efflux, the increase of HDL-cholesterol with dalcetrapib in patients is not dependent on the genotype at position rs1967309 in the ADCY9 gene.…”

“… 10 Furthermore, the demonstrated relationship between ADCY9 and CETP during recent human evolution has pointed towards a biological link between dalcetrapib’s effect modifier gene ADCY9 and its therapeutic target CETP. 11 The multiple observed interactions between ADCY9 and CETP in both animals and patients suggested that they represent a real biological phenomenon and not a spurious statistical association. Accordingly, we designed and conducted the dal-GenE study to test prospectively the pharmacogenetic hypothesis that dalcetrapib provides cardiovascular benefits when administered to patients with the favourable genotype.…”

Sex-Inclined Piwi-Interacting RNAs in Serum Exosomes for Sex Determination in the Greater Amberjack (Seriola dumerili)

“…Adcy9 was a target gene of piR-dre-332 and piR-dre-5797. Adcy9 , which encodes an adenylyl cyclase [ 57 , 58 , 59 , 60 ], can regulate the metabolism associated with the estrogen receptor pathway and is a sex-specific gene in patients with coronary artery disease [ 61 , 62 ]. In addition, adcy9 is a female-inclined gene that is regulated by an estrogen-related receptor (ERR) to modulate ovarian development in the giant freshwater prawn ( Macrobrachium rosenbergii ) [ 63 ].…”

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 assess the external validity of drug effects on other patient populations. Genetic studies of CETP variants have highlighted possible effect modification by sex on HDL-c levels, carotid intima-media thickness, the HDLc/apoAI ratio, and on the dynamics of postprandial triglyceride levels (Anagnostopoulou et al, 2009;Christen et al, 2018;Gamache et al, 2021;Kark et al, 2000;Klingel et al, 2017). 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 (Schaefer et al, 1982;Villard et al, 2013).…”