A sex-specific evolutionary interaction between ADCY9 and CETP. A sex-specific evolutionary interaction between ADCY9 and CETP

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 3,400 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. Overall design: RNAseq: HepG2 ADCY9 knock down

药物基因组学研究已揭示，9型腺苷酸环化酶（adenylyl cyclase type 9, ADCY9）基因中的rs1967309位点与胆固醇酯转移蛋白（cholesteryl ester transfer protein, CETP）调节剂达塞曲匹的临床响应存在关联，但该相互作用背后的分子机制仍未明确。本研究对人类群体中与药物基因组学响应相关的该基因座的选择信号进行了系统表征，结果显示rs1967309区域在多个人类群体中均呈现自然选择的特征信号。此外，本研究在CETP基因中鉴定出rs158477位点，该位点在秘鲁人群中与rs1967309存在长程连锁不平衡。该信号主要在男性群体中被观测到，这一性别特异性结果在包含超过3400名秘鲁人的LIMAA队列中得到了重复验证。我们进一步在英国生物银行（UK Biobank）中检测到这两个单核苷酸多态性（single nucleotide polymorphism, SNPs）与性别对心血管表型的交互作用，这与在秘鲁人群上述基因座中发现的性别特异性基因型关联结果一致。对RNA测序（RNA-seq）数据的分析还表明，这两个SNPs之间在多个组织中存在对CETP表达水平的上位相互作用。我们提出，ADCY9与CETP在近期人类演化过程中发生了共进化，这一结果提示了达塞曲匹的药物基因ADCY9与其治疗靶点CETP之间存在生物学联系。整体实验设计：RNA测序：HepG2细胞ADCY9基因敲低