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Updated: Jul 3, 2026
09:30
Phosphopeptide Analysis of Rodent Epididymal Spermatozoa
Published on: December 30, 2014
A sex-specific evolutionary interaction between ADCY9 and CETP
Isabel Gamache1,2, Marc-André Legault1,2,3, Jean-Christophe Grenier2
1Université de Montréal, Montréal, Canada.
Elife
|October 5, 2021
Summary
Genetic variants in ADCY9 and CETP show sex-specific selection and interact to influence cardiovascular traits. This suggests a coevolutionary link between ADCY9, important for dalcetrapib response, and its therapeutic target CETP.
Area of Science:
- Human evolutionary genetics
- Pharmacogenomics
- Cardiovascular disease research
Background:
- Pharmacogenomic studies link ADCY9 (adenylyl cyclase type 9) rs1967309 to dalcetrapib response.
- The underlying mechanism of this pharmacogenomic association remains unclear.
Purpose of the Study:
- Investigate the evolutionary basis and biological mechanism of the ADCY9-dalcetrapib pharmacogenomic interaction.
- Characterize population-level genetic signals and sex-specific effects.
Main Methods:
- Analysis of population genetic data for positive selection signatures.
- Identification of linkage disequilibrium between ADCY9 and CETP variants.
- RNA-seq analysis to assess gene expression interactions.
- Examination of genotype-phenotype associations in human cohorts (Peruvian, LIMAA, UK Biobank).
Main Results:
- The ADCY9 rs1967309 region shows signatures of positive selection in multiple human populations.
- A CETP variant (rs158477) is in linkage disequilibrium with rs1967309, with sex-specific effects observed in Peruvians.
- Epistatic interactions between ADCY9 and CETP variants on CETP expression are sex-dependent.
- Interactions between these SNPs and sex influence cardiovascular phenotypes.
Conclusions:
- ADCY9 and CETP likely coevolved due to recent, sex-specific human selection.
- This evolutionary process suggests a biological link between ADCY9, the pharmacogene for dalcetrapib, and its therapeutic target CETP.
- Sex-specific genetic effects on cardiovascular traits are influenced by interactions between ADCY9 and CETP.
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