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 sele...

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Autores principales:	Isabel Gamache, Marc-André Legault, Jean-Christophe Grenier, Rocio Sanchez, Eric Rhéaume, Samira Asgari, Amina Barhdadi, Yassamin Feroz Zada, Holly Trochet, Yang Luo, Leonid Lecca, Megan Murray, Soumya Raychaudhuri, Jean-Claude Tardif, Marie-Pierre Dubé, Julie Hussin
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	population genetics pharmacogenomics transcriptomics phenotype associations cardiovascular disease linkage disequilibrium Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1eb82435960b4dda9cb9c0f636c44f60
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spelling	oai:doaj.org-article:1eb82435960b4dda9cb9c0f636c44f602021-11-16T17:24:44ZA sex-specific evolutionary interaction between ADCY9 and CETP10.7554/eLife.691982050-084Xe69198https://doaj.org/article/1eb82435960b4dda9cb9c0f636c44f602021-10-01T00:00:00Zhttps://elifesciences.org/articles/69198https://doaj.org/toc/2050-084XPharmacogenomic 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.Isabel GamacheMarc-André LegaultJean-Christophe GrenierRocio SanchezEric RhéaumeSamira AsgariAmina BarhdadiYassamin Feroz ZadaHolly TrochetYang LuoLeonid LeccaMegan MurraySoumya RaychaudhuriJean-Claude TardifMarie-Pierre DubéJulie HussineLife Sciences Publications Ltdarticlepopulation geneticspharmacogenomicstranscriptomicsphenotype associationscardiovascular diseaselinkage disequilibriumMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	population genetics pharmacogenomics transcriptomics phenotype associations cardiovascular disease linkage disequilibrium Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	population genetics pharmacogenomics transcriptomics phenotype associations cardiovascular disease linkage disequilibrium Medicine R Science Q Biology (General) QH301-705.5 Isabel Gamache Marc-André Legault Jean-Christophe Grenier Rocio Sanchez Eric Rhéaume Samira Asgari Amina Barhdadi Yassamin Feroz Zada Holly Trochet Yang Luo Leonid Lecca Megan Murray Soumya Raychaudhuri Jean-Claude Tardif Marie-Pierre Dubé Julie Hussin A sex-specific evolutionary interaction between ADCY9 and CETP
description	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.
format	article
author	Isabel Gamache Marc-André Legault Jean-Christophe Grenier Rocio Sanchez Eric Rhéaume Samira Asgari Amina Barhdadi Yassamin Feroz Zada Holly Trochet Yang Luo Leonid Lecca Megan Murray Soumya Raychaudhuri Jean-Claude Tardif Marie-Pierre Dubé Julie Hussin
author_facet	Isabel Gamache Marc-André Legault Jean-Christophe Grenier Rocio Sanchez Eric Rhéaume Samira Asgari Amina Barhdadi Yassamin Feroz Zada Holly Trochet Yang Luo Leonid Lecca Megan Murray Soumya Raychaudhuri Jean-Claude Tardif Marie-Pierre Dubé Julie Hussin
author_sort	Isabel Gamache
title	A sex-specific evolutionary interaction between ADCY9 and CETP
title_short	A sex-specific evolutionary interaction between ADCY9 and CETP
title_full	A sex-specific evolutionary interaction between ADCY9 and CETP
title_fullStr	A sex-specific evolutionary interaction between ADCY9 and CETP
title_full_unstemmed	A sex-specific evolutionary interaction between ADCY9 and CETP
title_sort	sex-specific evolutionary interaction between adcy9 and cetp
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/1eb82435960b4dda9cb9c0f636c44f60
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A sex-specific evolutionary interaction between ADCY9 and CETP

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