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A sex-specific evolutionary interaction between ADCY9 and CETP

View ORCID ProfileIsabel Gamache, View ORCID ProfileMarc-André Legault, View ORCID ProfileJean-Christophe Grenier, Rocio Sanchez, Eric Rhéaume, View ORCID ProfileSamira Asgari, Amina Barhdadi, Yassamin Feroz Zada, View ORCID ProfileHolly Trochet, View ORCID ProfileYang Luo, View ORCID ProfileLeonid Lecca, Megan Murray, View ORCID ProfileSoumya Raychaudhuri, View ORCID ProfileJean-Claude Tardif, View ORCID ProfileMarie-Pierre Dubé, View ORCID ProfileJulie G. Hussin
doi: https://doi.org/10.1101/2021.05.12.443794
Isabel Gamache
1Montreal Heart Institute, Montreal, Québec, Canada
2Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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Marc-André Legault
1Montreal Heart Institute, Montreal, Québec, Canada
2Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
3Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre, Montreal, Canada
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Jean-Christophe Grenier
1Montreal Heart Institute, Montreal, Québec, Canada
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Rocio Sanchez
1Montreal Heart Institute, Montreal, Québec, Canada
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Eric Rhéaume
1Montreal Heart Institute, Montreal, Québec, Canada
2Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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Samira Asgari
4Center for Data Sciences, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02115, USA
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Amina Barhdadi
1Montreal Heart Institute, Montreal, Québec, Canada
3Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre, Montreal, Canada
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Yassamin Feroz Zada
3Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre, Montreal, Canada
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Holly Trochet
1Montreal Heart Institute, Montreal, Québec, Canada
2Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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Yang Luo
4Center for Data Sciences, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02115, USA
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Leonid Lecca
6Socios En Salud, Lima, Peru
7Department of Global Health and Social Medicine, Harvard Medical School
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Megan Murray
4Center for Data Sciences, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Soumya Raychaudhuri
4Center for Data Sciences, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02115, USA
8Centre for Genetics and Genomics Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK
9Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
10Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Jean-Claude Tardif
1Montreal Heart Institute, Montreal, Québec, Canada
2Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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Marie-Pierre Dubé
1Montreal Heart Institute, Montreal, Québec, Canada
2Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
3Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre, Montreal, Canada
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Julie G. Hussin
1Montreal Heart Institute, Montreal, Québec, Canada
2Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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  • For correspondence: julie.hussin@umontreal.ca
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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 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.

Competing Interest Statement

J.G.H. has received speaker honoraria from Dalcor and District 3 Innovation Centre. J.C.T. reports grants from Government of Quebec, National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health (NIH), the MHI Foundation, from Bill and Melinda Gates Foundation, Amarin, Esperion, Ionis, Servier, RegenXBio; personal fees from Astra Zeneca, Sanofi, Servier; and personal fees and minor equity interest from Dalcor. M.P.D. and J.C.T. have a patent Methods for Treating or Preventing Cardiovascular Disorders and Lowering Risk of Cardiovascular Events issued to Dalcor, no royalties received, a patent Genetic Markers for Predicting Responsiveness to Therapy with HDL-Raising or HDL Mimicking Agent issued to Dalcor, no royalties received, and a patent Methods for using low dose colchicine after myocardial infarction with royalties paid to Invention assigned to the Montreal Heart Institute. M.P.D. reports personal fees and other from Dalcor and personal fees from GlaxoSmithKline, other from AstraZeneca, Pfizer, Servier, Sanofi. The remaining authors have nothing to disclose.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted May 14, 2021.
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A sex-specific evolutionary interaction between ADCY9 and CETP
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 G. Hussin
bioRxiv 2021.05.12.443794; doi: https://doi.org/10.1101/2021.05.12.443794
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A sex-specific evolutionary interaction between ADCY9 and CETP
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 G. Hussin
bioRxiv 2021.05.12.443794; doi: https://doi.org/10.1101/2021.05.12.443794

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