1. Computational and Systems Biology
  2. Genetics and Genomics
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A sex-specific evolutionary interaction between ADCY9 and CETP

  1. Isabel Gamache
  2. Marc-André Legault
  3. Jean-Christophe Grenier
  4. Rocio Sanchez
  5. Eric Rhéaume
  6. Samira Asgari
  7. Amina Barhdadi
  8. Yassamin Feroz Zada
  9. Holly Trochet
  10. Yang Luo
  11. Leonid Lecca
  12. Megan Murray
  13. Soumya Raychaudhuri
  14. Jean-Claude Tardif
  15. Marie-Pierre Dubé
  16. Julie Hussin  Is a corresponding author
  1. Université de Montréal, Canada
  2. Montreal Heart Institute, Canada
  3. Broad Institute, United States
  4. Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre, Canada
  5. Socios En Salud, Peru
Research Article
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Cite this article as: eLife 2021;10:e69198 doi: 10.7554/eLife.69198

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.

Data availability

- 1000 Genomes Project, GEUVADIS is freely available.- The Native American genetic dataset was shared to us upon request to the authors of the initial paper and through a data access agreement with Universidad de Antioquia (Prof. Omar Triana Chavez). We contacted bedoya.g@gmail.com and a.ruizlin@ucl.ac.uk to get access to the dataset and we completed a data access application form and signed a data access approval once approved. Applications for access to these data can be submitted at any time. These are considered on a rolling basis and a decision was given within 1 month of receipt. PhD student applicants must include their supervisors as a co-applicant and provide their full contact details. A publication list must be provided for the applicant, co-applicants and PhD supervisors where PhD students have applied to provide proof of competence in handling datasets of this size and nature. - UK Biobank was accessed through data access approval under the project number #15357 and #20168. Information to apply for data access can be found here: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access - CARTaGENE biobank was accessed through data access approval under the project number #406713. Information to apply for data access can be found here: https://www.cartagene.qc.ca/en/researchers/access-request - GTEx v8 dataset was accessed through dbGaP under project number #19088 LIMAA dataset was accessed through dbGaP under the project number #26882. Information to apply for data access through dbGAP can be found here: https://dbgap.ncbi.nlm.nih.gov- RNA-sequencing of ADCY9-knocked-down HepG2 cell line data has been deposited under GSE174640 (embargo): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE174640For reviewers/editors: Enter token ktaxgqkkrxupjkl into the box- Source data files and code for all main figures are available here: https://github.com/HussinLab/adcy9_cetp_Gamache_2021

The following data sets were generated
The following previously published data sets were used
    1. Sudlow
    2. C. et al
    (2015) UK Biobank
    UKB project #15357, 20168.
    1. Reich
    2. D. et al
    (2012) Native American genetic dataset (NAGD)
    rom authors bedoya.g@gmail.com and a.ruizlin@ucl.ac.uk.

Article and author information

Author details

  1. Isabel Gamache

    Université de Montréal, Montréal, Canada
    Competing interests
    No competing interests declared.
  2. Marc-André Legault

    Université de Montréal, Montréal, Canada
    Competing interests
    No competing interests declared.
  3. Jean-Christophe Grenier

    Montreal Heart Institute, Montréal, Canada
    Competing interests
    No competing interests declared.
  4. Rocio Sanchez

    Montreal Heart Institute, Montréal, Canada
    Competing interests
    No competing interests declared.
  5. Eric Rhéaume

    Montreal Heart Institute, Montreal, Canada
    Competing interests
    No competing interests declared.
  6. Samira Asgari

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  7. Amina Barhdadi

    Montreal Heart Institute, Montreal, Canada
    Competing interests
    No competing interests declared.
  8. Yassamin Feroz Zada

    Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre, Montréal, Canada
    Competing interests
    No competing interests declared.
  9. Holly Trochet

    Université de Montréal, Montréal, Canada
    Competing interests
    No competing interests declared.
  10. Yang Luo

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  11. Leonid Lecca

    Socios En Salud, Lima, Peru
    Competing interests
    No competing interests declared.
  12. Megan Murray

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  13. Soumya Raychaudhuri

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  14. Jean-Claude Tardif

    Université de Montréal, Montréal, Canada
    Competing interests
    Jean-Claude Tardif, 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. Has a patent (US20190070178A1) Methods for Treating or Preventing Cardiovascular Disorders and Lowering Risk of Cardiovascular Events issued to Dalcor, no royalties received, a patent (US20170233812A1) Genetic Markers for Predicting Responsiveness to Therapy with HDL-Raising or HDL Mimicking Agent issued to Dalcor, no royalties received, and a patent (US Provisional Applications No. 62/935,751 and 62/935,865) Methods for using low dose colchicine after myocardial infarction with royalties paid to Invention assigned to the Montreal Heart Institute..
  15. Marie-Pierre Dubé

    Université de Montréal, Montréal, Canada
    Competing interests
    Marie-Pierre Dubé, has a patent (US20190070178A1) Methods for Treating or Preventing Cardiovascular Disorders and Lowering Risk of Cardiovascular Events issued to Dalcor, no royalties received, a patent (US20170233812A1) Genetic Markers for Predicting Responsiveness to Therapy with HDL-Raising or HDL Mimicking Agent issued to Dalcor, no royalties received, and a patent (US Provisional Applications No. 62/935,751 and 62/935,865) 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..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8442-4393
  16. Julie Hussin

    Université de Montréal, Montréal, Canada
    For correspondence
    julie.hussin@umontreal.ca
    Competing interests
    Julie Hussin, has received speaker honoraria from Dalcor and District 3 Innovation Centre..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4295-3339

Funding

Institut de Cardiologie de Montréal

  • Isabel Gamache
  • Marc-André Legault
  • Jean-Christophe Grenier
  • Rocio Sanchez
  • Eric Rhéaume
  • Holly Trochet
  • Jean-Claude Tardif
  • Marie-Pierre Dubé
  • Julie Hussin

Université de Montréal

  • Isabel Gamache

Canadian Institutes of Health Research

  • Marc-André Legault

Canada Research Chairs

  • Jean-Claude Tardif
  • Marie-Pierre Dubé

Fonds de Recherche du Québec - Santé

  • Julie Hussin

Institut de Valorisation des Données

  • Isabel Gamache
  • Jean-Christophe Grenier
  • Julie Hussin

Health collaboration acceleration fund from the Ministère de l'Économie et de l'Innovation of the Government of Quebec

  • Jean-Claude Tardif
  • Marie-Pierre Dubé

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The analyses done in this study were approved by the different cohorts used. Participants in these cohorts gave their general consent for their data to be used for research purposes. All individual-level data was anonymized and no efforts were made by the authors to deanonymize or recontact any of the participants from the cohorts, in keeping with our agreements with the UK Biobank, CARTaGENE, dbGAP, 1000Genomes and the Native American Genetics dataset (Universidad de Antioquia).

Reviewing Editor

  1. Ellen Leffler, University of Utah, United States

Publication history

  1. Received: April 7, 2021
  2. Accepted: October 4, 2021
  3. Accepted Manuscript published: October 5, 2021 (version 1)

Copyright

© 2021, Gamache et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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