May 26, 2016

GENdEr and Sex DetermInantS of Cardiovascular Disease (GENESIS-PRAXY) – Rapid Funding for DSEN Cont’d IV

NPI: Louise Pilote

Co-PI Sasha Bernatsky

Duration: 1 year

This project aims to determine whether sex differences in clopidogrel metabolism genes in young acute coronary syndrome (ACS) patients exist. The GENESIS PRAXY cohort was enriched through the genotyping of the relevant CYP genes. DNA from the PRAXY cohort was sent to the genome center for genotyping. The results were analysed and provided pilot data to calculate the required sample size for more definitive results. Since, our collaborations with similar cohorts have been established, including the VIRGO cohort (an international collaboration between United States, Spain, and Australia). The VIRGO database is especially useful given its large sample size and similar patient baseline characteristics. In November 2017, we received funding from CIHR catalyst grant to amalgamate these aforementioned cohorts. We have signed the Data User Agreement for acquiring VIRGO data with collaboration of PI Dr. Rachel Dreyer from Yale University. Since we now have access to the VIRGO cohort data along with whole genome sequencing data, we have a large collation cohort with a higher proportion of female patients. All the analyses have been performed and a manuscript is now in progress. Our abstract was accepted as a poster presentation and presented at the American College of Cardiology meeting in New Orleans March 16-19, 2019.

Our PRAXY cohort had 743 patients genotyped. We also obtained data from the VIRGO cohort, including an additional 2,080 patients with whole genome sequencing data. This provides a total of 2,823 patients who have been genotyped.

A Genetic Risk Score (GRS) for CYP alleles was calculated. Women had a higher mean score as compared to men though not significant. Sex differences in thrombotic and bleeding risk were explored through sex-gene interactions in patients on clopidogrel at the time of AMI presentation and discharge respectively. Among clopidogrel users at AMI onset (n=164), thrombotic risk was greater in female carriers of CYP2C9*3 loss-of-function allele (likely explained by a higher on-clopidogrel platelet reactivity. The gain of function variant (CYP2C9*17) was not associated with bleeding risk in clopidogrel users at discharge (n=481) regardless of sex.

CYP3A (hepatic cytochrome enzymes) has been shown to have an increased effect in females (Hunt CM, et al. 1992). This sexually dimorphic expression of CYP3A is caused in response to sex-dependent growth hormone secretion (Li J, et al. 2015). Since limited data is available on the effect of sex on CYP alleles, we propose to investigate the sex-drug-gene interaction of clopidogrel with CYP alleles.

As drug efficacy and safety can differ between men and women, our study aims to demonstrate that sex-specific policies would be better suited for female patients as women are highly underrepresented in drug trials. Our collection of two large, highly characterized cohorts of patients with ACS with oversampling of women has provided us with a powerful investigation of sex-drug-gene interaction. Therefore, we anticipate policy implications in prescribing drugs based on patients’ sex.

Health Canada could request more information on sex-specific data to be able to determine drug prescriptions better suited for women.

DSEN stakeholders could raise queries related to sex and gender interactions in the safety and effectiveness of medications, leading to sex-specific drugs tailored for women and to personalized medicine.

Publications

  1. Moura et al. Treatment discontinuation and clinical events in type 2 diabetes patients treated with dipeptidyl peptidase-4 inhibitors or NPH insulin as third-line therapy. Journal of Diabetes Research, 2018: 4817178

Abstracts

  1. Moura et al. Treatment discontinuation and rates of hypoglycemia in type 2 diabetes patients treated with dipeptidyl peptidase-4 (DDP4) inhibitors or NPH insulin as third line therapy. 2016 (ICPE abstract)
  2. Elharram M, Pilote L. Novel glucose lowering agents are associated with a lower risk of cardiovascular and adverse events in type 2 diabetes: a population-based analysis. Abstract– Moderated Presentation. Canadian Cardiovascular Congress (CCC), Toronto, Ontario, October 20-23, 2018.
  3. Elharram M, Pilote L. Risk of cardiovascular events in type 2 diabetes patients initiating novel agents as second line therapy with glucose lowering drugs: a population-based analysis. Oral Presentation. McGill Cardiovascular Research Day, Jewish General Hospital, Montreal, Quebec, May 2, 2018.

For more information contact: Jessica (Lifang) Wang. Research Coordinator. [email protected]   514.934.1934 ext.44718