'To get to the truth'

In general, woman have more negative reactions to medication than men. For instance, those who take statins to lower their cholesterol often report more severe muscle pain as a result. Similarly, women taking angiotensin-converting enzyme (ACE) inhibitors to lower their blood pressure are more likely to end up with a persistent dry cough. And those taking sotalol to correct abnormal heart rhythms can more frequently wind up with fast, chaotic heartbeats that make them faint or worse.

In ongoing research with colleagues Marc-Olivier Pilon, Simon de Denus and Grégoire Leclair at the MHI, Dubé is looking at how one's sex affects dosing, concentrations and pharmacogenomics of 47 heart drugs – everything from blood thinners and diuretics to Beta- blockers and antidepressants. The scientists have the benefit of having not only a lot of drugs at their disposal, but also an exceptionally high number of heart patients: a cohort of just over 10,000, over one-third of whom are women.

In their analyses, the researchers employ two techniques: genotyping, using the genomics platform at UdeM's Beaulieu-Saucier Centre for Pharmacogenomics; and, to measure and quantify drugs in the patients' blood, liquid chromatography coupled with mass spectrometry deployed by the team at the UdeM Biopharmacy Platform.

Preliminary results of this work show that for close to half of the drugs, women show much higher concentrations in their blood. 

"We'll keep studying these differences between men and women, building on this unique data resource when, hopefully, my Chair is renewed for 2017," said Dubé, "including studying environmental heat and dehydration as additional factors that may impact variability in drug response.”

Women are not Dubé's only concern.

In a more recent study, published in February in the journal Circulation, Dubé focused on a major randomised clinical trial that led to the global approval of colchicine, a drug usually prescribed for gout, for preventing cardiovascular disease. She and her team showed, for the first time in a randomised setting, that colchicine is associated with a reduction in clonal haematopoiesis, a process of acquired blood mutations recognised as a risk factor for cardiovascular disease and mortality. 

"What we've done is pave the way for using drugs to attack a biological mechanism of ageing that used to be considered unmodifiable," she said. “It helps clear things up in a situation where observational data and recent clinical trials yielded conflicting results. Clonal hematopoiesis represents a new and promising biomarker for cardiovascular disease and aging in general, and will constitute a major focus of my work in the coming years.”

In her research as a chairholder, Dubé sees herself as a "data miner," deeply probing very large genomic datasets such as the U.K. Biobank, the MHI Biobank, and trials done with clinicians at the MHI and pharmaceutical giants including AstraZeneca, GSK, Sanofi, Pfizer and Servier.

One key achievement from her last five years as holder of the Chair: the development of ExPheWas, "a gene-based phenome-wide association study browser and platform that supports gene-based Mendelian randomization analyses." It includes sex-stratified and sex-combined association results from 26,616 genes across 1,746 phenotypes from over 400,000 U.K. Biobank participants, all part of Dubé's effort to investigate sex and gender differences in genetic susceptibility to disease and drug response.

"Our overarching goal is to identify subgroups of people who are most likely to benefit most from specific therapies, as well as to identify novel drug targets, and advance understanding of genetic susceptibility to disease," she explains. “We're not alone: across the globe, scientists are busy developing faster rotes to new therapies. Drug targets with genetic support are far more likely to advance successfully through all stages of development, driving major investment.”

Still, she's not naïve.

Despite, and maybe because of, her background in it, Dubé understands that if the pharmaceutical industry is interested in precision medicine, it's because there's some profit to be made from it – even from addressing differences between the sexes.

“Industry plays a crucial role in bringing new drugs to patients,” she said. “But precision medicine also forces us to think about affordability and access. The goal isn’t just better therapies - it’s making sure people can actually benefit from them.”