Genetics

Geneticist attacks potentially fatal drug

Statins are a class of medications that have been used since the 1980s to bring down cholesterol rates in people with hypercholesterolemia who are at risk of suffering a cardiovascular event. Although statins have undergone many clinical trails, they can cause unpleasant side effects in 10% of patients, mainly acute muscle pain in the legs. In a few rare cases, however (fewer than 1% of statin users), a potentially fatal reaction called rhabdomyolysis may occur. “This reaction is due to failure to tolerate the active molecule,” explains geneticist Marie-Pierre Dubé of the Montreal Heart Institute and the Université de Montréal. In fact, Bayer had to withdraw the drug Cerivastatin from the market due to that side effect.”

A research project currently underway is designed to find out how to get the benefits of statins without the life-threatening side effects. What sets this clinical trial apart is that it’s genetically based. “We’re trying to identify the phenotype of the patients who are most at risk. Once we have that information, we can intervene more effectively at the pharmacological level. This is what’s called pharmaco-genomics,” notes Dubé, who’s affiliated with the Department of Pharmacology in the Faculty of Medicine.

One thousand patients have been recruited so far to take part in the protocol for this project. A total of 4,000 will be recruited (in addition to 1,000 subjects with no side effects, who will form the control group) prior to proceeding with the final analysis of data. “We didn’t wait to find the last patient before starting work. We already know which genes we’re looking at,” says Dubé. Most of the patients come from the Montreal area or from the Saguenay-Lac Saint-Jean, where genetic causes of side effects are easier to trace due to what’s known as the founders’ effect (a population descended from a relatively small number of individuals). 

For this research project, supervised by UdeM professors Jean-Claude Tardif and Michael Phillips at the Pharmaco-Genomics Centre of the Université de Montréal, which is located at the Montreal Heart Institute, Dubé’s essential contribution as a genetic statistician involves finding the most direct route to the gene(s) involved. “There are millions of false pathways in the genome,” says Dubé. “My work involves sorting out the noise from the real signal.” The objective is twofold: to identify biomarkers that indicate the toxicity of the treatment, and then to develop a genetic test to evaluate risk in patients who are predisposed to the deleterious effects of the drug.

After completing a post-doc in genetic epidemiology at the University of Toronto, Marie-Pierre Dubé worked in the pharmaceutical industry for four years before accepting a job at the Université de Montréal. “Yes, I went over to the dark side,” she says ironically, referring to the black-and-white universe of Star Wars. But she learned a great deal from her experience with the pharmaceutical industry, she says. “In the private sector, you learn to think about patents, applications, and effectiveness.”  At Xenon Pharmaceuticals, where she headed the genetic statistics department, she contributed to major breakthroughs in the treatment of dyslipidemia and pain control. The research team she set up at the Montreal Heart Institute (affiliated with the UdM) includes four scientists and several graduate students. Her work involves epidemiological genetics, pharmaco-genetic statistics, adverse responses to drugs in children, co-morbidity of depression and cardiovascular disease, and the pharmaco-genetics of drugs for hypolipidemia.