Pharmacogenomics for All

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Sometimes finding the appropriate drug for a patient comes down to an exercise of trial and error. Even though physicians take personalized factors into account when prescribing a medication, such as a patient’s age or organ function, it is still common for people to experience adverse reactions or simply fail to respond to an initial therapy. That process is costly, potentially dangerous and means patients can spend time taking an ineffective drug that may unnecessarily expose them to side effects.

Physicians and scientists believe that the emerging field of pharmacogenomics — the study of how genetic variation affects drug response — will bring much-needed optimization to this process. Using key information already encoded in a person’s unique genome, physicians hope to predict the medication that will be both safe and most effective for a patient.

“It has become very evident that there are mutations in the genome that predispose people to very serious side effects, and that these relationships are predictable. If you have this information, you must use it,” says Minoli Perera, PharmD, PhD, associate professor of Pharmacology. “Ten to 20 years from now, this won’t even be a hot topic — it will just be what we do.”

ELIMINATING A HEALTH DISPARITY

But while the field has made important advancements in recent years, it’s also been held back by a key limitation: Almost all research that has identified relevant biomarkers in the genome has been performed exclusively in populations of European descent. As a result, some novel genomic tests currently being pushed into the clinic may be virtually useless in patients of African descent or other minority populations, who carry genetic mutations different than Caucasian patients.

Perera has dedicated her career to making sure this disparity does not remain. A pioneer in the field of pharmacogenomics specifically for African-Americans, Perera is now the principal investigator of a five-year, $7.5 million grant from the National Institute on Minority Health and Health Disparities. Awarded last summer, the grant funds a project called ACCOuNT (African-American Cardiovascular pharmacogenomics CONsorTium), which aims to discover genetic variations specific to African-Americans to predict patient response to common cardiovascular drugs. The project will also begin to translate those findings in clinical settings.

For Perera, the motivation behind her work is fueled not only by the pursuit of scientific discovery, but also by a deep sense of social justice.

“Since these studies began 20 to 25 years ago, we have continued to only investigate people of European descent. And I think most people in the scientific community unconsciously don’t realize that this is pushing us farther back,” she says. “There is a real lack of social justice in this world, and we can feel very powerless to do something about it. If this project helps in any way to make people feel heard — or feel that their problems and their experiences matter — then that’s something I can feel very good about.”

ACCOUNTING FOR ALL PATIENTS

After earning doctorate degrees in pharmacy and pharmaceutics in 2001 and 2003, Perera began a postdoctoral fellowship in pharmacogenomics at the University of Chicago, where she remained for 10 years until joining Northwestern in July of last year.

“Northwestern seemed like a very exciting institution that really had its eye on the personalized medicine initiative and the push for genome-guided therapy,” Perera says. “Many people say that the slogan for pharmacogenomics is ‘the right drug, at the right dose, to the right patient.’ That’s really the goal of what we’re doing.”

Her lab at Feinberg is now committed to making sure that the benefit of such personalized medicine will be made available to all patients. Along with ACCOuNT, Perera and her collaborators are also actively involved in a number of other research projects, including pharmacogenomics for inflammatory bowel disease and investigating the genome’s role in the regulation of drug-metabolizing enzymes in the livers of African-Americans.

Still, cardiovascular drugs and anticoagulants have always remained a key research focus for Perera.

In part, it’s because the population she studies is at a higher risk. Consider venous thromboembolism (VTE), a type of blood clot that forms in a vein that can be fatal if it migrates to the lungs. African-Americans have a 30 to 60 percent higher incidence rate of VTE compared to other populations, and they also suffer a higher mortality rate from the disease.

Extensive studies have identified two genetic markers that predispose people to clotting, and there are now tests used clinically to identify those most at risk. But the research had only been conducted in people of European descent — and in fact those two key variants don’t exist in populations of African descent.

“That means if you had an African-American patient who kept having clots, the genetic test would come back negative — but that doesn’t mean they are not at risk,” Perera explains. “I thought it was important to discover something that would matter for African-American patients.”

In 2016, Perera and her team identified, for the first time, three common genetic variants in African-Americans that double a patient’s risk for VTE. The findings were published in the journal Blood.

“There’s still much work to do to get these genetic biomarkers into the clinic, but this is the first step,” Perera says. “I want everything we do to be translatable and useful to the clinic. My whole point is to give physicians tools that they can use if they have a diverse patient population.”

FROM BENCH TO BEDSIDE

The goal of the ACCOuNT grant is to discover novel genetic variants relevant to pharmacology in African-Americans, but also to ensure that those findings quickly get translated into clinical use, where they can truly benefit patients.

“There needs to be an acceleration of the discovery and translation of pharmacogenomics in this population. That was the motivation for this grant,” says Perera, who will conduct the research in collaboration with investigators at the University of Chicago and other academic medical centers.

The initial basic science component of the project will focus on identifying genetic variants that might affect either the response or dose of anti-clotting and anti-platelet drugs, such as Clopidogrel. The translational side will then use the resulting genetic variants to guide therapy in African-Americans.

The study, the first to investigate pharmacogenomics in African-Americans on this scale, plans to recruit thousands of participants throughout both Chicago and Washington, D.C.

Kevin O’Leary, MD, MS, chief of Hospital Medicine in the Department of Medicine, will help lead the grant’s translational efforts at the Northwestern site, along with Marc Rosenman, MD, associate professor of Pediatrics.

“This exciting project may illustrate new ways for us to improve the safety and effectiveness of medications,” Rosenman says. “We thereby might be able to improve patients’ overall satisfaction with healthcare and improve the regularity with which they take their prescribed medications.”

Beyond its fundamental goals, the project also has the potential to inform medicine in a much broader sense: As part of the grant, the investigators will build an African-American Genomics Common, a first-of-its-kind repository of participants’ genomic, transcriptomic and clinical data that the scientific community at large can access for future research.

“I created this because there are questions I want to answer, for sure. But there are so many questions — more questions than I could ever answer in an entire career in science,” Perera says. “I want to spur interest in this field. For the scientific community to be motivated to look at this population, they must have public data.”

At the same time, Perera notes that while ACCOuNT, and her lab’s research in general, is specifically focused on African-Americans and discovering variants in that group, much work is still needed in pharmacogenomics for all minority populations.

“I came to this research very scientifically; the science is incredibly interesting, especially when you think about the genome and drug differences between populations,” she says. “But as I started to present my research, I realized how personal this is to so many. Somebody needs to be the voice to advocate for those patients we don’t have data for.”

Rosenman adds that he admires the way Perera thoughtfully elicits input from African-American patients and community organizations to help shape the way the studies will be conducted.

“In research, the United States historically has shortchanged the African-American and other minority populations,” Rosenman says. “Dr. Perera’s project is a step in the right direction in redressing the imbalance.”