Polygenic risk scores: Potential game changer
Scores could pave the way for better prevention and treatment in stroke.
A wider lens on the genetics of human disease is reshaping risk oprediction, with polygenic risk scores poised to help better personalize cardiovascular treatmwent decisions.
Polygenic risk scores (PRS) combine information from thousands of different genetic variants into a single number reflecting a person’s genetic risk of someone having a specific outcome. The growing potential of PRS is the topic of a session Thursday, “Polygenic Risk Scores in Stroke: From Genomics to Precision Care.”
Guillaume Paré, MD, director of the Clinical Research Library and Biobank at McMaster University in Hamilton, Ontario, will share how PRS can help stroke patients by guiding aspirin and statin therapy.
“For a very long time, we had this notion that diseases and traits were the result of a handful of genes that determine the risk of disease,” said Paré, who is also deputy director of the Thrombosis and Atherosclerosis Research Institute at the university. “But what has happened in the last 10 to 15 years is the realization that this isn’t how it works. It turns out that for most diseases it’s the interactions of thousands of different genes and thousands of different genetic barriers together that explain the genetic risk.”
Polygenic risk scores are not all that different from the existing clinical risks scores, such as the Framingham Risk Score, used in medical clinics around the world, according to Paré.
“The big difference is that instead of putting together clinical risk factors, we’re putting together genetic risk factors,” he said.
He said research has shown that the latest generation of PRS can identify people who have a risk for coronary artery disease, for example, based solely on genetics.”
“The advances have been phenomenal,” he said. “And it turns out that these polygenetic risk scores are now quite predictive for the risk of disease. And in many cases, they are on par, or even more predictive, than even the strongest clinical risk factors.”
Paré’s presentation will specifically focus on how the PRS can help better tailor the use of two commonly used medications for preventing coronary artery disease (CAD): aspirin and statins.
Paré uses the example of CAD because research is “one step ahead of stroke,” with larger studies available demonstrating how PRS can be an effective way to determine the best course of preventative treatment for CAD.
“If we can identify people who are genetically at risk for the disease, these people will benefit the most from the therapy,” he said. “For example, if we have two individuals, one with a 5% risk and one with a 20% risk, and we know statins will cut the risk by 50%, we know the person with a 20% risk will benefit more from the statin.
“People who have an increased genetic risk do seem to have an increased benefit from statins, and it appears this pattern also applies to aspirin.”
Beyond just determining who will benefit most, Paré said, polygenic risk scores raise the possibility that medical professionals could predict whether the effect of the drug will be bigger on some individuals than on others.
“So basically, that one person, based on genetics, if you give them a statin the risk will decrease by, say, 20%,” he said. “But then in another person based on genetics, the statin will cut the risk of cardiovascular disease by 60%.”
For aspirin, a PRS raises a different set of questions because there is a need to maintain a balance between the increased risk of bleeding that comes with aspirin and its benefits in the prevention of ischemic effects.
“I would say that currently the consensus is to not give aspirin as a primary prevention,” Paré said. “But if we can identify a group of people who have a greater benefit from the aspirin with respect to ischemic reduction without the concurrent increase in risk for hemorrhagic events or bleeding, then perhaps we could identify a portion of participants who actually could benefit from aspirin in a primary prevention setting.”
The key question, Paré said, is whether polygenic risk scores are ready to be used in a clinical setting.
“The evidence is tantalizing and exciting, but we are probably not there yet,” he said. “A lot of [the findings] are subgroup analyses of larger trials. The hypothesis hasn’t been tested as the primary hypothesis in a trial, and that needs to happen.”
Paré said additionally, more research is needed into PRS involving both aspirin and statins because scientists don’t fully understand yet why people with higher PRS benefit more from statins and perhaps aspirin.
“The potential is clearly there, but it also raises clinical questions. How are we going to be able to generate the evidence and answer those questions,” he said. “Once we understand this, we may be able to do polygenic risk scores that are even better.”
