About one in five heart attack patients had no warning. Their cholesterol levels were fine, their blood pressure normal. They weren't smokers, and their family members didn’t have heart trouble.
The same is true for breast cancer: A woman may have no obvious risks, nor the dreaded BRCA1 or BRCA2 genes, but still gets a scary diagnosis.
Medicine has never been able to do anything to prevent those unhappy surprises, because there had been no way to know who might be struck.
Now, Boston-area researchers have developed a tool to identify people at high genetic risk for a handful of common conditions — not from a single, rare, faulty gene but from tens or hundreds of tiny alterations that add up with accumulating risk.
These so-called polygenic risk scores can be identified as early as birth, allowing doctors to prescribe medications and counsel patients about lifestyle habits that can reduce or limit their increased risk, says Sekar Kathiresan, the study’s lead author and a professor of medicine at Harvard Medical School, director of the Center for Genomic Medicine at Mass. General Hospital and director of the Cardiovascular Disease Initiative at the Broad Institute.
“Over the last couple of years we've shown that the DNA is not destiny here,” says Kathiresan, whose study was published Monday in Nature Genetics. “Basically being optimal on lifestyle can cut that risk in half and statin medications that lower cholesterol can cut the risk in half, as well.”
He and his colleagues developed the risk score by looking at 6.6 million spots in the genome to flag gene mutations that individually are almost irrelevant but collectively can increase someone’s risk of disease.
Their research found that about 8 percent of the general public is at unusually high risk for heart attack without any warning signs; 6 percent are at high risk for an irregular, rapid heart rate known as atrial fibrillation; 3.5 percent for diabetes; 3 percent for inflammatory bowel disease; and 1.5 percent for breast cancer — five times more than have either BRCA gene mutation.
“What's exciting here is that we have an entirely new genetic path to risk — this polygenic model that is identifying a set of people that heretofore have been kind of under the radar,” Kathiresan says.
He says improvements in computer algorithms, a deeper understanding of genetics and large medical data sets now allow researchers to estimate this cumulative risk in a way they couldn't before.
Katherisan wants to provide the score as part of his research — at no cost to the curious. His team is working on an online calculator that would determine risk among the 17 million Americans who have already submitted their data to companies that offer inexpensive genetic tests like 23andMe or Ancestry.com. (The link will probably be here when it is completed.) The Scripps Research Institute already has a similar app for calculating coronary artery disease risk.
Using the tests more broadly would require approval by the U.S. Food and Drug Administration, which until earlier this year had blocked 23andMe from offering a BRCA test.
The genetic mutations that confer extra risk were validated using databases of hundreds of thousands of people of mainly European ancestry. That means the risk scores will be most accurate for people who descended from Europeans, though Katherisan says it’s still helpful for those with other ancestries. Hopefully, he says, better scoring methods can be developed for people from other ethnic and racial groups over time as researchers grow their data sets representing those groups.
The new analysis builds on more than 15 years of research into the genetic basis for common diseases like heart attacks, “so you're able to more precisely say for any given spot in the genome how much risk it increases,” Katherisan says.
He is now working on similar scores for other diseases, including Alzheimer’s, prostate and colorectal cancer, and predicts the scores will soon be commonly used by doctors.
“In a few years most people will have the opportunity to know this this polygenic risk number, similar to the way we know our cholesterol right now,” Katherisan says.
Eric Topol, a cardiologist and geneticist at the Scripps Research Institute in La Jolla, California, who has led similar work on cardiac risk, says he was shocked to learn his own risk score.
“For heart disease, I have very high risk and I didn’t anticipate it since neither of my parents had heart disease,” he says. As a cardiologist he says he lives a healthy lifestyle, but he’s added a statin to his daily routine since seeing his results. “I think that’s the best justification I have for taking a statin.”
Robert Yeh, a cardiologist at Beth Israel Deaconess Medical Center who wasn’t involved in the research, says he’d rather not know his risk scores for other conditions — at least not yet.
He wants further research to ensure that having this kind of information improves how patients are cared for and how they fare. “Short of that evidence, I'm not sure that I'm ready today to say that I want this test done on me,” says Yeh, who is also an associate professor of medicine at Harvard Medical School and the director of the Smith Center for Outcomes Research in cardiology at Beth Israel.
But eventually, Yeh says he expects this kind of information will prove extremely useful for a whole host of conditions.
“People represent a constellation of genes of environment,” Yeh says. “The greater ability that we have to integrate more information pieces to identify patients at elevated risk, I think the more successful we're going to be in ultimately preventing and treating diseases before they occur.”