Polygenic risk scores could help patients understand whether they really need early treatment for heart disease.
Katie Elkins has a family history of heart disease on both sides of the family, and she was worried. Her father had a heart attack this year on Easter morning at the age of 53 — the same age his mother was when she had one.
Ms. Elkins’s primary care doctor ordered a blood test, which revealed that her LDL cholesterol level was 160. That is high for someone at her age of 34. The doctor referred her to Dr. Daniel Rader, at the University of Pennsylvania, who specializes in preventive cardiology.
The question for Dr. Rader was: Should Ms. Elkins start taking a cholesterol-lowering statin? The guidelines say she is too young — the treatment is typically reserved for people at least age 40. But high cholesterol levels damage blood vessels slowly, over a period of decades. Was her risk high enough to intervene early?
To find out, Dr. Rader suggested Ms. Elkins take a new genetic test, known as a polygenic risk score. It looks at a collection of thousands of genetic variants. Each variant contributes little on its own to heart disease risk, but the variants together might point to those who are likely to have heart attacks.
Cardiologists hope to use such tests, which cost about $150 and are not typically covered by health insurance, to identify people most likely to have heart attacks long before they have them. Some doctors envision testing children as part of routine pediatric care.
“There’s a real unmet need to identify high-risk people very early in life,” said Dr. Nicholas Marston, a cardiologist at Brigham and Women’s Hospital in Boston. He has studied polygenic risk scores and has also been involved in trials for pharmaceutical companies that make cholesterol medicines. “We know the solution to preventing heart disease is getting your bad cholesterol as low as possible for as long as possible.”
Those at high risk would be treated aggressively. But the test may also spare some patients, including possibly Ms. Elkins, from unnecessary treatment if their risk turns out to be low.
Dr. Rader said Ms. Elkins’s LDL level could put her at risk for a heart attack — but probably not for at least a couple of decades. But a heart attack at any age is life-altering and can have severe effects, even with advances in medicine. So the question of how to protect young people whose risk may manifest years later is pressing.
(Dr. Rader, who has no financial interests in polygenic risk tests, is on the scientific advisory boards of Alnylam and Novartis, which have commercial interests in inclisiran, an LDL-lowering drug.)
Despite the high hopes for the new tests, there are many questions.
Some critics say that a focus on treating younger people is misplaced because they may not comply with taking a statin or another drug for the rest of their lives. It can be difficult for young people to focus on possible threats to their health decades in the future, and some of Dr. Rader’s patients have put off even getting polygenic risk tests after he recommends them.
The real need, these critics say, is with the huge group of older people who need cholesterol-lowering treatment but are not getting it, or who are abandoning their prescriptions. In one study, about 40 percent of people 65 and older who had a heart attack and need lipid-lowering medications for the rest of their lives stop taking statins within two years.
Others, like Dr. Rita F. Redberg, a cardiologist at the University of California, San Francisco, the editor at JAMA Internal Medicine and a critic of the overuse of statins, is concerned that polygenic risk scores could introduce new problems.
“There is a lot of downside to labeling people with a disease,” she said.
The label, she added, “inexorably leads to tests and a search for treatments.” And, she said, “because the person, who now has become a ‘patient,’ is asymptomatic, more tests and possible treatments in most cases will not make the person feel any better.”
People can go from thinking of themselves as healthy to thinking of themselves as someone with a disease. “Now, whenever they experience the common aches, pains and twinges of life, they wonder if it is because they have this ‘disease,’” Dr. Redberg said. “And they may then go to the doctor or even emergency room for things they would not have previously. And that also will lead to more tests and procedures, with their attendant risk of harms.”
Others, while enthusiastic about the prospects for polygenic risk scores, say that doctors need to know more about how effective early intervention might be.
Dr. Iftikhar Kullo of the Mayo Clinic in Rochester, Minn., asked, “Do you actually improve long-term outcomes” by using the tests and acting on them?
Suppose your young patient has a score indicating a heart attack is likely, perhaps a few decades or more later. If that patient starts taking a statin right away, as opposed to in midlife, will a heart attack be prevented?
Dr. Sadiya Sana Khan of Northwestern University emphasized the need for more research. She has a new study showing that, in middle-aged to older adults, CT scans of the heart, which can show the buildup of plaque, are better than genetics in predicting risk. But that leaves a question about how to manage risk in young people, who almost never have visible plaque on a CT scan, even if they are at greater danger for a heart attack later in life.
“We need more studies that focus on younger people with follow-up over several decades,” she said. If risk scores in young adults predict a greater likelihood of a heart attack, she asked, will that prediction be borne out when the people are older, at ages when heart attacks are more likely? Or will those with high risk scores instead be needlessly worried about their hearts?
One hint comes from a recent study by Dr. Marston and his colleagues. They used data from hundreds of thousands of people in Britain and Japan whose genetic material and clinical outcomes are available to researchers.
By doing the genetic tests and looking at 10 years of data on the subjects’ health, he and his colleagues asked if those with high risk scores were in fact more likely to have a heart attack. They were — but only if the people were younger than 50. In older people, the cumulative effect of traditional risk factors — like smoking, LDL levels and diabetes — were so powerful that they dominated the risk picture.
Dr. Rader and his colleagues in preventive cardiology at Penn are proceeding with the assumption that the risk scores can help them make treatment decisions for patients when it is not clear whether or how aggressively to lower their LDL levels. These people typically are between the ages of 20 and 50 in whom traditional risk assessments are not helpful.
They also include patients who are reluctant to take statins any sooner than absolutely necessary.
Such was the situation for Sally Thompson, another patient of Dr. Rader.
Ms. Thompson, in her late 40s, has an LDL cholesterol level of 160 milligrams per deciliter, not high enough to make a statin imperative. But her doctor said it was advisable. She has no family history of heart disease. She said she would prefer to postpone starting a statin because she already is taking seven drugs for other chronic conditions.
She agreed to have the genetic test and take a statin, if it showed her risk is high. It was — in the 70th percentile — and she was persuaded.
Other preventive cardiology experts are not yet ready to use the tests to make most treatment decisions.
Dr. Marston, for example, so far is only ordering the test for young people who had a heart attack at an early age and are trying to understand why.
Even then, polygenic risk scores do not always provide answers.
Kori Green, 39, had severe chest pain last year and discovered that one of her coronary arteries was almost completely blocked. The news came as a complete surprise. “I am an avid skier and have a healthy diet,” she said. Neither of her parents have heart disease.
The genetic test Dr. Marston suggested did not solve the mystery of why her artery was blocked.
“What’s really unfortunate is we still don’t know how this happened,” Ms. Green said.
But polygenic risk scores are not going away. At Geisinger, a medical care system in Pennsylvania, researchers are mapping out strategies for introducing them, including clinical trial planning.
“I predict it will be part of routine care,” Dr. Christa Martin, Geisinger’s chief scientific officer, said. “We will treat it no differently than cholesterol screening or screening for diabetes.”
To Prevent Heart Attacks, Doctors Try a New Genetic Test - The New York Times
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