Flying Under the Radar: The Genotype-First Trial That Found Hidden Heart Disease in Healthy Adults

For more than half a century, the way doctors decide who is at risk for a heart attack has rested on a short list of numbers anyone can recite. Cholesterol. Blood pressure. Blood sugar. Whether you smoke. How old you are. Feed those figures into a risk calculator and out comes a percentage, a tidy estimate of the odds that your arteries will betray you in the next ten years. It is a system built on the body’s present-day biology, the wear and tear visible at the moment of measurement.

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But that system has a blind spot, and a new wave of research is exposing exactly how large it is. Some people walk into a clinic with pristine cholesterol, normal blood pressure, a healthy weight, and a clean bill of health, and they are quietly building dangerous plaque inside their coronary arteries anyway. Their risk was written before they were born, encoded across millions of tiny variations in their DNA. The standard calculators never see it coming.

In February 2026, a team based at Massachusetts General Hospital, Harvard Medical School, and the Broad Institute of MIT and Harvard published a report in the Journal of the American College of Cardiology that put hard numbers to this hidden population. The study, drawn from the PROACT clinical trials, did something that until recently belonged to the realm of science fiction. It recruited research participants not by their symptoms or their lab values, but by reading their genomes first. The results suggest that a genetic test most patients have never heard of may be one of the most powerful early-warning tools cardiology has ever had.

The Idea of Reading Risk in the Genome

Coronary artery disease is not caused by a single faulty gene the way cystic fibrosis or Huntington’s disease is. It is what geneticists call a polygenic condition, the cumulative product of hundreds of thousands, even millions, of common DNA variants. Each variant on its own nudges risk only a hair in one direction or the other. Inherit an unlucky combination of them and the small effects stack up into a substantial lifetime burden.

A polygenic risk score, or PRS, is the attempt to capture that burden in a single number. Researchers scan large databases of genomes from people who did and did not develop heart disease, identify which variants tilt the odds, and weight them by their individual contribution. Add up a given person’s variants, each multiplied by its weight, and the result places them somewhere on a bell curve of genetic predisposition. Someone in the top few percent of that distribution can carry a risk comparable to that of a person with a major clinical risk factor, even if every conventional measurement looks reassuring.

The appeal for prevention is obvious. Your cholesterol can change next month. Your genome cannot. A polygenic score is fixed from birth, which means it can flag elevated risk decades before plaque, symptoms, or a first heart attack ever appear. The question that has dogged the field for years is whether that theoretical promise translates into something useful at the bedside. PROACT was designed to find out.

Genotype First: Turning Recruitment Inside Out

The intellectual leap at the heart of PROACT, led by Akl C. Fahed and first author Roukoz Abou-Karam with senior collaborators including Pradeep Natarajan, Patrick Ellinor, and the prevention researcher Paul Ridker, was to invert the usual order of medicine. Ordinarily a patient arrives with a complaint, gets tested, and a risk picture emerges. PROACT started from the DNA.

Working within a large hospital-based biobank, the investigators screened 64,092 genotyped participants. They were hunting for a specific and counterintuitive group: adults between 40 and 75 years old who carried a high coronary artery disease polygenic risk score, yet had no diagnosed cardiovascular disease and were not taking any cholesterol-lowering medication. In other words, people whose genes said danger while their charts said nothing at all.

That group turned out to number 2,495 individuals, about 3.9 percent of everyone screened. What made them remarkable was how healthy they looked on paper. Their median ten-year risk of atherosclerotic cardiovascular disease, calculated using the standard pooled cohort equations, was just 3 percent. By every conventional yardstick, these were low-risk people, the kind a physician would reassure and send home without a second thought.

The researchers then tested whether a genotype-first invitation could actually bring people through the door. Of the first 1,314 individuals invited, 283 opted in, a participation rate of 21.5 percent, and 204 completed baseline imaging. That alone was a meaningful proof of concept. It showed that a hospital can reach into its biobank, identify people by an invisible genetic trait, contact them, and persuade a real fraction of them to take part in a prevention study. Genotype-first recruitment, long discussed in theory, worked in practice.

What the Scans Revealed

The decisive moment came when those 204 participants underwent coronary computed tomography angiography, a detailed CT scan that visualizes the coronary arteries and detects plaque long before it produces symptoms. This is where the abstraction of a genetic score met the physical reality of the arterial wall.

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The participants were, if anything, healthier than average Americans. Their mean age was 56, roughly 69 percent were women, and their mean score on Life’s Essential 8, the American Heart Association’s composite measure of cardiovascular health, was 73.3, well above the United States average of about 65. These were not people neglecting their hearts. They were doing most things right.

And yet half of them, 102 of the 204, already had subclinical coronary plaque. The disease was present and progressing silently in people whose clinical risk profile had effectively declared them safe. The pattern broke down sharply by sex: plaque appeared in 76.2 percent of the men and 38.3 percent of the women, and it was common across every age group studied, not confined to the oldest participants.

The phrase the authors used to describe these individuals captures the stakes precisely. They were "flying under the radar," carrying meaningful arterial disease that standard assessment was structurally incapable of detecting. The investigators concluded that their findings reveal a large population of silent, high-genetic-risk individuals with subclinical plaque for whom preventive treatment could plausibly change the trajectory, but who remain invisible to the tools cardiology currently relies on.

From Detection to Intervention

Finding hidden disease is only valuable if something can be done about it, and the PROACT program is structured as a sequence of trials that move from detection toward treatment. The first arm, PROACT 1, focused on detecting subclinical atherosclerosis and tracking change in cardiovascular health. The published 2026 report represents its interim feasibility findings. The second arm, PROACT 2, takes the next step, randomizing high-genetic-risk individuals to pharmacologic intervention with a statin and colchicine, an inexpensive anti-inflammatory drug that has gained traction in cardiology for its ability to calm the smoldering inflammation that drives plaque rupture.

That combination is telling. It pairs a drug that lowers LDL cholesterol with one that targets inflammation, attacking two distinct engines of atherosclerosis in people identified purely by their DNA. If PROACT 2 shows that treating genetically flagged, clinically silent adults slows or reverses plaque progression, it would establish polygenic risk not just as a forecasting tool but as a legitimate trigger for action.

A third arm, PROACT 3, asks a more human question: what happens when you actually tell someone their genetic risk? It is studying how disclosing a coronary artery disease polygenic risk score influences LDL cholesterol levels, preventive behaviors, and engagement with care, with results expected to mature through 2026. Knowing your number, it turns out, may itself be a kind of intervention, one that motivates the lifestyle and treatment changes that bend the curve.

The Engine Behind the Score

None of this would be possible without dramatic improvements in the scores themselves. Early polygenic risk scores were promising but crude, and they carried a serious flaw that the field has been racing to fix.

A turning point came with the development of more sophisticated multi-ancestry scores. One landmark effort from the Broad Institute’s Cardiovascular Disease Initiative, with Amit Khera among its leaders, produced a score known as GPSMult. Rather than relying on a single population, it integrated genome-wide association data across five ancestries, drawing on more than 269,000 people with coronary artery disease and over 1,178,000 without it, and folded in genetic information on ten additional cardiovascular risk factors.

The performance gains were substantial. GPSMult was associated with roughly double the odds of prevalent coronary artery disease per standard deviation increase in score, and a sharply elevated hazard for developing the disease over time. Crucially, compared with an earlier widely used score from 2018, it improved predictive strength across the board, with effect-size increases of 73 percent for individuals of African ancestry, 46 percent for those of European ancestry, and 113 percent for those of South Asian ancestry.

That last set of numbers points to the field’s most important unresolved problem.

The Equity Problem the Field Cannot Ignore

Polygenic risk scores are only as good as the genetic data used to build them, and that data has long been lopsided. Roughly 79 percent of all participants in genome-wide association studies have been of European descent, even though that group makes up only about 16 percent of the global population. People of African ancestry, by contrast, have been represented at a fraction of their share of humanity.

This is not a minor statistical footnote. Because patterns of genetic variation differ between populations, a score trained mostly on European genomes loses accuracy when applied to people of other ancestries. The risk is concrete and serious: a tool meant to democratize early detection could, if deployed carelessly, widen the very health disparities it was supposed to close, working best for the populations already best served by medicine.

This is why the multi-ancestry push behind scores like GPSMult matters so much, and why the PROACT program’s later phases have incorporated multi-ancestry polygenic risk testing, with companies such as Allelica providing the analytic backbone for PROACT 3. Building scores that perform fairly across all backgrounds is not an optional refinement. It is the difference between a precision-medicine advance that lifts everyone and one that quietly leaves much of the world behind.

A Different Way of Thinking About Heart Disease

Step back from the individual numbers and PROACT represents something larger than one biobank study. It is a glimpse of how prevention may work in the coming decade. For a century, cardiology has been fundamentally reactive, waiting for risk factors to accumulate, for cholesterol to climb, for the first chest pain to send someone to a cardiologist. The genotype-first model flips that logic. It identifies the people most likely to develop disease before any conventional sign exists, then watches and, increasingly, intervenes.

Plenty of questions remain unanswered, and the researchers themselves are careful to frame the published results as exploratory and focused on feasibility. We do not yet have the definitive trial proving that treating genetically flagged but clinically healthy adults prevents heart attacks and saves lives. PROACT 2 is designed to start answering that. Questions of cost, of how to counsel people about probabilistic genetic risk, and of how to deploy these tools equitably are far from settled. A high score is a statement of probability, not destiny, and a low score is no guarantee of safety, particularly given the ancestry limitations that still shadow the technology.

But the core finding is hard to dismiss. In a group of healthy, low-risk, health-conscious adults, selected by nothing but their DNA, half were already harboring the early stages of the disease that remains the leading cause of death worldwide. The information to find them existed in their genomes the entire time. We are only now learning how to read it.

What This Means For You

If you have a family history of early heart disease, or you have ever been puzzled by a relative who suffered a heart attack despite seeming perfectly healthy, the PROACT findings offer a concrete explanation and a path forward. Genetic predisposition to coronary artery disease is real, common, and frequently invisible to standard risk calculators.

Polygenic risk scores for heart disease are increasingly available, both through research programs and a growing number of commercial and clinical services. If you are considering one, the single most important question to ask is whether the score has been validated for your ancestry, because accuracy still varies meaningfully across populations. Bring any result to a physician rather than interpreting it alone. A high score is not a diagnosis and not a sentence. It is a prompt to look more closely, potentially with imaging such as a coronary CT scan or a coronary artery calcium score, and to be more proactive about the factors you can control.

And that is the genuinely hopeful part. Even a risk written into your DNA is not fixed in its outcome. The same levers that protect everyone, not smoking, keeping LDL cholesterol low, staying physically active, managing blood pressure and blood sugar, and following medical guidance on statins or other therapies when warranted, work especially powerfully in people at high genetic risk, because they have the most to gain. A genome you cannot change can still point you toward a future you can. The lesson of PROACT is not that some of us are doomed by our genes. It is that, for the first time, we can find the people most at risk early enough to do something about it.

This article is for informational purposes and does not constitute medical advice. Decisions about genetic testing, screening, and cardiovascular treatment should be made in consultation with a qualified healthcare professional.

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