Podcast recap: Pradeep Natarajan on the blood mutations underlying cardiovascular risk
By Joy N. Ismail, PhD
Most people accumulate cancer-associated blood mutations as they age, and quietly, without ever developing cancer. A growing body of evidence now links those mutations to cardiovascular disease, and points to treatments that already exist. That reframes how we predict and prevent the leading cause of death, and it moves the frontier of heart disease from the biology to the clinic.
In a recent episode of The Genetics Podcast, host Patrick Short spoke with Dr. Pradeep Natarajan, Director of Preventive Cardiology at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Pradeep led the seminal 2017 work connecting clonal hematopoiesis to coronary artery disease, and he is now moving to Amgen to lead cardiometabolic and human genetics research. The conversation covered how these mutations drive disease, why the mechanism is treatable, and how polygenic risk scores can flag risk long before today's tools do.
A cardiovascular risk factor hiding in the blood
Clonal hematopoiesis describes acquired, cancer-associated mutations that expand across blood cells with age. The field emerged from exome sequencing intended to find inherited variants, which instead surfaced these acquired clones. Three 2014 papers launched the area, and Pradeep's 2017 paper showed that clonal hematopoiesis was enriched in coronary artery disease patients and reproduced atherosclerosis in mice.
The prevalence is substantial. Roughly 10% of people over 70 carry expanded cancer-associated mutations without having cancer. Those mutations carry a 10 to 11 times increased blood cancer risk from a low base, and about 40% higher overall mortality. This is a population-level signal, not an edge case.
The mechanism points to causality, and to existing drugs
The strength of this work is that it explains why the association exists. TET2, which accounts for roughly 20 to 25% of clonal hematopoiesis cases, shows the clearest cardiovascular signal, and it converges on a defined inflammatory cascade running through the NLRP3 inflammasome, IL-1β, and IL-6.
Three independent lines of evidence support causation rather than correlation. In the CANTOS trial, the IL-1β antibody canakinumab lowered cardiovascular events by about 15% overall, and by an exploratory 60 to 70% in the small subgroup carrying TET2 mutations. A common IL6R missense variant, present in about 40% of people, confers roughly 5% cardiovascular risk reduction generally but around 40% in CHIP carriers. And colchicine, an FDA-approved, low-cost drug that likely acts on the same inflammasome, already lowers cardiovascular risk today.
"It's very exciting that there is a potentially new precision medicine paradigm for coronary artery disease. It's like us trying to become oncologists."
That framing is the core of the shift. Risk is tied to a specific, identifiable clone and matched to a targeted intervention, the same logic oncology already uses.
Clonal hematopoiesis is the visible tip of a larger phenomenon
Blood is easy to sample, which is why clonal hematopoiesis was seen first. Somatic mosaicism spans every tissue, and the NIH Common Fund SMaHT consortium is now mapping normal mosaicism across the body. Pradeep noted that these mutations may persist for a reason, tied to bone marrow reserve later in life, which shapes how and when to intervene.
"If you deeply sequenced individuals in middle age... almost everybody has a chip mutation, has a cancer causing mutation that is quiescent, that has not led to clonal proliferation."
Timing matters for treatment. Addressing inflammation late in the process has limited reach, while acting earlier changes the outcome.
"The inflammation is almost like a band aid, but if you can do it earlier, there's a prospect of substantially more value."
Polygenic risk scores fill the early-detection gap
Today's standard 10-year risk estimation is largely a function of age and sex, so it misses younger patients whose risk has not yet surfaced. As Pradeep put it, that model works for people who have already reached middle age without an event. Genetics is knowable early in life, which addresses the part of the population current tools overlook.
The scale of that gap is concrete. Severe hypercholesterolemia, with LDL above 190, affects about 3 to 5% of people at roughly 3 times the risk. The same risk level corresponds to about the top 20th percentile of contemporary polygenic risk scores, or roughly 1 in 5 people. Statin and PCSK9-inhibitor trials also show greater relative risk reduction per unit of LDL lowering in high-PRS individuals, so identifying these patients has direct treatment implications.
The bottleneck has moved from science to adoption
Polygenic risk scoring has now entered cholesterol guidelines for the first time, which Pradeep called the start rather than the finish. The open problems are practical: there is no single canonical score, standardization remains unresolved, and trial enrichment is still being worked out as a way to make cardiovascular trials more efficient.
His move to Amgen fits this arc. The company has deep human-genetics roots, including well-known assets such as evolocumab (Repatha) targeting PCSK9 and olpasiran targeting Lp(a), on a foundation that traces back to its 2012 acquisition of deCODE genetics. The science to predict and act on cardiovascular risk far earlier already exists. What remains is screening, standardization, and getting it into routine care.
Listen to the full episode below.