EP 248: The blood mutations rewriting cardiovascular risk with Pradeep Natarajan

Value of the Information & Strength of the Argument

The value of the information is high, as it provides an expert’s perspective on cutting-edge research in cardiovascular genetics. Dr. Natarajan offers detailed insights into the discovery and implications of clonal hematopoiesis, supported by references to key studies and clinical trials. The argumentation is solid, with logical progression from basic biology to therapeutic strategies. He presents evidence from mouse models, human genetic studies, and clinical trials to support the causal role of CH in cardiovascular disease. The discussion on polygenic risk scores is also valuable, addressing both their potential and the practical hurdles. The reasoning is clear and well-supported, though some speculative elements are acknowledged, such as the evolutionary purpose of CH.

The title accurately reflects the content, focusing on blood mutations (clonal hematopoiesis) and their impact on cardiovascular risk.

8/10

The discussion is led by a leading expert in cardiovascular genetics, with references to peer-reviewed studies and clinical trials. The content is well-structured and grounded in scientific evidence, though it is an interview format with some speculative elements.

• 00:00Intro to The Genetics Podcast
• 00:59Welcome to Pradeep
• 01:31The origin story of clonal hematopoiesis (CH) as a cardiovascular risk factor
• 10:10CH mutations such as TET2 that are linked to cardiovascular disease
• 13:06Evidence tying inflammation to CH and drugs that could target it
• 17:35TenSixteen Bio’s strategy for targeting CH and the challenge of finding the right patients
• 22:30Trajectory of CH across age and somatic mosaicism beyond blood
• 27:58How polygenic risk scores fill a gap in cardiovascular risk prediction
• 36:20The future clinical applications of polygenic risk scores
• 41:00The challenge of standardizing polygenic risk scores for clinical and regulatory use
• 44:13Pradeep's move to pharmaceutical company Amgen and his reasons for it
• 48:22Closing remarks

• Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease — Referenced as the key paper from 2017 that established the link between clonal hematopoiesis and cardiovascular disease.

• Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease — The primary study discussed, supporting the link between CH and cardiovascular risk.