Using genomic modifiers to mechanistically link clonal hematopoiesis of indeterminate potential penetrance to coronary artery disease

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Project Summary/Abstract Though cardiovascular disease (CVD) management has advanced, CVD remains the leading cause of premature death worldwide. As age remains the dominant factor in CVD risk and the population ages, the poorly understood age-related factors promoting CVD risk require urgent investigation. This proposal uses functional human genomic and multi-omics modifier analyses with the human specimen to investigate the mechanistic links between clonal hematopoiesis of indeterminate potential (CHIP) and CVD toward improving clinical management. CHIP is common in elders (≥1 in 10 among >70 years), and recent data establish coronary artery disease (CAD), a primary cause of CVD, as the primary cause of the increased mortality in those with CHIP. With the discovery in N~37K and replication in N~5K, preliminary data show that SNPs on chromosome 10q23.32 increase the CAD hazard among those with CHIP 10-fold but are not associated with CAD among those without CHIP. Downstream analyses showed the potential role of CPEB3, which modulates the IL-6 signaling pathway, in line with the previous studies showing the importance of the IL-6 pathway for CAD development in CHIP carriers. However, the exact mechanisms are yet to be elucidated. Further genomic and functional molecular analyses would identify novel CHIP-specific mechanisms in CAD pathogenesis and lead to CAD prevention strategies among CHIP carriers with the most robust preclinical evidence in humans. The aims of this proposal will: discover the further germline genetic predisposition that induces CHIP-related CVD with an increased sample size (~575K: >10-fold from the preliminary study) to construct CHIP specific polygenic interaction risk score (PIRS) for CAD, which stratifies the risk of CVD in CHIP carriers (Aim 1 and 3), prioritize causal mechanisms for CHIP-related CAD with the integration of genomic data and multi-omics data (Aim 2), and dissect the molecular mechanisms for CHIP-related CAD combining population genetics and analyses of human specimens (Aim4). Successful completion of the aims will pave the way for cardiovascular risk management of CHIP carriers by (i) improving risk stratification and (ii) improving our understanding of the causal underpinnings of CAD and CHIP. Through this award period, PI will receive invaluable guidance from mentors and advisory board members, the world leaders in these fields, and also take rich didactic courses provided by the world-class environment of Harvard, MIT, and Broad Institute to gain new knowledge and skills to be a competitive independent investigator, which will be directly implemented to this study. The PI will gain extensive experience in translational research of cardiovascular medicine under the mentorship of Dr. Natarajan, a world-class leader in the genomics of cardiovascular medicine and a member of Harvard Medical School. Furthermore, this research will provide vital career guidance on the PI’s path to becoming an independent investigator.