Impact of clonal hematopoiesis on atherosclerotic cardiovascular disease according to low-density lipoprotein cholesterol levels

Background Clonal hematopoiesis of indeterminate potential (CHIP), defined as a clonal expansion of hematopoietic stem cells with age-related recurrent somatic mutations, has recently emerged as a novel cardiovascular risk factor. However, the pathogenic mechanism of CHIP in atherosclerotic cardiovascular disease (ASCVD) development is not yet fully understood. Methods In a cohort comprising 4,300 asymptomatic Korean participants aged 40–79 years, we investigated the risks associated with ASCVD by CHIP and the interplay of CHIP with other traditional risk factors for developing ASCVD. Using coronary computed tomography angiography (CCTA), we noninvasively assessed the changes in coronary arteries to evaluate CHIP-associated atherosclerosis. Results CHIP was present in 368 participants (8.6%). The most commonly mutated genes in CHIP included DNMT3A, TET2 , and ASXL1 . During follow-up (median, 4.7 years), 18 ASCVD cases (4.9%) were observed in CHIP carriers vs. 62 (1.6%) in non-carriers ( p <0.001). The presence of CHIP was associated with an increased risk of ASCVD (adjusted hazard ratio [HR] 2.54, 95% confidence interval [CI] 1.48–4.37, p <0.001) after adjusting for other conventional cardiovascular risk factors. Particularly, in participants with high levels of low-density lipoprotein (LDL) cholesterol, CHIP enhanced the risk of ASCVD development (adjusted HR 4.18, 95% CI 1.99–8.77, p <0.001), demonstrating a significant synergism between CHIP and LDL cholesterol ( S -index, 4.61; 95% CI 1.04–20.57, p =0.045). Serial CCTAs supported our findings by displaying de novo measurable coronary atherosclerosis with unstable plaque and in proximal lesions only in CHIP carriers with high LDL cholesterol. Conclusion The presence of CHIP was significantly associated with the risk of ASCVD through synergy with LDL cholesterol in the general population, which might promote the early stage of coronary atherosclerosis. ### Competing Interest Statement H.S. and Y.K. are shareholders of Genome Opinion, Inc. The content of this study has been applied as a patent with H.S. and S.C. ### Funding Statement This work was supported by Genome Opinion, Inc. Blinded to clinical information, Genome Opinion, Inc. provided the next-generation sequencing. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Seoul National University Hospital (H-1908-121-1056) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors