{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:36:46Z","timestamp":1768570606974,"version":"3.49.0"},"posted":{"date-parts":[[2025,1,15]]},"group-title":"Cardiovascular Medicine","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T00:00:00Z","timestamp":1736899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related presence of expanded somatic clones secondary to leukemogenic driver mutations and is associated with cardiovascular (CV) disease and mortality. We sought to evaluate relationships between CHIP with cardiometabolic diseases and incident outcomes in high-risk individuals.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>CHIP genotyping was performed in 8469 individuals referred for cardiac catheterization at Duke University (CATHGEN study) to identify variants present at a variant allele fraction (VAF) \u22652%. Associations were tested among any CHIP variant, large CHIP clones (VAF \u226510%) and individual CHIP genes with prevalent cardiometabolic traits. Cox proportional hazard models tested CHIP associations with time-to-overall mortality and Fine-Gray analyses tested CHIP associations with incident cardiovascular outcomes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We identified 463 CHIP variants in 427 individuals (5.0%) of which 268 (3.2%) harbored large CHIP clones. CHIP and large CHIP were associated with lower odds of obesity (OR 0.79 [95% CI 0.65-0.98], p=0.03; OR 0.76 [95% CI 0.57-0.99], p=0.04, respectively). CHIP was associated with prevalent HF (OR 1.25 [95% CI 1.01 - 1.55], p=0.04; especially for non-\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    CHIP (OR 1.38 [95% CI 1.04-1.82], p=0.02). CHIP was also associated with incident events: Non-\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    CHIP was associated with increased risk of time-to-HF hospitalization (HR 1.29 [95% CI 1.02-1.63], p=0.03).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    In high-risk individuals referred for cardiac catheterization, large CHIP and non-\n                    <jats:italic>DNTM3A<\/jats:italic>\n                    CHIP were associated with obesity, prevalent HF, incident CV events. These findings strengthen the importance of CHIP as a biomarker for CV disease and highlight the contributing risk of large CHIP clones and non-\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    CHIP variants.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Condensed Abstract<\/jats:title>\n                  <jats:p>\n                    CHIP, the presence of somatic expanded mutations in myeloid driver genes in hematopoietic cells, is an emerging CVD biomarker. Using whole exome sequencing of peripheral blood derived DNA from participants in the CATHGEN cohort, we identified significant associations with obesity, prevalent HF, incident mortality, HF hospitalization and AF after adjusting for established clinical risk factors. These findings add strength to the growing literature of CHIP as a CVD biomarker, emphasizing large CHIP and non-\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    CHIP variants for driving risk. Future studies should aim to further elucidate gene-specific risk and the inflammatory and metabolic mechanisms possibly mediating these relationships.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Clinical Perspective<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What Is New?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>\n                          In a cohort with high prevalence of CAD, CHIP is inversely associated with obesity and associated with higher odds of prevalent HF and subsequent mortality, even after adjustment for relevant clinical comorbidities. Risk of incident events of mortality, HF hospitalization and AF were driven by large CHIP variants (VAF\u226510%) and CHIP variants in genes other than\n                          <jats:italic>DNMT3A<\/jats:italic>\n                          .\n                        <\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What are the Clinical Implications?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Though more research is needed, as the evidence around the risk associated with specific CHIP variants continues to grow, clinicians should be prepared to provide gene- specific counseling for cardiometabolic disease risk.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                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