Abstract 13711: Clonal Hematopoiesis Driven by TET2 and ASXL1 but Not DNMT3A is Associated With Interleukin 6 Levels, Cardiac Biomarkers, Cardiac Remodeling, and Risk of Atrial Fibrillation

Abstract

Introduction: Aging and inflammation are associated with risk of atrial fibrillation (AF), to which clonal hematopoiesis of indeterminate potential (CHIP) may contribute. We investigated whether CHIP was associated with AF, inflammatory and cardiac biomarkers and cardiac structural changes. Methods: We ascertained CHIP (variant allele frequency, VAF ≥2%) in the Atherosclerosis Risk in Community Study (ARIC visit-5, n = 4,131) and the UK Biobank (UKBB, n = 195,851) participants. Using multivariable Cox regression models, we studied the association of CHIP and the top three implicated genes (i.e., DNMT3A , TET2 , ASXL1 ) with incident AF and conducted a meta-analysis on both cohorts. We also ascertained high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL6), IL18, high-sensitivity troponin T and I (hs-TnT and hs-TnI), NT-proBNP, and echocardiography indices in ARIC. We first standardized the natural log of all markers (st-ln) and used the adjusted quantile regression to compare the median in those with and without CHIP. Results: In ARIC, the mean ± SD age was 75.8 ± 5.2 years, 41% were men, 23% were Black, 25% had CHIP, and 11.6% had large CHIP (VAF ≥10%). These measures in UKBB were 56.4 ± 8.1 years, 45%, 2%, 5.8%, and 2.6%, respectively. In the meta-analysis, compared to those without CHIP, the hazard ratios (95% confidence interval) for AF were 1.12 (1.01 - 1.25, P =0.035), 1.31 (1.07 - 1.60, P =0.009), and 1.48 (1.05 - 2.08, P =0.026) for Large-CHIP, Large- TET2, and Large- ASXL1 , respectively. hs-CRP and IL18 levels were similar in those with and without CHIP as well as gene-specific subgroups. Large- TET2 and ASXL1 were associated with higher IL6, which was separately associated with AF. Additionally, Large- ASXL1 was associated with increased left ventricle mass index and NT-proBNP (coefficients in Figure 1 ). Conclusion: Large TET2 and ASXL1 but not DNMT3A CHIP is associated with higher IL6 levels, indices of cardiac remodeling, and an increased risk of AF.