Abstract 15784: Clonal Hematopoiesis of Indeterminate Potential is Associated With Increased Risk of Incident Hypertension

Abstract

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of heart failure (HF) and stroke, particularly HF with preserved ejection fraction and hemorrhagic stroke (HS). Hypothesis: We hypothesized that CHIP is associated with incident hypertension and this association mediates the effect of CHIP on HF and HS. Methods: In 200K UK-Biobank participants with exome sequencing, we ascertained CHIP as variant allele fraction (VAF) ≥2% and large CHIP as VAF ≥10%. Hypertension, HF, and HS diagnosis were determined based on the ICD-9 and ICD-10 codes. Cox proportional hazards models were used to test the association of both CHIP and the CHIP subtypes based on the most implicated driver genes (i.e., DNMT3A , TET2 , and ASXL1 ) with incident hypertension. Logistic regression models were used for mediation analyses, quantifying the extent to which hypertension mediates the effects of CHIP. Results: After excluding those with hematological malignancy (n=1,025) and pre-existing hypertension (n=14,754), 184,760 participants (56.14±8.12 years, 44.25% male, and 95.33% white ethnicity) were included. During a median follow-up of 12.2 years, 42,049 (22.76%) participants developed hypertension. CHIP mutations were significantly associated with incident hypertension (Table). Mutations in DNMT3A and TET2 but not ASXL1 drove this association. Mediation analysis revealed 17.9% (9.4% - 38.2%, P<0.001) of the effect of CHIP on HF and 5.7% (2.4% - 22.4%, P<0.001) of the effect on HS were mediated through the increased risk of hypertension. Conclusion: CHIP is associated with an increased risk of hypertension. The association of CHIP with HF and HS is partially mediated by hypertension. These findings suggest a new mechanistic pathway for the association of CHIP with cardiovascular diseases.