Clonal Hematopoiesis of Indeterminate Potential Is Associated With Incident Abdominal Aortic Aneurysm

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging risk factor for cardiovascular diseases. Genetic IL (interleukin)-6 signaling deficiency reduced cardiovascular disease risk in CHIP carriers. However, the association between CHIP and incident abdominal aortic aneurysm (AAA) and whether IL-6 signaling inhibition attenuates AAA risk among individuals with CHIP remained unclear. METHODS: Participants without prevalent AAA from the UK Biobank were included. The associations of any CHIP (variant allele fraction, ≥2%), large CHIP (variant allele fraction, ≥10%), and gene-specific CHIP subtypes with incident AAA were investigated. The protection role of IL6R p.Asp358Ala, a genetic proxy for IL-6 deficiency, was tested after stratification by CHIP status. Furthermore, the interaction and joint effects of CHIP and genetic susceptibility on AAA risk were tested. RESULTS: This study included 425 211 participants. Any CHIP and large CHIP was identified in 13 768 (3.2%) and 8576 (2.0%) participants, respectively. CHIP was associated with an increased risk of incident AAA (hazard ratio [HR], 1.21 [95% CI, 1.01–1.44]; P =0.034), with large CHIP clones exhibiting greater effect size (HR, 1.35 [95% CI, 1.10–1.66]; P =0.0045). Driver gene-specific analyses revealed that ASXL1 -mediated CHIP exerted the strongest effect size on AAA risk (HR, 2.10 [95% CI, 1.54–2.88]; P <0.001). The presence of 2 IL6R p.Asp358Ala alleles attenuated the risk of AAA in large CHIP carriers (HR, 0.48 [95% CI, 0.23–0.99]; P =0.046). In the joint analysis, participants with CHIP and high genetic risk had a higher risk of developing AAA than those without CHIP and with low genetic risk (HR, 2.15 [95% CI, 1.63–2.85]; P <0.001). CONCLUSIONS: CHIP is associated with an increased risk of AAA. Genetic IL-6 signaling deficiency attenuates the risk of AAA in large CHIP carriers. CHIP may serve as an attractive target for the prevention and treatment of AAA.