Abstract Body (Do not enter title and authors here): Background:
Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the expansion of somatic leukemogenic variations in hematopoietic stem cells, has been linked to atherosclerotic cardiovascular disease. While particulate matter with aerodynamic diameter ≤2.5 micrometers (PM_2.5) is known to elevate major adverse cardiovascular event (MACE) risk, potentially through enhanced leukopoietic activity, the specific connection between PM_2.5 and CHIP and their combined role in MACE risk, remains unclear.

Hypothesis: We hypothesized that high levels of PM_2.5 exposure are associated with increased CHIP prevalence, which in turn mediates the relationship between PM_2.5 exposure and MACE risk.

Methods:
We analyzed data of 7015 participants from the Mass General Brigham Biobank, who had undergone genotyping and had their PM_2.5 exposure quantified (for the year prior to consent) based on residential addresses. CHIP detection utilized whole-exome sequencing of blood DNA. MACE diagnosis and risk factors were assessed using ICD codes and health surveys. Multivariable logistic regressions and mediation analysis were employed.

Results:
Of the participants (mean age of 64 (SD 0.2) years and 47.8% male), 972 exhibited CHIP. High PM_2.5 exposure was associated with an increased risk of CHIP (standardized odds ratio [OR] 1.140 [95% CI: 1.031, 1.262], p=0.011; Fig 1A) and a higher number of CHIP mutations (OR:1.403 [95% CI: 1.123, 1.753], p=0.003; Fig 1B) after adjusting for covariables related to CHIP*. Further, CHIP mediated the relationship between PM_2.5 exposure and MACE risk (p<0.05). Notably, MACE risk was greatest among individuals with CHIP who were exposed to higher PM_2.5 (OR:1.405 [95% CI: 1.104,1.786], p=0.006*; Fig 2).

Conclusion:
Our findings suggest that ambient air pollution exposure not only associates with the CHIP prevalence but also exacerbates the risk of adverse cardiovascular events through these genetic mutations. This study highlights the importance of addressing air quality as a modifiable risk factor in the prevention of cardiovascular diseases, particularly among individuals with or at risk for CHIP.