Healthy lifestyle attenuates the clonal hematopoiesis-associated coronary artery disease risk

Lifestyle factors and clonal hematopoiesis of indeterminate potential (CHIP) both contribute to the risk of developing coronary artery disease (CAD), but whether a healthy lifestyle could attenuate CHIP-related CAD risk is unknown. A total of 6113 participants from the Prediction for Atherosclerotic Cardiovascular Disease Risk in China project were included. Lifestyle was categorized as unfavorable, intermediate, and favorable according to the number of healthy lifestyle factors (body mass index, smoking, sleep, physical activity, and diet). CHIP mutations were detected by targeted deep sequencing (mean depth, 916 ×). After a median follow-up of 12.1 years, 760 cases of CAD were recorded. A favorable lifestyle and CHIP were associated with 53% lower (HR (hazard ratio) = 0.47; 95% CI (confidence interval): 0.36-0.61) and 41% higher (HR = 1.41; 95% CI: 1.17-1.72) CAD risk, respectively. Of note, the elevated CAD risk attributed to CHIP was found in the intermediate (HR = 1.48; 95% CI: 1.03-2.11) and unfavorable (HR = 1.57; 95% CI: 1.22-2.01) lifestyle groups, but not in the favorable (HR = 0.71; 95% CI: 0.36-1.42) group. Unfavorable lifestyle and CHIP jointly contributed to a 2.78-fold increased risk of CAD (95% CI: 1.95-3.97) compared with non-CHIP carriers with a favorable lifestyle, indicating a significant additive interaction between CHIP and lifestyle (RERI (relative excess risk due to interaction) = 1.08; 95% CI: 0.40-1.77). Specifically, the protective effect of lifestyle depends on the size of cell fractions, with an intermediate lifestyle mitigating CAD risk in small clone carriers (VAF (variant allele fraction): 0.5%-2%), and a favorable lifestyle being necessary for common clone carriers (VAF ≥ 2%). In summary, CHIP carriers exhibited a higher risk of CAD, while a favorable lifestyle could attenuate the excess risk related to CHIP. Efforts should be made to promote intensive behavioral interventions among CHIP carriers.