Abstract
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) was associated with diabetes and cardiovascular diseases (CVD). However, the effect of CHIP on CVD have not been evaluated among patients with diabetes, and whether maintaining the healthy indictors could mitigate the adverse influence was also unclear. METHODS: A total of 22,239 adults from the UK Biobank with diabetes and available whole-exome sequence data, and free of CVD were included. Multivariable-adjusted Cox regressions were used to explore the associations of any CHIP (variant allele fraction ≥ 2%), large CHIP (variant allele fraction ≥ 10%), and the top 10 commonly mutated driver genes for CHIP and with risk of CVD. The joint associations between health indicators (body mass index [BMI], HbA1c, blood pressure [BP], and low-density lipoprotein cholesterol [LDL]) and CHIP were further investigated. RESULTS: Over a median follow-up of 13.2 years, 5366 participants with diabetes developed CVD events. The hazard ratios (HRs) (95% confidence intervals [CIs]) of any CHIP and large CHIP were (1.21, 1.08-1.36) and (1.25, 1.09-1.43) for incident CVD, respectively. Significant associations between any CHIP and coronary heart disease (HR, 95%CI: 1.18, 1.03-1.36) and heart failure (1.73, 1.46-2.06) were observed, but not for stroke (1.14, 0.89-1.48). Gene-specific analyses suggested that the greatest association were for SF3B1 (HR, 95%CI: 2.50, 1.25-5.01) and TET2 (HR, 95%CI: 1.36, 1.07-1.77) with risk of CVD. There was no significant interaction between the four health indicators and CHIP in relation to incident CVD. Compared to patients without CHIP, those with any CHIP and ideal health indicators still exhibited significantly or nonsignificantly higher HRs (BMI: 1.18, 0.82-1.68; HbA1c: 1.12, 0.96-1.30; BP: 1.24, 1.03-1.49; LDL: 1.29, 1.09-1.53). Similar results were demonstrated using large CHIP. CONCLUSIONS: CHIP is independently associated with an increased risk of CVD in patients with diabetes, regardless of health indicator levels. Diabetic patients with CHIP but ideal health indicators still exhibited higher CVD risk compared with diabetic patients without CHIP.