Association of Clonal Hematopoiesis of Indeterminate Potential with Cardiovascular Events in Patients with CKD.

Abstract

In patients with CKD, non-<i>DNMT3A</i> clonal hematopoiesis of indeterminate potential (CHIP) was associated with higher risk of cardiovascular events. There was no significant difference in the CHIP–cardiovascular disease association based on baseline eGFR, diabetes status, or race. The protective effect of <i>IL6R</i> p.Asp358Ala on non-<i>DNMT3A</i> CHIP cardiovascular risk was similar to the general population. Patients with CKD are at higher risk of cardiovascular disease. Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular disease in the general population, with a causal role observed in animal models. In the general population, the effect of CHIP is greater for somatic mutations in predefined CHIP driver genes other than <i>DNMT3A</i> (referred to as non-<i>DNMT3A</i> CHIP). We sought to assess the prospective association between CHIP and cardiovascular events in patients with CKD. CHIP was measured by high-depth targeted sequencing. The primary analysis tested the association of somatic mutations in non-<i>DNMT3A</i> CHIP driver genes with a composite cardiovascular disease end point of myocardial infarction, stroke, congestive heart failure, and peripheral artery disease in 5043 patients with CKD in four prospective cohorts. Sensitivity analyses examined the effect of CHIP subtypes, race, baseline comorbidities, <i>APOL1</i> risk alleles, and <i>IL6R</i> p.Asp358Ala genotype. At baseline, patients had a mean age of 66±12 years and eGFR of 43±18 ml/min per 1.73 m². CHIP was present in 24% of patients, with 13% of all patients carrying acquired non-<i>DNMT3A</i> mutations. Non-<i>DNMT3A</i> CHIP was associated with a 36% higher risk of the composite cardiovascular end point (95% confidence interval [CI], 6% to 76%). Among composite components, non-<i>DNMT3A</i> CHIP was associated with a higher risk of stroke (hazard ratio, 1.65; 95% CI, 1.10 to 2.47). Baseline eGFR, diabetes status, or race did not alter the association of non-<i>DNMT3A</i> CHIP with cardiovascular risk. Those without genetically reduced IL-6 signaling (noncarriers of <i>IL6R</i> p.Asp358Ala) had worse disease (hazard ratio, 1.46; 95% CI, 1.17 to 1.83; <i>P</i>_{<i>subgroup difference</i>} = 0.05). In patients with CKD, non-<i>DNMT3A</i> CHIP was associated with cardiovascular disease with an effect size similar to that reported in the general population.