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

Background: 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 pre-defined CHIP driver genes other than DNMT3A (referred to as non- DNMT3A CHIP). We sought to assess the prospective association between CHIP and cardiovascular events in patients with CKD. Methods: CHIP was measured by high-depth targeted sequencing. The primary analysis tested the association of somatic mutations in non- DNMT3A CHIP driver genes with a composite cardiovascular disease endpoint of myocardial infarction, stroke, congestive heart failure, and peripheral artery disease in 5,043 patients with CKD in four prospective cohorts. Sensitivity analyses examined the effect of CHIP subtypes, race, baseline comorbidities, APOL1 risk alleles, and IL6R p.Asp358Ala genotype. Results: At baseline, patients had a mean age of 66 ± 12 years and eGFR of 43 ± 18 ml/min/1.73m 2 . CHIP was present in 24% of patients, with 13% of all patients carrying acquired non- DNMT3A mutations. Non- DNMT3A CHIP was associated with a 36% higher risk of the composite cardiovascular endpoint [95% confidence interval (CI), 6% - 76%]. Among composite components, non- DNMT3A CHIP was associated with a higher risk of stroke (HR 1.65; 95% CI 1.10 – 2.47). Baseline eGFR, diabetes status, or race did not alter the association of non- DNMT3A CHIP with cardiovascular risk. Those without genetically reduced interleukin-6 signaling (non-carriers of IL6R p.Asp358Ala) had worse disease (HR 1.46; 95% CI 1.17– 1.83, P subgroup difference = 0.05). Conclusions: In patients with CKD, non- DNMT3A CHIP was associated with cardiovascular disease with an effect size similar to that reported in the general population.