Clonal hematopoiesis of indeterminate potential (CHIP) is associated with macrovascular diseases, including coronary artery disease and stroke. However, the effects of CHIP on microvascular complications have not been evaluated in individuals with type 2 diabetes (T2D). This study included 20,712 participants with T2D without prevalent diabetic microvascular complication (DMCs) and hematologic malignancy at baseline. CHIP and related phenotypes were identified using whole-exome sequencing derived from peripheral blood samples. The incidence of DMCs was defined as a composite of diabetic kidney disease, diabetic retinopathy, or diabetic neuropathy. Associations of any CHIP with incident DMCs and subtypes were assessed using Cox regression. Gene-specific analyses were also conducted to determine the effect of mutated driver genes with DMCs. During a median follow-up of 13.0 years, DMCs developed in 5,673 participants. Any CHIP was associated with a high risk of DMCs (hazard ratio [HR] 1.23; 95% CI 1.10–1.38; P < 0.001), specifically, diabetic retinopathy (HR 1.34; 95% CI 1.13–1.57; P = 0.001) and diabetic kidney disease (HR 1.26; 95% CI 1.10–1.45; P = 0.001), but not diabetic neuropathy. Gene-specific analyses suggested that DNMT3A, TET2, NF1, and spliceosome genes were associated with the risk of developing DMCs. CHIP increases the risk of developing DMCs in individuals with T2D, independently of other risk factors. These findings offer potential implications for the prevention and management of DMCs.
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related disorder that is associated with macrovascular diseases, such as coronary artery disease and stroke. However, the effects of CHIP on microvascular complication have not been explored in individuals with type 2 diabetes.
We wanted to determine whether CHIP is associated with diabetic microvascular complications (DMCs).
CHIP was associated with a high risk of DMCs, specifically, diabetic retinopathy and diabetic kidney disease, but not diabetic neuropathy. Gene-specific analyses suggested that some driver genes were associated with risk of developing DMCs.
These findings indicated that CHIP may represent a novel risk factor for DMCs among individuals with type 2 diabetes, distinct from traditional risk factors, which may have implications for prevention and management of DMCs.
This article contains supplementary material online at https://doi.org/10.2337/figshare.28174115.
