DNA Methylation Changes Associated with Type 2 Diabetes and Diabetic Kidney Disease in an East Asian Population

CONTEXT There is a growing body of evidence that epigenetic changes including DNA methylation influence the risk of type 2 diabetes (T2D) and its microvascular complications. OBJECTIVE We conducted a methylome-wide association study (MWAS) to identify differentially methylated sites (DMSs) of T2D and diabetic kidney disease (DKD) in a Korean population. METHODS We performed an MWAS in 232 participants with T2D and 197 nondiabetic controls with the Illumina EPIC bead chip using peripheral blood leukocytes. The T2D group was subdivided into 87 DKD patients and 80 non-DKD controls. An additional 819 individuals from 2 population-based cohorts were used to investigate the association of identified DMSs with quantitative metabolic phenotypes. A mendelian randomization (MR) approach was applied to evaluate the causal effect of metabolic phenotypes on identified DMSs. RESULTS We identified 8 DMSs (each at BMP8A, NBPF20, STX18, ZNF365, CPT1A, and TRIM37, and 2 at TXNIP) that were significantly associated with the risk of T2D (P < 9.0 × 10-8), including 3 that were previously known (DMSs in TXNIP and CPT1A). We also identified 3 DMSs (in COMMD1, TMOD1, and FHOD1) associated with DKD. With our limited sample size, we were not able to observe a significant overlap between DMSs of T2D and DKD. DMSs in TXNIP and CTP1A were associated with fasting glucose and glycated hemoglobin A1c. In MR analysis, fasting glucose was causally associated with DMS in CPT1A. CONCLUSION In an East Asian population, we identified 8 DMSs, including 5 novel CpG loci, associated with T2D and 3 DMSs associated with DKD at methylome-wide statistical significance.