DNAme is associated with past HbA1c in DCCT/EDIC but these associations were examined when there was separation in HbA1c distribution by trial intervention arm. Thus, we performed an epigenome-wide association study (EWAS) of DNAme and HbA1c in a T1D cohort without intervention or risk factor exclusion to identify loci with DNAme associated with concurrent and future HbA1c over 28 years. Whole blood DNAme was assayed via Illumina EPIC beadchip in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood onset (<17 years) T1D (n=411; mean age 29, T1D duration 21 yrs) . After quality control DNAme at 683,597 CpGs were analyzed. We performed cross-sectional EWAS with baseline HbA1c in linear models adjusted for T1D duration, sex, smoking pack-years, estimated blood cell composition, and batch covariates and longitudinal repeated measures analyses of HbA1c (2, 4, 6, 8, 16, 23, and 28 yrs post-baseline) . DNAme was significantly inversely associated with current HbA1c at two CpGs: cg19693031 (Chr 1, TXNIP locus, p=9.5x10-11) and cg21534330 (Chr 17, CSNK1D locus, p=3.3x10-10) . In GWAS, we further identified 34 methylation quantitative trait loci (meQTLs) in the SLC2A1 - SLC2A1-AS1 linkage-disequilibrium block (Chr 1: 43408279-43438299) associated with cg19693031 DNAme. All cg19693031 meQTLs identified were also reported as whole blood expression QTLs (eQTLs) in GTEx. For cg21534330, none of 15 trans meQTLs were eQTLs in GTEx. In repeated measures analysis, cg19693031 DNAme was consistently associated with lower average HbA1c over 28 years (-0.26 per 5% DNAme, p<0.0001, no time interaction) . DNAme at cg21534330 was not associated with HbA1c after baseline. Our results replicate prior findings that DNAme at cg19693031 in TXNIP relates to glycemic control in T1D and extend this association prospectively over 28 years. These findings strengthen the potential for interventions targeting TXNIP to improve glycemic control in T1D through its role in SLC2A1/GLUT1-mediated glucose regulation.
R.G.Miller: Stock/Shareholder; Becton, Dickinson and Company. J.Mychaleckyj: None. S.Onengut-gumuscu: None. T.J.Orchard: None. T.Costacou: None.
American Diabetes Association (1-19-JDF-109) ; NIH/NIDDK (R01-DK034818) , Rossi Memorial Fund