DPN is a common T1D complication that can greatly affect quality of life. DPN likely results from a combination of genetic risk and glycemic exposure. DNAm may help identify potential therapeutic targets; however, epigenome-wide association studies (EWAS) of DPN are lacking. We performed a prospective EWAS of 28-yr DPN risk and assessed associations adjusting for established risk factors in the EDC study of childhood-onset (<17 yrs) T1D (baseline mean age 27, T1D duration 19 yrs). DPN was defined as ≥2 of: DPN symptoms, decreased tendon reflexes, abnormal sensory exam. After quality control, baseline whole blood DNAm (EPIC array) at 683,597 CpGs was analyzed in Cox models for time to DPN in 282 persons free of DPN at baseline. Models were adjusted for T1D duration, sex, smoking pack years, estimated blood cell composition and technical variables. False discovery rate (FDR)<0.05 was considered significant. Genetic variants (meQTLs) associated with significant CpGs were identified. Over 28 yrs, 154 (54.6%) developed DPN. Three CpGs significantly associated with DPN: cg06163904 (CHMP6, log β per 5% DNAm=-0.98±0.19, p=1.05E-07, FDR=0.04), cg10835127 (CACNA1B, log β=-0.79±0.15, p=1.12E-07, FDR=0.04), and cg18945945 (PKNOX1, log β=-0.99±0.19, p=1.93E-07, FDR=0.04). Both cg10835127 and cg18945945 were associated with albumin excretion rate (β=-0.51±0.17, p<0.01; β=0.50±0.23, p=0.03) but their associations with DPN were unaltered after adjustment. There were 75 meQTLs for cg18945945 in the PKNOX1 region, 59 of which were previously reported cg18945945 meQTLs in the Chronic Renal Insufficiency Cohort. This prospective EWAS in T1D identified loci where DNAm associated with DPN after adjusting for known risk factors, highlighting mechanisms for further study including cell repair/death (CHMP6), presynaptic depolarization and calcium channel activity (CACNA1B), and chemokine transcription regulation (PKNOX1).

Disclosure

J. Zhou: None. J. Mychaleckyj: None. S. Onengut-Gumuscu: None. T.J. Orchard: None. T. Costacou: None. R.G. Miller: None.

Funding

American Diabetes Assoication (1-19-JDF-109); NIDDK (R01DK034818); Rossi Memorial Fund (Pittsburgh, PA)

© 2024 by the American Diabetes Association
2024
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