DNA methylation and 28 year incidence of two neuropathy phenotypes in type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications cohort study
Authors' conclusion
Our study identified associations between DNAm and 28 year incidence of DPN and NP at several biologically plausible loci. Most notably, we identified a novel association between DNAm of PKNOX1 and future DPN, including evidence of a genetic influence on PKNOX1 methylation that was validated in an external diabetes cohort. PKNOX1 has previously been implicated in drug-induced neuropathy; our results provide strong evidence that epigenetic regulation of PKNOX1 may also play a functional role in the development of diabetic neuropathy. Our results suggest that epigenetic modification of the identified loci warrants further study to inform potential targets for prevention of DPN.
Study context
- Population
- Childhood-onset (<17 years) T1D, Pittsburgh Epidemiology of Diabetes Complications (EDC) study; baseline blood DNA 1988–1998 (mean age 27 years; diabetes duration 19 years)282 diabetic peripheral neuropathy (DPN)-free
- Outcome
- Incidence of DPN and NP in relation to DNA methylation (DNAm) (EPIC array, 683,597 CpGs); FDR <0.05 significant
- Follow-up
- 28 years
Methodological detailsepigenome-wide association study, epigenome-wide association studies (EWAS), Cox models, Mendelian randomisation
- Epigenome-wide association study
- EWAS
- Cox models
- Mendelian randomisation
Main finding
As reported in the abstract
Developed DPN
154
54.6%
Developed neuropathic pain (NP)
148
40.5%
No individual CpGs significantly associated with NP; NP-associated differentially methylated regions (DMRs)
49
Observational data: associations, not effects.
Further findings
meQTLs for cg18945945 (PKNOX1 region)
- meQTLs identified
- 75
- Validated in external diabetes cohort
- 59
One-sample Mendelian randomisation (MR), cg18945945 and DPN
- Nominal evidence for potentially causal association
- P = 0.01
Original publication
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