Introduction: A family history of type 1 diabetes (T1D) increases T1D risk, but the increase is lower for maternal compared to paternal T1D. We aimed to identify epigenetic markers of this parent-of-origin effect by testing whether the effect of DNA methylation on T1D risk differs by T1D family history in The Environmental Determinants of Diabetes in the Young (TEDDY) Study.
Methods: For 106 T1D cases and 99 matched controls in TEDDY, methylation was measured in 1,424 peripheral blood samples collected prospectively from 3-75 months of age using the MethylationEPIC Beadchip. Following data processing, we performed an epigenome-wide association study across 534,790 CpGs using linear regression adjusted for age, sex, and HLA-DR3/4. We used an interaction term to test whether the difference in mean longitudinal methylation (%) between T1D cases and controls differed by T1D family history (affected: mother, N=19; father or sibling, N=50; none, N=136).
Results: We identified 141 CpGs where the effect of methylation on T1D risk differed by T1D family history (FDR-adjusted Pinteraction<0.01). Among children exposed to maternal T1D in utero, methylation levels differed between cases and controls; however, in those with no T1D family history or with an affected father or sibling there was no difference in methylation. In those with an affected mother, the largest effect sizes included hypomethylation in T1D cases near glucose metabolism genes ASTN2 (-11.3%) and ACOT7 (-7.8%), and hypermethylation near PTEN (11.3%), a key insulin signaling gene. Over 24% (35/141) of CpGs localized in previously identified loci exhibiting allele-specific methylation, implicating genetic-epigenetic interplay.
Conclusion: We identified epigenetic changes preceding T1D that differ by T1D family history. At these loci, methylation differences occurred only among children exposed to T1D in utero and localized near glucose metabolism genes, suggesting epigenetic mechanisms may be involved in the long-described maternal effect in T1D risk.
R.K. Johnson: None. S.D. Slack: None. L.A. Vanderlinden: None. K. Hohsfield: None. P.M. Carry: None. S. Onengut-Gumuscu: None. S.S. Rich: None. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. K. Kechris: None. J.M. Norris: None.
The Leona M. and Harry B. Helmsley Charitable Trust (2103-05094). The TEDDY Study is a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC).
