Longitudinal DNA methylation differences precede type 1 diabetes

Randi K Johnson,Kathleen Waugh,Fran Dong,Brigitte I Frohnert,Hanan Shorrosh,Jill M Norris,Ivana V Yang,Lauren A Vanderlinden,Patrick M Carry,Katerina Kechris,Tasha Fingerlin,Jennifer Seifert,Marian Rewers

doi:10.1038/s41598-020-60758-0

Abstract

DNA methylation may be involved in development of type 1 diabetes (T1D), but previous epigenome-wide association studies were conducted among cases with clinically diagnosed diabetes. Using multiple pre-disease peripheral blood samples on the Illumina 450 K and EPIC platforms, we investigated longitudinal methylation differences between 87 T1D cases and 87 controls from the prospective Diabetes Autoimmunity Study in the Young (DAISY) cohort. Change in methylation with age differed between cases and controls in 10 regions. Average longitudinal methylation differed between cases and controls at two genomic positions and 28 regions. Some methylation differences were detectable and consistent as early as birth, including before and after the onset of preclinical islet autoimmunity. Results map to transcription factors, other protein coding genes, and non-coding regions of the genome with regulatory potential. The identification of methylation differences that predate islet autoimmunity and clinical diagnosis may suggest a role for epigenetics in T1D pathogenesis; however, functional validation is warranted.

Highlights

DNA methylation may be involved in development of type 1 diabetes (T1D), but previous epigenomewide association studies were conducted among cases with clinically diagnosed diabetes
Using a meta-analysis of the two platforms, we identified longitudinal differential methylation that changed with age and longitudinal differential methylation that did not change with age
For investigating pre-disease methylation in Diabetes Autoimmunity Study in the Young (DAISY), we frequency-matched 87 T1D cases to autoantibody-negative controls based on age at seroconversion to islet autoimmunity (IA), race-ethnicity and sample availability (Fig. 1)

Summary

Introduction

DNA methylation may be involved in development of type 1 diabetes (T1D), but previous epigenomewide association studies were conducted among cases with clinically diagnosed diabetes. Differences in DNA methylation levels and variability have been associated with T1D in previous case-control studies[17,18,19,20,21] Given these epigenome-wide association studies were performed on individuals already diagnosed with diabetes, it has yet to be established whether methylation plays a role in the development of disease or whether it is merely a marker of the metabolic derangements associated with symptomatic (prevalent) diabetes. We measured DNA methylation in peripheral whole blood collected prior to onset of clinical T1D from individuals enrolled in the prospective Diabetes Autoimmunity Study in the Young (DAISY) cohort, which follows high-risk children for the development of IA and T1D. Subjects were split into two sets for methylation quantification using the Infinium HumanMethylation450K Beadchip (“450 K”)

Methods

Results

Conclusion