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. 2023:2023:5367637.
doi: 10.1155/2023/5367637. Epub 2023 Sep 11.

DNA Methylation Near DLGAP2 May Mediate the Relationship between Family History of Type 1 Diabetes and Type 1 Diabetes Risk

Randi K Johnson  1   2 , Amanda J Ireton  2 , Patrick M Carry  2   3 , Lauren A Vanderlinden  2 , Fran Dong  4 , Alex Romero  1 , David R Johnson  2 , Debashis Ghosh  5 , Fan Yang  5 , Brigitte Frohnert  4 , Ivana V Yang  1 , Katerina Kechris  5 , Marian Rewers  4 , Jill M Norris  2
Affiliations

DNA Methylation Near DLGAP2 May Mediate the Relationship between Family History of Type 1 Diabetes and Type 1 Diabetes Risk

Randi K Johnson et al. Pediatr Diabetes. 2023.

Abstract

Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted DLGAP2 gene compared to controls, we examined whether methylation near DLGAP2 mediates the association between T1D family history and T1D risk. In a nested case-control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 DLGAP2 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model). For 8 of the 12 CpGs, we identified a significant interaction between T1D family history and methylation on T1D risk. Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the DLGAP2 region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06-3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16-16.62) (for cg00565786). In contrast, the increased risk of T1D for children with an affected father or sibling was not explained by DNA methylation changes at these CpGs. Results were similar for cg27351978 and robust in sensitivity analyses. Lastly, we found that DNA methylation in the DLGAP2 region was associated (P<0:05) with gene expression of nearby protein-coding genes DLGAP2, ARHGEF10, ZNF596, and ERICH1. Results indicate that the maternal protective effect conferred through exposure to T1D in utero may operate through changes to DNA methylation that have functional downstream consequences.

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Conflict of interest statement

Conflicts of Interest The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Figures

Figure 1:
Figure 1:
Mediation conceptual model and analytical approach. The directed acyclic graph shows the hypothesized relationships between family history of T1D (exposure), DNA methylation (mediator), and risk of T1D (outcome). Colors of the arrows represent the indirect (pink) and direct (tan) mediation effects. We implemented three models to first summarize longitudinal DNA methylation over time and then combined results from the mediator and outcome models in a counterfactual framework to estimate the causal indirect and direct effects. To accommodate possible interaction between the family history of T1D and DNA methylation, the outcome model includes an interaction term, and indirect and direct effects are reported separately for subjects with affected mothers and subjects with affected fathers or siblings, both compared to subjects with no family history of T1D.
Figure 2:
Figure 2:
Analysis results for DLGAP2 probes with significant associations at each step (cg00565786, cg27351978). (a) Mediator model results from robust linear regression of the association between family history of T1D and methylation. (b) Outcome model interaction where the difference in methylation between T1D cases and controls differed by a family history of T1D—among those with an affected mother, cases had decreased methylation compared to controls, while the opposite relationship was seen among those with an affected father or no family history of T1D. (c) Mediation effect estimation combining the mediator and outcome model results. The significant indirect effect (PNIE) indicates that for those with an affected mother, the risk for T1D was mediated through DNA methylation at these locations. (d) Methylation associations with changes to cis-gene expression. PNIE, pure natural indirect effect; TNDE, total natural direct effect. All methylation was modeled on the M-value scale.
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