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DNA methylation near the INS gene is associated with INS genetic variation (rs689) and type 1 diabetes in the Diabetes Autoimmunity Study in the Young
Author(s) -
Carry Patrick M.,
Vanderlinden Lauren A.,
Johnson Randi K.,
Dong Fran,
Steck Andrea K.,
Frohnert Brigitte I.,
Rewers Marian,
Yang Ivana V.,
Kechris Katerina,
Norris Jill M.
Publication year - 2020
Publication title -
pediatric diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.678
H-Index - 75
eISSN - 1399-5448
pISSN - 1399-543X
DOI - 10.1111/pedi.12995
Subject(s) - dna methylation , single nucleotide polymorphism , methylation , snp , human leukocyte antigen , odds ratio , genetics , quantitative trait locus , medicine , type 1 diabetes , genetic association , oncology , biology , genotype , gene , diabetes mellitus , endocrinology , antigen , gene expression
Objective Mechanisms underlying the role of non‐human leukocyte antigen (HLA) genetic risk variants in type 1 diabetes (T1D) are poorly understood. We aimed to test the association between methylation and non‐HLA genetic risk. Methods We conducted a methylation quantitative trait loci (mQTL) analysis in a nested case‐control study from the Dietary Autoimmunity Study in the Young. Controls (n = 83) were frequency‐matched to T1D cases (n = 83) based on age, race/ethnicity, and sample availability. We evaluated 13 non‐HLA genetic markers known be associated with T1D. Genome‐wide methylation profiling was performed on peripheral blood samples collected prior to T1D using the Illumina 450 K (discovery set) and infinium methylation EPIC beadchip (EPIC validation) platforms. Linear regression models, adjusting for age and sex, were used to test to each single nucleotide polymorphism (SNP) ‐probe combination. Logistic regression models were used to test the association between T1D and methylation levels among probes with a significant mQTL. A meta‐analysis was used to combine odds ratios from the two platforms. Results We identified 10 SNP‐methylation probe pairs (false discovery rate (FDR) adjusted P < .05 and validation P < .05). Probes were associated with the GSDMB , C1QTNF6 , IL27 , and INS genes. The cg03366382 (OR: 1.9, meta‐ P = .0495), cg21574853 (OR: 2.5, meta‐ P = .0232), and cg25336198 (odds ratio: 6.6, meta‐ P = .0081) probes were significantly associated with T1D. The three probes were located upstream from the INS transcription start site. Conclusions We confirmed an association between DNA methylation and rs689 that has been identified in related studies. Measurements in our study preceded the onset of T1D suggesting methylation may have a role in the relationship between INS variation and T1D development.