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

Pediatr Diabetes. 2020 Jun;21(4):597-605. doi: 10.1111/pedi.12995. Epub 2020 Feb 28.


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.

Keywords: INS; T1D; islet autoimmunity; mQTL; methylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autoimmunity / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Collagen / genetics
  • DNA Methylation / physiology*
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / genetics*
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • HLA-DR3 Antigen / genetics
  • HLA-DR4 Antigen / genetics
  • Humans
  • Insulin / genetics*
  • Interleukins / genetics
  • Male
  • Neoplasm Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci / genetics


  • C1qTNF6 protein, human
  • GSDMB protein, human
  • HLA-DR3 Antigen
  • HLA-DR4 Antigen
  • Insulin
  • Interleukins
  • MYDGF protein, human
  • Neoplasm Proteins
  • Collagen