Functional relevance for type 1 diabetes mellitus-associated genetic variants by using integrative analyses

Hum Immunol. 2015 Oct;76(10):753-8. doi: 10.1016/j.humimm.2015.09.033. Epub 2015 Sep 30.


Aim: Type 1 diabetes mellitus (type 1 DM) is an autoimmune disease. Although genome-wide association studies (GWAS) and meta-analyses have successfully identified numerous type 1 DM-associated susceptibility loci, the underlying mechanisms for these susceptibility loci are currently largely unclear.

Methods: Based on publicly available datasets, we performed integrative analyses (i.e., integrated gene relationships among implicated loci, differential gene expression analysis, functional prediction and functional annotation clustering analysis) and combined with expression quantitative trait loci (eQTL) results to further explore function mechanisms underlying the associations between genetic variants and type 1 DM.

Results: Among a total of 183 type 1 DM-associated SNPs, eQTL analysis showed that 17 SNPs with cis-regulated eQTL effects on 9 genes. All the 9 eQTL genes enrich in immune-related pathways or Gene Ontology (GO) terms. Functional prediction analysis identified 5 SNPs located in transcription factor (TF) binding sites. Of the 9 eQTL genes, 6 (TAP2, HLA-DOB, HLA-DQB1, HLA-DQA1, HLA-DRB5 and CTSH) were differentially expressed in type 1 DM-associated related cells. Especially, rs3825932 in CTSH has integrative functional evidence supporting the association with type 1 DM.

Conclusions: These findings indicated that integrative analyses can yield important functional information to link genetic variants and type 1 DM.

Keywords: Functional relevance; Immunogenetics; Integrative analyses; Type 1 DM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 3
  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / immunology
  • Binding Sites
  • Cathepsin H / genetics*
  • Cathepsin H / immunology
  • Computational Biology
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / pathology
  • Gene Ontology
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • HLA Antigens / genetics*
  • HLA Antigens / immunology
  • Humans
  • Molecular Sequence Annotation
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • Quantitative Trait Loci
  • Transcription Factors / genetics
  • Transcription Factors / immunology


  • ATP Binding Cassette Transporter, Subfamily B, Member 3
  • ATP-Binding Cassette Transporters
  • HLA Antigens
  • Transcription Factors
  • TAP2 protein, human
  • CTSH protein, human
  • Cathepsin H