Exploring the diabetogenicity of the HLA-B18-DR3 CEH: independent association with T1D genetic risk close to HLA-DOA

Genes Immun. 2009 Sep;10(6):596-600. doi: 10.1038/gene.2009.41. Epub 2009 May 21.


The objective of this study was to identify additional diabetes susceptibility markers in the MHC that could be responsible for the differential diabetogenicity of different HLA-DR3 CEHs. High-resolution SNP genotyping of the MHC was carried out in 15 type 1 diabetes (T1D) patients and 39 non-diabetic controls, homozygous for DR3-DQ2 and with one copy of the A(*)30-B(*)18-MICA(*)4-F1C30-DRB1(*)0301-DQB1(*)0201-DPB1(*)0202 HLA haplotype. Significantly associated SNPs were replicated in an independent sample of 554 T1D patients and 841 controls without HLA matching. Electrophoretic mobility shift assay was used to show a functional effect of an associated SNP. Seven SNPs showed evidence of association in the initial discovery experiment. Upon replication, only rs419434 (upstream HLA-DOA gene) remained significant. A functional variant (rs432375) in complete LD with rs419434 was shown to affect USF-1 binding and could be responsible for the association signal in the region. We have identified a new susceptibility locus within the MHC with a modest contribution to T1D (OR=1.93; CI: 1.52-2.44; P=10(-8)) that is independent of HLA-DRB1 locus.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Electrophoretic Mobility Shift Assay
  • Genotype
  • HLA-B Antigens / genetics*
  • HLA-B18 Antigen
  • HLA-D Antigens / genetics*
  • HLA-DR3 Antigen / genetics*
  • Haplotypes / genetics*
  • Humans
  • Microsatellite Repeats / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Prognosis
  • Spain / epidemiology


  • HLA-B Antigens
  • HLA-B18 Antigen
  • HLA-D Antigens
  • HLA-DO antigens
  • HLA-DR3 Antigen