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

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. Genes and Immunity ( 2009) 10, 596-600; doi:10.1038/gene.2009.41; published online 21 May 2009