title: Exploring the diabetogenicity of the HLA-B18-DR3 CEH: independent association with T1D genetic risk close to HLA-DOA.
abstract: 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.
authors.affiliation: Endocrinology and Diabetes Research Group--CIBERDEM, Hospital de Cruces and University of the Basque Country School of Medicine, Bilbao, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Santin
authors.forename: A
authors.initials: A
authors.lastname: Castellanos-Rubio
authors.forename: A M
authors.initials: AM
authors.lastname: Aransay
authors.forename: G
authors.initials: G
authors.lastname: Gutierrez
authors.forename: S
authors.initials: S
authors.lastname: Gaztambide
authors.forename: I
authors.initials: I
authors.lastname: Rica
authors.forename: J L
authors.initials: JL
authors.lastname: Vicario
authors.forename: J A
authors.initials: JA
authors.lastname: Noble
authors.forename: L
authors.initials: L
authors.lastname: Castaño
authors.forename: J R
authors.initials: JR
authors.lastname: Bilbao
mesh_terms: D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics*; D059911:HLA-B18 Antigen; D006681:HLA-D Antigens / Q000235:genetics*; D015803:HLA-DR3 Antigen / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D013030:Spain / Q000453:epidemiology
chemical_list: D015235:HLA-B Antigens; D059911:HLA-B18 Antigen; D006681:HLA-D Antigens; C046148:HLA-DO antigens; D015803:HLA-DR3 Antigen