title: Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A.
abstract: The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK.
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
authors.forename: Joanna M M
authors.initials: JM
authors.lastname: Howson
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Szeszko
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Field
authors.forename: Helen E
authors.initials: HE
authors.lastname: Stevens
authors.forename: Pamela
authors.initials: P
authors.lastname: Reynolds
authors.forename: Matthew
authors.initials: M
authors.lastname: Hardy
authors.forename: Erna
authors.initials: E
authors.lastname: King
authors.forename: Jennifer
authors.initials: J
authors.lastname: Masters
authors.forename: John
authors.initials: J
authors.lastname: Hulme
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Maier
authors.forename: Deborah
authors.initials: D
authors.lastname: Smyth
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bailey
authors.forename: Jason D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Gloria
authors.initials: G
authors.lastname: Ribas
authors.forename: R Duncan
authors.initials: RD
authors.lastname: Campbell
authors.forename: David G
authors.initials: DG
authors.lastname: Clayton
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D030541:Databases, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005787:Gene Frequency; D005805:Genes, MHC Class I / Q000235:genetics*; D005802:Genes, MHC Class II / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018401:Sample Size; D044465:White People / Q000235:genetics
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains