The MHC type 1 diabetes susceptibility gene is centromeric to HLA-DQB1

Z Husain, Marilyn Kelly, GS Eisenbarth, A Pugliese, ZL Awdeh, CE Larsen, CA Alper

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    10 Citations (Scopus)


    HLA-DQB1 is widely considered to be the major histocompatibility complex (MHC) susceptibility gene for type I diabetes (T1D). However, since inheritance of the gene in T1D is recessive, the presence of the protective HLA-DQB1*0602 allele with normal nucleotide sequence in some patients raises the question of whether HLA-DQB1 is not the susceptibility locus itself but merely a good marker. HLA-DQB1*0602 is part of a conserved extended haplotype (CEH) [HLA-B7, SC31, DR2] (137, DR2) with fixed DNA over more than 1 Mb of genomic DNA that normally carries a protective allele at the true susceptibility locus. We postulated that, in patients with HLA-DQB1*0602, the protective allele at the susceptibility locus has been replaced by a susceptibility allele through an ancient crossover at meiosis centromeric to HLA-DQB1. We analyzed single nucleotide polymorphisms (SNPs) distinguishing the HLA-DQA2 (the first expressed gene centromeric to HLA-DQB1) allele on the normal HLA-B7, DR2 CEH from those on susceptibility CEHs in T1D patients and controls with HLA-DQB1*0602. All but 1 of 20 healthy control HLA-DQB1*0602 haplotypes had identical (consensus) first intron HLA-DQA2 5-SNP haplotypes. Fifteen of 19 patients with HLA-DQB1*0602 were homozygous for I or more HLA-DQA2 SNPs differing from consensus HLA-DQA2 SNPs, providing evidence of crossover involving the HLA-DQA2 locus. The remaining 4 patients were heterozygous at all positions and therefore uninformative. The loss of dominant protection usually associated with HLA-DQB1*0602 haplotypes is consistent with a locus centromeric to HLA-DQB1 being a major determinant of MHC-associated susceptibility, and perhaps the true T1D susceptibility locus. (C) 2007 Published by Elsevier Ltd.
    Original languageEnglish
    Pages (from-to)266-272
    Number of pages7
    JournalJournal of Autoimmunity
    Issue number4
    Publication statusPublished - 1 Jun 2008


    • susceptibility gene
    • single nucleotide polymorphism
    • type 1 diabetes
    • major histocompatibility complex


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