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

Zaheed Husain, M. Ann Kelly, George S. Eisenbarth, Alberto Pugliese, Zuheir L. Awdeh, Charles E. Larsen, Chester A. Alper

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

HLA-DQB1 is widely considered to be the major histocompatibility complex (MHC) susceptibility gene for type 1 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] (B7, 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 We postulated that, in patients with HLA-DQB1*0602, the protective allele at the susceptibility locus has been replaced by a susceptibility allele through an ancient crossover at meiosis centromeric to HLA-DQB1.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 1 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.

Original languageEnglish (US)
Pages (from-to)266-272
Number of pages7
JournalJournal of Autoimmunity
Volume30
Issue number4
DOIs
StatePublished - Jun 2008

Keywords

  • Major histocompatibility complex
  • Single nucleotide polymorphism
  • Susceptibility gene
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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    Husain, Z., Kelly, M. A., Eisenbarth, G. S., Pugliese, A., Awdeh, Z. L., Larsen, C. E., & Alper, C. A. (2008). The MHC type 1 diabetes susceptibility gene is centromeric to HLA-DQB1. Journal of Autoimmunity, 30(4), 266-272. https://doi.org/10.1016/j.jaut.2007.10.006