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

• Published in: Journal of autoimmunity 2008-06, Vol.30 (4), p.266-272
• Main Authors: Husain, Zaheed, Kelly, M. Ann, Eisenbarth, George S, Pugliese, Alberto, Awdeh, Zuheir L, Larsen, Charles E, Alper, Chester A
• Format: Article
• Language: English
• Subjects: Adult; Allergy and Immunology; Biological and medical sciences; Centromere; Chromosome Mapping; Diabetes Mellitus, Type 1 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic Predisposition to Disease; Haplotypes; HLA-DQ Antigens - genetics; HLA-DQ beta-Chains; Humans; Major histocompatibility complex; Medical sciences; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Single nucleotide polymorphism; Susceptibility gene; Type 1 diabetes
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2007.10.006

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 We postulated that, in patients with HLA-DQB1*0602 , the protective allele at the susceptibility locus has been replaced by a susceptibility allele through an ancient crossover at meiosis centromeric to HLA-DQB1 .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.