Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have suggested that the HLA-DQA2 gene may be associated with IDDM. The apparently limited allelism at this locus prompted us to investigate whether this association might be with the level of gene expression rather than with specific alleles. The proximal promoter region of HLA-DQA2 was sequenced in three homozygous DR4;DQ8 subjects with IDDM, six homozygous DR3;DQ2 subjects (three healthy controls and three with IDDM), and selected DR4 and DR6 cell lines. This 388-bp region encompassed the known control W/Z/H/S, X, and Y boxes and included a previously unremarked variant octamer sequence 40 bp upstream of the transcription start site. Only one polymorphic site was present among these 15 sequences, found in one DR3;DQ2 subject and a DR6;DQ6 cell line. This indicates that any disease association with HLA-DQA2, at least among DR3;DQ2 individuals, cannot be accounted for solely by polymorphism of the proximal promoter region.
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PMID:Limited polymorphism of the HLA-DQA2 promoter and identification of a variant octamer. 802 91

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 1Mb 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 We postulated that, in patients with HLA-DQB1 0602, the protective allele at the susceptibility locus has been replaced by a susceptibility allele through an ancient crossover at meiosis centromeric to HLA-DQB1.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.
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PMID:The MHC type 1 diabetes susceptibility gene is centromeric to HLA-DQB1. 1806