HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus

Todd, John A.; Bell, John I.; McDevitt, Hugh O.

doi:10.1038/329599a0

Cited by 1,984 publications

(1,086 citation statements)

References 54 publications

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“…9 The absence of Asp at b57 is related to the preference of these alleles for the binding of acid residues in the P9 pocket. [10][11][12][13] This common feature, known to be involved in clinical disease 14,15 is also found in HLA-DR8, with Ser at b57, but not in the DQ4 (DQA1*0401/DQB1*0402), molecule of the DR8 haplotype that has an Asp at b57.…”

Section: Introductionmentioning

confidence: 94%

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

et al. 2011

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The objective of this study was to characterize the peptide-binding motif of the major histocompatibility complex (MHC) class II HLA-DR8 molecule included in the type 1 diabetes-associated haplotype DRB1*0801-DQA1*0401/DQB1*0402 (DR8-DQ4), and compare it with that of other diabetes-associated MHC class II alleles; DR8-bound peptides were eluted from an HLA-DR homozygous lymphoblastoid cell line. The repertoire was characterized by peptide sequencing using a LTQ ion trap mass spectrometer coupled to a multidimensional liquid chromatography system. After validation of the spectra identification, the definition of the HLA-DR8 peptide-binding motif was achieved from the analysis of 486 natural ligands, based on serial alignments of all possible HLA-DR-binding cores. The DR8 motif showed a strong similarity with the peptide-binding motifs of other MHC class II diabetes-associated alleles, HLA-DQ8 and H-2 I-A g7 . Similar to HLA-DQ8 and H-2 I-A g7 , HLA-DR8 preferentially binds peptides with an acidic residue at position P9 of the binding core, indicating that DR8 is the susceptibility component of the DR8-DQ4 haplotype. Indeed, some DR8 peptides were identical to peptides previously identified as DQ8-or I-A g7 ligands, and several diabetes-specific peptides associated with DQ8 or I-A g7 could theoretically bind to HLA-DR8. These data further strengthen the association of HLA-DR8 with type I diabetes.

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Section: Introductionmentioning

confidence: 94%

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

et al. 2011

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“…Early associations based on serological typing were established for multiple sclerosis, 3,4 type I diabetes 5,6 and celiac disease 7,8 which were subsequently resolved to specific human leukocyte antigen (HLA)-DR/DQ haplotypes. 9,10 Moreover, recent genomewide association studies using common single nucleotide polymorphism (SNP) markers have served to underline the remarkable contribution of this region in susceptibility to autoimmune disease, 11 which dwarfs any other genetic effect. Although the functional basis for the observed class II associations in autoimmune disease remain incompletely understood, one long held view suggests a breakdown in immunological tolerance to self-antigens through presentation of peptides to autoreactive T cells.…”

Section: Introductionmentioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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“…The serologically detected HLA-DR4 molecule can be encoded by 1 of 8 polymorphic variants of HLA-DR4 genes: Dw4, DwlO, Dw13.1, Dw14.1, Dw15, DKT2, Dw13.2, and Dw14.2 (by the 1989 Nomenclature Committee for Factors of the HLA System, these are called HLA-DRB1*0401, DRB 1 *0402, DRB 1 *0403, DRB 1 *0404, DRB 1 *0405, DRB1*0406, DRB1*0407, and DRB1*0408, respectively) (12,13). In some DR4-associated autoimmune diseases, such as rheumatoid arthritis (RA) and pemphigus vulgaris, disease susceptibility has been shown to be associated with select subtypes of DR4 (14)(15)(16), while in another DRCassociated disease, type I diabetes mellitus, the primary genetic association has been shown to be with DRCassociated DQBl genes (17,18).…”

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confidence: 99%

Molecular Genetic Analysis of HLA—DR and HLA—DQ Genes Among Anti—U1‐70‐kd Autoantibody Positive Connective Tissue Disease Patients

Kaneoka

Hsu

Takeda

et al. 1992

Arthritis & Rheumatism

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Objective. We have recently found that the presence of autoantibodies against the 70-kd polypeptide of U1 RNP (Ul-70-kd) is associated with HLA-DR4 and DR2. To further characterize this association, we performed a molecular genetic analysis of HLA-DR and DQ genes among patients with autoantibodies against Methods. The polymerase chain reaction (PCR), sequence-specific oligonucleotide hybridization, and U1-70-kd.

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HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus

Cited by 1,984 publications

References 54 publications

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Molecular Genetic Analysis of HLA—DR and HLA—DQ Genes Among Anti—U1‐70‐kd Autoantibody Positive Connective Tissue Disease Patients

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