HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

Erlich, Henry A.; Valdes, Ana M.; Noble, Janelle A.; Carlson, Joyce; Varney, Mike; Concannon, Patrick; Mychaleckyj, Josyf C.; Todd, John A.; Bonella, Persia; Fear, Anna Lisa; Lavant, Eva; Louey, Anthony; Moonsamy, P. V.

doi:10.2337/db07-1331

Cited by 686 publications

(637 citation statements)

References 44 publications

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“…This feature is also absent from the HLA-DQ4 peptide-binding motif. 29 An immortalized homozygous HLA-DR8 cell line carrying the T1D-associated HLA-DR8-DQ4 haplotype 6 was used for the analysis. There is little information about peptides binding DR8 and no concrete information about the peptide-binding motif.…”

Section: Discussionmentioning

confidence: 99%

“…A dose effect of this polymorphism in relation to the risk of T1D has not been established, although the highest association corresponds to a haplotype without Asp57 in both DR and DQ b-chains (DRB1*0405/DQA1*0301-DQB1*0302) (ref. 6) and the highest protection to the DR15 haplotypes, with Asp57 in both DR and DQ b chains (DRB1*15/DQA1*0102-DQB1*06). However, the presence of only one DQ allele lacking Asp57 appears to be enough for susceptibility, as it is the case for DR3 and the other associated DR4 haplotypes (Supplementary Table 2).…”

Section: Hla-dr8-binding Motif L Muixí Et Almentioning

confidence: 99%

“…2 The HLA-DR allele HLA-DR8 has been associated with the susceptibility to some autoimmune diseases [3][4][5] and the DRB1*0801 (DR8)-DQA1*0401/DQB1*0402 (DQ4) haplotype is, after the high-risk DR3 and DR4, the next most predisposing haplotype to type 1 diabetes (T1D). 6 The major susceptibility alleles are HLA-DQ2 and DQ8, of the DR3 and DR4 haplotypes, respectively, as well as their NOD mouse homologous, I-A g7 (ref. 7,8).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Hla-dr8-binding Motif L Muixí Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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 most important susceptibility factors reside within the major histocompatibility complex (MHC) where particular human leukocyte antigen (HLA) class II DRB1-DQA1-DQB1 haplotypes confer high disease risk. 1,2 However, numerous studies have strongly implicated additional T1D risk loci within the MHC. [3][4][5][6][7][8][9][10][11][12] This complex contains an unusually high density of genes involved in immunological responses, 13 of which many are good candidates for involvement in autoimmune processes.…”

Section: Introductionmentioning

confidence: 99%

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

et al. 2008

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The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.

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“…Genetic studies have shown that particular combinations of class II HLA alleles of the DRB1, DQA1 and DQB1 loci determine the extent of risk of developing T1D. High genetic risk conferring susceptibility to T1D have been reported for the DR3-DQ2 (DRB1*0301-DQA1*0501-DQB1*0201) and DR4-DQ8 haplotypes (DRB1*0401-DQA1*0301-DQB1*0302), in particular for heterozygous subjects (Erlich et al 2008). Since the physiological role of these class II molecules is to present peptide epitopes to CD4 + T lymphocytes, most studies focused on the role of CD4 + T lymphocytes in T1D pathogenesis.…”

Section: Genetics: Focus On Hlamentioning

confidence: 99%