The DRB1 Val86/Val86genotype associates with multiple sclerosis in Australian patients

Teutsch, Suzy; Bennetts, Bruce; Buhler, Marc M; Heard, Robert; Stewart, Graeme J.

doi:10.1016/s0198-8859(99)00033-6

Cited by 17 publications

(11 citation statements)

References 35 publications

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“…The high LD across the *15:01-*06:02 haplotype make it problematic to dissect whether the primary association is with the DRB1* or with the DQB1 molecules. Findings from African-American MS patients seem to support the idea that DRB1* is the primary driver of the association [35], but other data indicate that both DRB1 and DQB1 molecules are fundamental players in determining individuals' MS risk [19]. The present data from a Sardinian population suggest that both DRB1 and DQB1 chains contribute to MS predisposition, highlighting the importance of the amino acid residue in binding pockets and surrounding areas, particularly concerning their steric and the electrostatic properties.…”

Section: Discussionmentioning

confidence: 40%

HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

et al. 2012

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IntroductionGenetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS.Methods and ResultsA transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10−3), *04:05-*03:01 (OR = 2.4, P = 4.4×10−6) and *03:01-*02:01 (OR = 2.1, P = 1.0×10−15) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10−11) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10−3) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05:02, *06:01 alleles.ConclusionsThese findings show that the association of specific, independent DRB1*-DQB1* haplotypes confers susceptibility or resistance to MS in the MS-prone Sardinian population. The data also supports a functional role for specific residues of the DRB1 and DQB1 proteins in predisposing patients to MS.

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Section: Discussionmentioning

confidence: 40%

HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

et al. 2012

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“…In some cases the susceptibility could be even linked to polymorphic P1-like pockets. This applies for type 1 diabetes, which is correlated with position ␤57 in pocket P9 (28), for rheumatoid arthritis, where the amino acid composition of the P4 pocket seems to be crucial (29,30) and, at least for a cohort of Australian patients, for MS, where susceptibility correlated with Val ␤86 of the P1 pocket (31). All these pockets accommodate anchor residues and participate in peptide selection but, as shown here for P1, might also represent specific target sites for ligand-exchange catalysts.…”

Section: ␤86mentioning

confidence: 99%

Small Organic Compounds Enhance Antigen Loading of Class II Major Histocompatibility Complex Proteins by Targeting the Polymorphic P1 Pocket

Höpner

Dickhaut

Hofstätter

et al. 2006

Journal of Biological Chemistry

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Major histocompatibility complex (MHC) molecules are a key element of the cellular immune response. Encoded by the MHC they are a family of highly polymorphic peptide receptors presenting peptide antigens for the surveillance by T cells. We have shown that certain organic compounds can amplify immune responses by catalyzing the peptide loading of human class II MHC molecules HLA-DR. Here we show now that they achieve this by interacting with a defined binding site of the HLA-DR peptide receptor. Screening of a compound library revealed a set of adamantane derivatives that strongly accelerated the peptide loading rate. The effect was evident only for an allelic subset and strictly correlated with the presence of glycine at the dimorphic position ␤86 of the HLA-DR molecule. The residue forms the floor of the conserved pocket P1, located in the peptide binding site of MHC molecule. Apparently, transient occupation of this pocket by the organic compound stabilizes the peptide-receptive conformation permitting rapid antigen loading. This interaction appeared restricted to the larger Gly ␤86 pocket and allowed striking enhancements of T cell responses for antigens presented by these "adamantyl-susceptible" MHC molecules. As catalysts of antigen loading, compounds targeting P1 may be useful molecular tools to amplify the immune response. The observation, however, that the ligand repertoire can be affected through polymorphic sites form the outside may also imply that environmental factors could induce allergic or autoimmune reactions in an allele-selective manner.

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“…The glycine/valine dimorphism at this position is crucial for peptide recognition and has been functionally implicated in susceptibility to several autoimmune diseases. 10,11 With regard to the steric conformation at the p1 pocket, HLA-DRB3*02:01 should be much more selective than DRB3*02:02 in peptide anchoring. In fact, it carries a valine dimorphism that makes the p1 pocket smaller, and excludes large aromatic and hydrophobic residues from binding.…”

Section: 2mentioning

confidence: 99%

The conundrum of HLA-DRB114:01/14:54 and HLA-DRB302:01/02:02 mismatches in unrelated hematopoietic SCT

Pasi

Crocchiolo

Bontempelli

et al. 2010

Bone Marrow Transplant

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The DRB1 Val86/Val86genotype associates with multiple sclerosis in Australian patients

Cited by 17 publications

References 35 publications

HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

Small Organic Compounds Enhance Antigen Loading of Class II Major Histocompatibility Complex Proteins by Targeting the Polymorphic P1 Pocket

The conundrum of HLA-DRB114:01/14:54 and HLA-DRB302:01/02:02 mismatches in unrelated hematopoietic SCT

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The DRB1 Val86/Val86genotype associates with multiple sclerosis in Australian patients

Cited by 17 publications

References 35 publications

HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

Small Organic Compounds Enhance Antigen Loading of Class II Major Histocompatibility Complex Proteins by Targeting the Polymorphic P1 Pocket

The conundrum of HLA-DRB1*14:01/*14:54 and HLA-DRB3*02:01/*02:02 mismatches in unrelated hematopoietic SCT

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The conundrum of HLA-DRB114:01/14:54 and HLA-DRB302:01/02:02 mismatches in unrelated hematopoietic SCT