The amino acid variation within the binding pocket 7 and 9 of HLA-DRB1 molecules are associated with primary Sjögren's syndrome

Huang, Renliang; Ju, Youlun; Chen, Yan; Deng, Fengyuan; Chen, Juan; Gao, Xing; Liu, Zuguo; Yu, Xinhua; Zheng, Jiangjun

doi:10.1016/j.jaut.2014.11.006

Cited by 24 publications

(17 citation statements)

References 24 publications

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“…Modification of DRβ1:37 residues is sufficient to alter the T cell receptor peptide recognition 52 53. Pocket P9 of HLA-DRβ has been linked to autoimmune diseases, such as primary Sjogren’s syndrome and primary sclerosing cholangitis 54 55. In the present work, by electrostatic potential surface analysis, we showed that three DRβ1:37N encoding alleles, *03:01 , *13:01 and *13:02 , have negatively charged P9 pocket, which benefits electrostatic interaction and could bind with epitope P9 arginine.…”

Section: Discussionmentioning

confidence: 52%

Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population

et al. 2019

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ObjectiveThe strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC.MethodsWe first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case–control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants.ResultsHLA-DQα1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10−36, OR=2.29). DRβ1:37N had an independent protective effect (p=5.81×10−16, OR=0.49). As predicted by comparative modelling, the negatively charged DQα1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRβ1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.ConclusionsWe provide the first evidence that HLA-DQα1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.

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Section: Discussionmentioning

confidence: 52%

Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population

et al. 2019

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“…For instance, several HLA alleles have been associated with increased risk for Sicca syndrome (SS) in European populations, including HLA-DQB1*02:01 (19, 20), but the association of non-synonymous variants with SS is largely unknown(21). This PheWAS identified HLA-DQB1*02:01 as the strongest HLA risk factor in our population and also implicated non-synonymous variation at position 77 in HLA-DRB1 with SS susceptibility.…”

Section: Resultsmentioning

confidence: 99%

Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants

et al. 2017

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While many phenotypes have been associated with variants in human leukocyte antigen (HLA) genes, the full phenotypic impact of HLA variants across all diseases is unknown. We imputed HLA genomic variation from two populations of 28,839 and 8,431 European ancestry individuals and tested association of HLA variation with 1,368 phenotypes. A total of 104 four-digit and 92 two-digit HLA allele-phenotype associations were significant in both discovery and replication cohorts, the strongest being HLA-DQB1*03:02 and type 1 diabetes. Four previously unidentified associations were identified across the spectrum of disease with two and four digit HLA alleles and ten with non-synonymous variants. Some conditions associated with multiple HLA variants and stronger associations with more severe disease manifestations were identified. A comprehensive, publicly-available catalog of clinical phenotypes associated HLA variation is provided. Examining HLA variant disease associations in this large dataset allows comprehensive definition of disease associations to drive further mechanistic insights.

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“…Our results demonstrate for the first time that the HLA class II allele DRB1*16:02 is associated with disease susceptibility and therapeutic response of patients with anti-NMDAR encephalitis. The DRB1*16:02 allele has previously been shown to be associated with an increased risk of multiple autoimmune diseases, including Graves’ disease,23 anti-topoisomerase I autoantibody-positive systemic sclerosis,24 anti-aquaporin 4 antibody-positive neuromyelitis optica spectrum disorder,25 relapsing polychondritis26 and primary Sjögren’s syndrome 27. Interestingly, all of these autoimmune diseases associated with the DRB1*16:02 are predominantly mediated by autoantibodies, suggesting that the DRB1*16:02 as an HLA class II molecule is involved in the autoantibody production.…”

Section: Discussionmentioning

confidence: 99%

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

Shu

Qiu

Zheng

et al. 2019

J Neurol Neurosurg Psychiatry

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Background and objectiveAetiology and pathogenesis of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most common autoimmune encephalitis, is largely unknown. Since an association of the disease with the human leucocyte antigen (HLA) has not been shown so far, we here investigated whether anti-NMDAR encephalitis is associated with the HLA locus.MethodsHLA loci of 61 patients with anti-NMDAR encephalitis and 571 healthy controls from the Chinese Han population were genotyped and analysed for this study.ResultsOur results show that the DRB1*16:02 allele is associated with anti-NMDAR encephalitis (OR 3.416, 95% CI 1.817 to 6.174, p=8.9×10−5, padj=0.021), with a higher allele frequency in patients (14.75%) than in controls (4.82%). This association was found to be independent of tumour formation. Besides disease susceptibility, DRB1*16:02 is also related to the clinical outcome of patients during treatment, where patients with DRB1*16:02 showed a lower therapeutic response to the treatment than patients with other HLA alleles (p=0.033). Bioinformatic analysis using HLA peptide-binding prediction algorithms and computational docking suggested a close relationship between the NR1 subunit of NMDAR and the DRB1*16:02.ConclusionsThis study for the first time demonstrates an association between specific HLA class II alleles and anti-NMDAR encephalitis, providing novel insights into the pathomechanism of the disease.

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The amino acid variation within the binding pocket 7 and 9 of HLA-DRB1 molecules are associated with primary Sjögren's syndrome

Cited by 24 publications

References 24 publications

Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population

Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population

Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

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