• Amino acid
• Balancing selection
• HLA-DPB1
• Linkage disequilibrium
• Population genetics

• HLA-DP beta-Chains/genetics
• Humans
• Selection, Genetic
• Gene Frequency
• Alleles
• Linkage Disequilibrium
• Polymorphism, Genetic
• Genetics, Population
• Exons/genetics

• HHSN272201200028C NIAID NIH HHS
• R01 AI029042 NIAID NIH HHS
• R01 AI128775 NIAID NIH HHS

• Amino acid
• Balancing selection
• DP serologic categories
• DPB1
• Population study

• R01 AI128775 NIAID NIH HHS

• Core T-cell epitope groups
• Directionality
• GvHD
• HLA-DP
• Immunopeptidome
• NRM
• Permissive mismatches
• Relapse
• Unrelated HCT

• Humans
• Hematopoietic Stem Cell Transplantation
• HLA-DP beta-Chains/genetics
• HLA-DP beta-Chains/immunology
• Graft vs Host Disease/immunology
• Histocompatibility Testing/methods
• Epitopes, T-Lymphocyte/immunology
• Unrelated Donors
• T-Lymphocytes/immunology

• Humans
• Antigen Presentation
• HLA-DR Antigens/metabolism
• HLA-DP Antigens/chemistry
• HLA-DQ Antigens/chemistry
• Peptides/chemistry

• 75N93019C00001 NIAID NIH HHS
• U24 CA248138 NCI NIH HHS
• National Cancer Institute
• National Institute of Allergy and Infectious Diseases

• hepatitis b
• epidemiology

• Genetic Polymorphism
• Hepatitis B virus
• Meta-analysis
• Seroconversion
• Systematic review

• Case-Control Studies
• HLA-DP Antigens/genetics
• HLA-DQ Antigens/genetics
• Hepatitis B/genetics
• Hepatitis B Surface Antigens/genetics
• Hepatitis B virus/genetics
• Hepatitis B, Chronic
• Humans
• Polymorphism, Single Nucleotide
• Seroconversion

• Alleles
• HLA-DP Antigens
• HLA-DP beta-Chains/genetics
• Hematopoietic Stem Cell Transplantation
• Histocompatibility Testing
• Permissiveness

• U24 CA076518 NCI NIH HHS
• National Institutes of Health

• TCGA
• immune
• immunotherapy
• lung cancer
• metabolic

• Adenocarcinoma of Lung/genetics
• Adenocarcinoma of Lung/pathology
• Gene Expression Regulation, Neoplastic
• Gene Ontology
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Tumor Microenvironment

• ANCA-associated vasculitis
• Anti-PR3
• Granulomatosis with polyangiitis
• HLA-DPB1

Multiple myeloma (MM) is an incurable hematological tumor, which is closely related to hypoxic bone marrow microenvironment. However, the underlying mechanisms are still far from fully understood. We took integrated bioinformatics analysis with expression profile GSE110113 downloaded from National Center for Biotechnology Information-Gene Expression Omnibus (NCBI-GEO) database, and screened out major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1) as a hub gene related to hypoxia in MM.

Differentially expressed genes (DEGs) were filtrated with R package “limma”. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed using “clusterProfiler” package in R. Then, protein-protein interaction (PPI) network was established. Hub genes were screened out according to Maximal Clique Centrality (MCC). PrognoScan evaluated all the significant hub genes for survival analysis. ScanGEO was used for visualization of gene expression in different clinical studies. P and Cox p value < 0.05 was considered to be statistical significance.

HLA-DPA1 was finally picked out as a hub gene in MM related to hypoxia. MM patients with down-regulated expression of HLA-DPA1 has statistically significantly shorter disease specific survival (DSS) (COX p = 0.005411). Based on the clinical data of GSE47552 dataset, HLA-DPA1 expression showed significantly lower in MM patients than that in healthy donors (HDs) (p = 0.017).

We identified HLA-DPA1 as a hub gene in MM related to hypoxia. HLA-DPA1 down-regulated expression was associated with MM patients’ poor outcome. Further functional and mechanistic studies are need to investigate HLA-DPA1 as potential therapeutic target.

• Bioinformatics analysis
• Hypoxia
• Multiple myeloma
• Prognosis

• HBV
• HLA class II
• HLA-DP
• immune cross-talk
• natural killer cells

• HLA-DPB1
• Korean
• hepatitis B virus
• vaccine response

• HBsAg loss
• hepatitis B
• human leucocyte antigen
• innate immunity
• single nucleotide polymorphisms

• balancing selection
• trans-species polymorphism
• likelihood method
• great ape
• pathogen defense

• Animals
• Extracellular Matrix Proteins/genetics
• Gene Frequency
• Genetic Techniques
• Humans
• Major Histocompatibility Complex
• Models, Genetic
• Mutation Rate
• Pan troglodytes/genetics
• Polymorphism, Genetic
• Receptors, Kainic Acid/genetics
• Recombination, Genetic
• Selection, Genetic

• Wellcome Trust
• R35 GM128590 NIGMS NIH HHS

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized with joint destructions; environmental and genetic factors were thought to be involved in the etiology of RA. The production of anti-citrullinated peptide antibodies (ACPA) is specifically associated with RA. DRB1 is associated with the susceptibility of RA, especially ACPA-positive RA [ACPA(+)RA]. However, a few studies reported on the independent associations of DPB1 alleles with RA susceptibility. Thus, we investigated the independent association of DPB1 alleles with RA in Japanese populations.

Association analyses of DPB1 were conducted by logistic regression analysis in 1667 RA patients and 413 controls.

In unconditioned analysis, DPB1*04:02 was nominally associated with the susceptibility of ACPA(+)RA (P = 0.0021, corrected P (Pc) = 0.0275, odds ratio [OR] 1.52, 95% confidence interval [CI] 1.16–1.99). A significant association of DPB1*02:01 with the susceptibility of ACPA(+)RA was observed, when conditioned on DRB1 (P_adjusted = 0.0003, Pc_adjusted = 0.0040, OR_adjusted 1.47, 95%CI 1.19–1.81). DPB1*05:01 was tended to be associated with the protection against ACPA(+)RA, when conditioned on DRB1 (P_adjusted = 0.0091, Pc_adjusted = 0.1184, OR_adjusted 0.78, 95%CI 0.65–0.94). When conditioned on DRB1, the association of DPB1*04:02 with ACPA(+)RA was disappeared. No association of DPB1 alleles with ACPA-negative RA was detected.

The independent association of DPB1*02:01 with Japanese ACPA(+)RA was identified.

• Adult
• Arthritis, Rheumatoid/genetics
• Case-Control Studies
• Female
• Genotype
• HLA-DP beta-Chains/genetics
• Humans
• Japan
• Male
• Middle Aged

• Japan Society for the Promotion of Science
• the ministry of health, labour, and welfare of japan
• Japan Agency for Medical Research and Development
• national hospital organization
• Daiwa Securities Health Foundation
• Japan Research Foundation for Clinical Pharmacology
• Nakatomi Foundation
• Takeda Science Foundation
• Mitsui Sumitomo Insurance Welfare Foundation
• Bristol-Myers KK
• Abbott Japan
• Astellas Pharma
• Chugai Pharmaceutical
• Eisai
• Mitsubishi Tanabe Pharma
• MSD K.K.
• Pfizer Japan
• Takeda Pharmaceutical Company
• Teijin pharma

• Antigen presentation
• Cirrhosis
• Genome-wide association studies
• Hepatitis B infection
• Hepatocellular carcinoma
• Immune response to hepatitis B virus

• Alleles
• Antigen Presentation/genetics
• Antigen Presentation/immunology
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• HLA Antigens/genetics
• HLA Antigens/immunology
• Hepatitis B/genetics
• Hepatitis B/immunology
• Hepatitis B/therapy
• Hepatitis B/virology
• Hepatitis B Vaccines/immunology
• Hepatitis B Vaccines/therapeutic use
• Hepatitis B virus/immunology
• Humans
• Immunogenicity, Vaccine/genetics
• Polymorphism, Single Nucleotide
• Precision Medicine/methods

T cell alloreactivity is mediated by a self-human leukocyte antigen (HLA)-restricted T cell receptor (TCR) repertoire able to recognize both structurally similar and dissimilar allogeneic HLA molecules (i.e., differing by a single or several amino acids in their peptide-binding groove). We hypothesized that thymic selection on self-HLA molecules could have an indirect impact on the size and diversity of the alloreactive response. To test this possibility, we used TCR Vβ immunophenotyping and immunosequencing technology in a model of alloreactivity between self-HLA selected T cells and allogeneic HLA-DPB1 (DPB1) differing from self-DPB1*04:02 by a single (DPB1*02:01) or several (DPB1*09:01) amino acids in the peptide-binding groove. CD4+ T cells from three different self-DPB1*04:01,*04:02 individuals were stimulated with HeLa cells stably transduced with the relevant peptide processing machinery, co-stimulatory molecules, and HLA-DP. Flow cytometric quantification of the DPB1-specific T cell response measured as upregulation of the activation marker CD137 revealed significantly lower levels of alloreactivity against DPB1*02:01 compared with DPB1*09:01 (mean CD4+CD137+ frequency 35.2 ± 9.9 vs. 61.5 ± 7.7%, respectively, p < 0.0001). These quantitative differences were, however, not reflected by differences in the breadth of the alloreactive response at the Vβ level, with both alloantigens eliciting specific responses from all TCR-Vβ specificities tested by flow cytometry, albeit with higher levels of reactivity from most Vβ specificities against DPB1*09:01. In line with these observations, TCRB-CDR3 immunosequencing showed no significant differences in mean clonality of sorted CD137+CD4+ cells alloreactive against DPB1*02:01 or DPB1*09:01 [0.39 (0.36–0.45) and 0.39 (0.30–0.46), respectively], or in the cumulative frequencies of the 10 most frequent responding clones (55–67 and 58–62%, respectively). Most of the clones alloreactive against DPB1*02:01 (68.3%) or DPB1*09:01 (75.3%) were characterized by low-abundance (i.e., they were not appreciable among the pre-culture T cells). Interestingly, however, their cumulative frequency was lower against DPB1*02:01 compared with DPB1*09:01 (mean cumulative frequency 35.3 vs. 50.6%, respectively). Our data show that, despite lower levels of alloreactivity, a similar clonal diversity can be elicited by structurally similar compared with structurally dissimilar HLA-DPB1 alloantigens and demonstrate the power of TCRB immunosequencing in unraveling subtle qualitative changes not appreciable by conventional methods.

• T-cell alloreactivity
• T-cell receptor repertoire
• human leukocyte antigen-DPB1
• next-generation sequencing
• permissive mismatches

• Allergic rhinitis
• Allergic sensitization
• Epidemiological survey
• HLA
• Japanese cedar pollinosis

Recently, human leukocyte antigen (HLA) class-II gene polymorphisms have been reported to be related to Hepatitis C virus (HCV) infection and chronicity. The objective of this study was to explore the relationship of HLA-DP rs9277535 and HLA-DQ rs7453920 with the outcomes of HCV infection.

The rs9277535 and rs7453920 were genotyped in 370 subjects with chronic HCV infection, 194 subjects with spontaneous HCV clearance, and 973 subjects with non-HCV infection from the Chinese population using the ABI TaqMan allelic discrimination assay.

Logistic regression analyses showed that the minor allele A of rs7453920 significantly increased the susceptibility of HCV infection in dominant model (adjusted OR = 1.33, 95% CI: 1.04–1.71, P = 0.026) and additive models (adjusted OR = 1.30, 95% CI: 1.06–1.60, P = 0.012). Rs9277535 A allele significantly increased the risk of chronic HCV infection in dominant model (adjusted OR = 1.52, 95% CI: 1.01–2.28, P = 0.046). Haplotype AA showed a higher risk of HCV infection than the most frequent haplotype GG (adjusted OR = 1.37, 95% CI: 1.05–1.78, P = 0.018).

The HLA-DQ rs7453920 and -DP rs9277535 mutations were significantly associated with HCV infection susceptibility and chronicity, respectively.

The online version of this article (10.1186/s12985-017-0901-7) contains supplementary material, which is available to authorized users.

• Drug use
• Gene polymorphism
• HLA
• Hemodialysis
• Hepatitis C virus
• Paid blood donors

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Host gene variants may influence hepatitis B virus- (HBV-) related HCC. Human leukocyte antigens (HLA) play an important role in presenting virus antigens to immune cells that are responsible for the clearance of virus-infected cells and tumor cells. Previous studies have investigated the HLA-DQ (rs2856718 and rs9275572) polymorphisms that may be associated with the development of HBV-related HCC. However, the results are controversial or inconclusive. Hence, we conducted a meta-analysis to derive a more precise estimation of the associations. A total of 6 articles were used to evaluate the effect of the two polymorphisms on the risk of HBV-related HCC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. We found that rs2856718 and rs9275572 in HLA-DQ significantly decreased HBV-related HCC in total population, especially in Chinese, but not in Saudi Arabian. Further validation of our results in larger populations and different ethnicities are required.

• HBcrAg
• HBeAg
• HBsAg
• HLA-DQ
• hepatitis B virus
• hepatocellular carcinoma

To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).

A genome‐wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta‐analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function.

Among the genome‐wide significant associations identified, the largest effect on risk of AAV came from the single‐nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top‐scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3‐ANCAs and those with myeloperoxidase‐ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%.

This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

• Chronic hepatitis B
• HBeAg seroconversion
• HLA-DPA1
• cirrhosis
• treatment response

• Adult
• China/epidemiology
• Cytokines/metabolism
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Genotype
• HLA-DP Antigens/genetics
• Humans
• Inflammation Mediators/metabolism
• Lupus Erythematosus, Systemic/epidemiology
• Lupus Erythematosus, Systemic/genetics
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Skin/pathology
• Vasculitis/epidemiology
• Vasculitis/genetics
• Young Adult

• Epitopes
• HLA
• HLA-DP antibodies
• Transplant

Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30–50%) than in European/Americans (10–20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 × 10⁻¹⁷, per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 × 10⁻⁹, per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations.

EGFR mutations in lung adenocarcinoma are more frequent in East Asians compared to other populations. Here, the authors carry out a genome-wide association study in EGFR mutant cancers and identify loci that are associated with risk of developing this molecular subtype of cancer.

• Epitope
• HLA
• Systemic sclerosis
• Topoisomerase I

• Celiac disease
• Epigenetics
• Gene expression
• HLA
• Microbiota

• GWAS
• HBV
• HCC
• HLA
• fibrosis

Human leukocyte antigen (HLA) class II molecule influences host antigen presentation and anti-viral immune response. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) within HLA class II gene were associated with different clinical outcomes of hepatitis C virus (HCV) infection. Three HLA class II SNPs (rs3077, rs2395309 and rs2856718) were genotyped by TaqMan assay among Chinese population, including 350 persistent HCV infection patients, 194 spontaneous viral clearance subjects and 973 HCV-uninfected control subjects. After logistic regression analysis, the results indicated that the rs2856718 TC genotype was significantly associated with the protective effect of the HCV natural susceptibility (adjusted OR: 0.712, 95% CI: 0.554–0.914) when compared with reference TT genotype, and this remained significant after false discovery rate (FDR) correction (p = 0.024). Moreover, the protective effect of rs2856718 was observed in dominant genetic models (adjusted OR: 0.726, 95% CI: 0.574–0.920), and this remained significant after FDR correction (p = 0.024). In stratified analysis, a significant decreased risk was found in rs2856718C allele in the male subgroup (adjusted OR: 0.778, 95% CI: 0.627–0.966) and hemodialysis subgroup (adjusted OR: 0.713, 95% CI: 0.552–0.921). Our results indicated that the genetic variations of rs2856718 within the HLA-DQ gene are associated with the natural susceptibility to HCV infection among the Chinese population.

• hepatitis C virus
• human leukocyte antigen
• infection
• outcome
• polymorphism

• HBV
• HLA-DP/DQ
• IL-28B
• STAT4
• Tibetan
• Uygur

• Adult
• Case-Control Studies
• China
• Female
• Gene Frequency
• HLA-DP Antigens/genetics
• HLA-DQ Antigens/genetics
• Haplotypes
• Hepatitis B/genetics
• Hepatitis B/immunology
• Hepatitis B/virology
• Hepatitis B e Antigens/blood
• Hepatitis B virus/genetics
• Humans
• Interferons
• Interleukins/genetics
• Male
• Middle Aged
• Polymorphism, Genetic
• STAT4 Transcription Factor/genetics
• Tibet/ethnology
• Viral Load
• Young Adult

• Adult
• Alleles
• Carcinoma, Hepatocellular/genetics
• Case-Control Studies
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease
• HLA-DP Antigens/genetics
• HLA-DQ Antigens/genetics
• Haplotypes
• Hepatitis B/diagnosis
• Hepatitis B/genetics
• Hepatitis B/pathology
• Humans
• Liver Neoplasms/genetics
• Male
• Middle Aged
• Odds Ratio
• Patient Outcome Assessment
• Polymorphism, Genetic
• Prognosis
• STAT4 Transcription Factor/genetics

• Alleles
• Biomarkers, Tumor/genetics
• Case-Control Studies
• Chromosomes, Human/genetics
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• HLA Antigens/genetics
• Haplotypes/genetics
• Humans
• Lymphoma, Follicular/genetics
• Polymorphism, Single Nucleotide/genetics

• UL1 TR000430 NCATS NIH HHS
• P42 ES004705 NIEHS NIH HHS
• P30 CA086862 NCI NIH HHS
• P30 CA008748 NCI NIH HHS
• R01 CA154643 NCI NIH HHS
• P30 CA015083 NCI NIH HHS
• R01 CA149445 NCI NIH HHS
• 001 World Health Organization
• P30 ES010126 NIEHS NIH HHS
• P30 CA016672 NCI NIH HHS
• 16491 Cancer Research UK
• UL1 TR000142 NCATS NIH HHS
• Intramural NIH HHS
• P30 CA033572 NCI NIH HHS
• P50 CA097274 NCI NIH HHS