Directionality of HLA-DP permissive mismatches improves risk prediction in HCT for acute leukemia and MDS.

ABSTRACT: HLA-DP permissive mismatches can be assigned a direction according to their immunopeptidome divergence across core and noncore subsets. Noncore permissive graft-versus-host mismatches show significantly reduced risks of relapse without increased nonrelapse mortality compared with allele-matched pairs.

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis.

BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. METHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. RESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. CONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC.

Mechanisms of HLA-DP Antigen Processing and Presentation Revisited.

Polymorphisms in HLA-DP can modulate interactions with the invariant chain chaperone, contributing independently to differences in the peptide repertoire presented on DP. The resulting presentation of intracellular antigens directly to CD4+ T cells may partly explain genetic and clinical studies describing previously unexplained links between polymorphism in DP and disease.

Genetic polymorphisms of the HLA-DP and HLA-DQ genes could influence Hepatitis B virus infection in Yunnan population.

Hepatitis B, caused by hepatitis B virus (HBV) infection, is one of the epidemic and infectious hepatitis diseases. The sigle-nucleotide polymorphisms were identified to associate with HBV infection in East Asian population by genome-wide association study (GWAS), but no study in Yunnan HBV population was reported. We recruited 493 HBV patients and 460 general controls to genotype 7 GWAS SNPs, and then, the association study was performed between these SNPs and biochemical features of HBV patients. The results showed that genotype and allele frequencies of SNPs in the HLA-DP (rs3077, 9277535, and 3128917) and HLA-DQ (rs2856718 and 7453920) genes were associated with HBV infection. Significantly different genotyping frequencies were investigated among three HBV subgroups. Genotype AA of rs3130542 (HLA-C) showed significantly higher frequency in subgroup #1 patients than the other two subgroups (#1 vs. #2, p = .02; #1 vs. #3, p = .03). Meanwhile, genotype frequencies of rs3077, rs9277535, and 3128917 (HLA-DP) were significantly different between patients in subgroup #2 and #3. The indirect bilirubin level was significantly lower in patients with genotype CT of rs3077 than patients with genotype CC (p = .009) or TT (p = .016), and it also showed lower level in patients with genotype GT of rs3128917 than patients with genotype GG (p = .015). The direct bilirubin level was higher in patients with genotype TT of rs4821116 (UBE2L3) than patients with genotype CT (p = .010). In summary, we identified the association between GWAS SNPs and HBV infection or biochemical features in Yunnan HBV population.

Limited MHC class II gene polymorphism in the West African chimpanzee is distributed maximally by haplotype diversity.

Chimpanzees have been used for some time as an animal model in research on immune-related diseases in humans. The major histocompatibility complex (MHC) region of the chimpanzee has also been the subject of studies in which the attention was mainly on the class I genes. Although full-length sequence information is available on the DRB region genes, such detailed information is lacking for the other class II genes and, if present, is based mainly on exon 2 sequences. In the present study, full-length sequencing was performed on DQ, DP, and DRA genes in a cohort of 67 pedigreed animals, thereby allowing a thorough analysis of the MHC class II repertoire. The results demonstrate that the number of MHC class II lineages and alleles is relatively low, whereas haplotype diversity (combination of genes/alleles on a chromosome) seems to have been maximised by crossing-over processes.

PR3-ANCA-associated vasculitis is associated with a specific motif in the peptide-binding cleft of HLA-DP molecules.

OBJECTIVES: This study aimed to characterize the association between HLA alleles and ANCA-associated vasculitis (AAV) in a genetically homogeneous population, and to analyse the contribution of specific HLA molecule amino acid sequences to the risk of AAV. METHODS: We included 187 Danish patients with AAV and 1070 healthy controls. All were HLA typed at two-field resolution. The association of HLA alleles to PR3- or MPO-AAV was analysed. The contribution of the dominant molecular motifs of the HLA-DPB1 molecule to the risk of AAV was investigated by association studies that included specific amino acid sequences of the hypervariable regions in exon 2. RESULTS: Ninety-four percent of patients with PR3-AAV were carriers of HLA-DPB1*04:01 while all patients with PR3-AAV were carriers of an HLA-DPB1*04 allele, and 85% were homozygous. This was significantly more than in the control group (P < 0.0001). The association was even stronger when HLA-DPB1*04:02 and -DPB1*23:01 were included. HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01 share amino acids in positions 8-9, 69, 76 and 84-87 within the hypervariable regions, but only positions 69 and 84-87 contributed significantly to the disease risk. HLA-DRB1*15 was associated with an increased risk of developing PR3-AAV, while HLA-DRB1*04, -DRB1*07 and -DQB1*03 were associated with a reduced risk of kidney involvement in PR3-AAV. MPO-AAV was only weakly associated with HLA class I alleles. CONCLUSION: PR3-AAV is strongly associated with the HLA-DPB1 alleles HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01, which share amino acid sequences crucial for the peptide-binding groove.

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities.

When considering HLA-matched hematopoietic cell transplantation (HCT), sibling and unrelated donors (UDs) are biologically different because UD-HCT is typically performed across HLA-DP disparities absent in sibling HCT. Mismatched HLA-DP is targeted by direct alloreactive T cell responses with important implications for graft-versus-host disease and graft-versus-leukemia. This concise review details special features of HLA-DP as model antigens for clinically permissive mismatches mediating limited T-cell alloreactivity with minimal toxicity, and describes future avenues for their exploitation in cellular immunotherapy of malignant blood disorders.

HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy.

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

Multiple genetic variants associated with posttransplantation diabetes mellitus in Chinese Han populations.

OBJECTIVES: Posttransplantation diabetes mellitus (PTDM) is a major complication after solid organ transplantation. This study is to investigate the association of nine genetic variant factors and PTDM in Chinese Han patients. METHODS: HLA-DP (rs3077, rs9277535), HLA-DQ (rs7453920), signal transducer and activator of transcription 4 (STAT4) (rs7574865), IL-28B (rs12979860, rs8099917, and rs12980275), and IL-18 (rs1946518 and rs187238) were investigated in 260 liver transplant recipients (PTDM vs non-PTDM) by high-resolution melting curve analysis. Serum interleukin (IL)-1ß, IL-6, IL-8, IL-17, interferon-γ, inducible protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1b were analyzed by a Bio-Plex suspension array system (Bio-Plex Multiplex Immunoassays, Bio-Rad, Hercules, CA, USA). RESULTS: Signal transducer and activator of transcription 4 (rs7574865) T allele and IL-18 (rs1946518) A allele increase the risk for insulin resistance and PTDM. CONCLUSIONS: Recipients with STAT4 (rs7574865) T allele are associated with an increased concentration of IL-1ß, interferon-γ, monocyte chemoattractant protein, and macrophage inflammatory protein-1b. The genetic variants of STAT4 (rs7574865) and IL-18 (rs1946518) may be new important markers for PTDM.

The orthologs of HLA-DQ and -DP genes display abundant levels of variability in macaque species.

The human major histocompatibility complex (MHC) region encodes three types of class II molecules designated HLA-DR, -DQ, and -DP. Both the HLA-DQ and -DP gene region comprise a duplicated tandem of A and B genes, whereas in macaques, only one set of genes is present per region. A substantial sequencing project on the DQ and DP genes in various macaque populations resulted in the detection of previously 304 unreported full-length alleles. Phylogenetic studies showed that humans and macaques share trans-species lineages for the DQA1 and DQB1 genes, whereas the DPA1 and DPB1 lineages in macaques appear to be species-specific. Amino acid variability plot analyses revealed that each of the four genes displays more allelic variation in macaques than is encountered in humans. Moreover, the numbers of different amino acids at certain positions in the encoded proteins are higher than in humans. This phenomenon is remarkably prominent at the contact positions of the peptide-binding sites of the deduced macaque DPß-chains. These differences in the MHC class II DP regions of macaques and humans suggest separate evolutionary mechanisms in the generation of diversity.

The relationship between human leukocyte antigen-DP/DQ gene polymorphisms and the outcomes of HCV infection in a Chinese population.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: The HLA-DQ rs7453920 and -DP rs9277535 mutations were significantly associated with HCV infection susceptibility and chronicity, respectively.

Genetic polymorphisms of HLA-DP and isolated anti-HBc are important subsets of occult hepatitis B infection in Indonesian blood donors: a case-control study.

BACKGROUND: Occult hepatitis B infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the serum and/or liver in HBsAg-negative individuals. OBI is associated with the risk of viral transmission, especially in developing countries, and with progressive liver disease and reactivation in immunosuppressive patients. The objective of this study was to evaluate the relation of OBI to HLA-DP single nucleotide polymorphisms (SNPs) encoding antigen-binding sites for the immune response to HBV infection. As HLA-DP variants affect the mRNA expression of HLA-DPA1 and HLA-DPB1 in the liver, we hypothesised that high levels of HLA-DPA1 and HLA-DPB1 expression favour OBI development. METHODS: The study enrolled 456 Indonesian healthy blood donors (HBsAg negative). OBI was defined as the presence of HBV-DNA in at least two of four open reading frames (ORFs) of the HBV genome detected by nested PCR. SNPs in HLA-DPA1 (rs3077) and HLA-DPB1 (rs3135021, rs9277535, and rs2281388) were genotyped using real-time Taqman® genotyping assays. RESULTS: Of 122 samples positive for anti-HBs and/or anti-HBc, 17 were determined as OBI. The minor allele in rs3077 was significantly correlated with OBI [odds ratio (OR) = 3.87, 95% confidence interval (CI) = 1.58-9.49, p = 0.0015]. The prevalence of the minor allele (T) was significantly higher in subjects with OBI than in those without (59% and 33%, respectively). The combination of haplotype markers (TGA for rs3077-rs3135021-rs9277535) was associated with increased risk of OBI (OR = 4.90, 95%CI = 1.12-21.52 p = 0.038). The prevalence of OBI was highest in the isolated anti-HBc group among the three seropositive categories: anti-HBs <500 mIU/ml, anti-HBs ≥500 mIU/ml, and isolated anti-HBc (29.41%, p = 0.014). CONCLUSION: Genetic variants of HLA-DP and the presence of anti-HBc are important predictors of OBI in Indonesian blood donors. TRIAL REGISTRATION: Ref: KE/FK/194/EC; registered 01 March 2013. Continuing approval Ref: KE/FK/536/EC; registered 12 May 2014.

[Study of polymorphisms of HLA class â (-A, -B, -C) and class â ¡ (DRB1, DQA1, DQB1, DPA1, DPB1) genes among ethnic Hans from Southern China].

OBJECTIVE: To study the genetic polymorphisms of human leukocyte antigen (HLA)- A, B, C, DRB1, DQA1, DQB1, DPA1and DPB1among ethnic Hans from southern China. METHODS: 481 randomly selected individuals were genotyped using a polymerase chain reaction (PCR) sequence-based typing (SBT) method for the above genes. Their allele frequencies were determined by direct counting. RESULTS: In total, 28 HLA-A, 57 HLA-B, 28 HLA-C, 40 HLA-DRB1, 18 HLA-DQA1, 17 HLA-DQB1, 6 HLA-DPA1and 21 HLA-DPB1alleles were identified. Among these, common alleles (with allelic frequencies > 0.05) included A*1101, A*2402, A*0207, A*3303, A*0201, B*40:01, B*46:01, B*58:01, B*13:01, B*15:02, C*01:02, C*07:02, C*03:04, C*03:02, C*08:01, C*03:03, C*04:01, DRB1*09:01, DRB1*15:01, DRB1*12:02, DRB1*08:03, DRB1*03:01, DRB1*04:05, DRB1*11:01, DQA1*01:02, DQA1*03:02, DQA1*03:03, DQA1*06:01, DQA1*01:03, DQA1*05:05, DQA1*01:04, DQA1*03:01, DQA1*05:01, DQB1*03:01, DQB1*03:03, DQB1*06:01, DQB1*05:02, DQB1*03:02, DQB1*02:01, DQB1*03:02, DQB1*06:02, DPA1*02:02, DPA1*01:03, DPA1*02:01, DPB1*05:01, DPB1*02:01, DPB1*13:01, DPB1*04:01and DPB1*02:02.For each of the locus, the overall frequencies of common alleles were 75.57%, 52.81%, 78.28%, 62.16%, 86.70%, 77.23%, 95.32% and 81.59%, respectively. CONCLUSION: The allelic frequencies of the 8 selected HLA loci among ethnic Hans from southern China may served as a reference for anthropology, legal medicine, transplantation and disease association studies.

HLA-DP is the cervical cancer susceptibility loci among women infected by high-risk human papillomavirus: potential implication for triage of human papillomavirus-positive women.

Given that only a small proportion of women infected by high-risk human papillomavirus (hrHPV) develop cervical cancer, it's important to identify biomarkers for distinguishing women with hrHPV positivity who might develop cervical cancer from the transient infections. In this study, we hypothesized that human leukocyte antigens (HLA) susceptibility alleles might contribute to cervical cancer risk among females infected by hrHPV, and interact with hrHPV types. A case-control study with 593 cervical cancer cases and 407 controls (all hrHPV positive) was conducted to evaluate the effect of eight HLA-related single-nucleotide polymorphisms (SNPs) and their interactions with hrHPV types on the risk of cervical cancer. Three HLA-DP SNPs (rs4282438, rs3117027, and rs3077) were found to be significantly associated with risk of cervical cancer (rs4282438: odds ratio (OR) = 0.72, 95 % confidence interval (CI) = 0.56-0.93; rs3117027: OR = 1.41, 95 % CI = 1.10-1.83; and rs3077: OR = 1.37, 95 % CI = 1.04-1.80) among women infected with hrHPV. An additive interaction between HPV16 and rs4282438 for cervical cancer risk was also found (P for interaction = 0.002). Compared with subjects carrying variant genotypes (GG/TG) and non-HPV16 infections, those carrying wild-type genotype (TT) of rs4282438 and HPV16 positive had a 5.22-fold increased risk of cervical cancer (95 % CI = 3.39-8.04). Our study supported that certain HLA-DP alleles in concert with HPV16 could have a predisposition for cervical cancer development, which may be translated for triage of hrHPV-positive women.

A novel family of human leukocyte antigen class II receptors may have its origin in archaic human species.

HLA class II α and ß chains form receptors for antigen presentation to CD4(+) T cells. Numerous pairings of class II α and ß subunits from the wide range of haplotypes and isotypes may form, but most of these combinations, in particular those produced by isotype mixing, yielded mismatched dimers. It is unclear how selection of functional receptors is achieved. At the atomic level, it is not known which interactions of class II residues regulate selection of matched αß heterodimers and the evolutionary origin of matched isotype mixed dimer formation. In this study we investigated assembly of isotype-mixed HLA class II α and ß heterodimers. Assembly and carbohydrate maturation of various HLA-class II isotype-mixed α and ß subunits was dependent on the groove binding section of the invariant chain (Ii). By mutation of polymorphic DPß sequences, we identified two motifs, Lys-69 and GGPM-(84-87), that are engaged in Ii-dependent assembly of DPß with DRα. We identified five members of a family of DPß chains containing Lys-69 and GGPM 84-87, which assemble with DRα. The Lys/GGPM motif is present in the DPß sequence of the Neanderthal genome, and this ancient sequence is related to the human allele DPB1*0401. By site-directed mutagenesis, we inspected Neanderthal amino acid residues that differ from the DPB1*0401 allele and aimed to determine whether matched heterodimers are formed by assembly of DPß mutants with DRα. Because the *0401 allele is rare in the sub-Saharan population but frequent in the European population, it may have arisen in modern humans by admixture with Neanderthals in Europe.

Genetically distinct subsets within ANCA-associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)). CONCLUSIONS: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection.

Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.

Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China.

BACKGROUND & AIMS: Several genome-wide association studies have revealed that HLA-DP/DQ, STAT4 and IL-28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance. METHODS: A total of 1341 subjects including 908 Tibetans and 433 Uygurs were recruited. Seven single nucleotide polymorphisms (SNP) were genotyped. RESULTS: HLA-DP/DQ polymorphisms associated with HBV natural clearance in both ethnicities (Tibetans, rs3077, OR = 0.61, 95% CI = 0.46-0.82; rs9277535, OR = 0.56, 95% CI = 0.41-0.75; rs7453920, OR = 0.64, 95%CI = 0.47-0.85; Uygurs, rs3077, OR = 0.48, 95% CI = 0.24-0.96; rs9277535, OR = 0.43, 95% CI = 0.20-0.91; rs7453920, OR = 0.62, 95% CI = 0.39-0.99), whereas no significant association was observed between IL-28B with HBV natural clearance in neither ethnicities (P > 0.05). STAT4 rs7574865 seemed to be Tibetan specific in HBV natural clearance (OR = 0.76, 95% CI = 0.58-0.99). Moreover, in Tibetan patients, HLA-DQ rs7453920 GG had a higher frequency in HBeAg positive patients (P = 0.032) and STAT4 rs7574865 GG genotype appeared more frequently in Genotype C virus infected patients (P = 0.005). In addition, Uygurs have higher frequencies of HLA-DP/DQ protective alleles (72.5% for rs3077, 76.6% for rs9277535 and 26.8% for rs7453920) than Tibetans (51.7% for rs3077, 52.5% for rs9277535 and 18.5% for rs7453920)(all P < 0.05), and a lower prevalence of HBV infection as previously reported. CONCLUSIONS: HLA-DP/DQ but not IL-28B polymorphisms correlate with HBV natural clearance, irrespective of race, and HLA-DP/DQ would be causative genes attributing to varying prevalence in different regions. STAT4 rs7574865 seemed to be population specific in Tibetans and it might synergistically interact with virus contributing to disease progression.

HLA-DP genes polymorphisms associate with hepatitis B surface antigen kinetics and seroclearance during nucleot(s)ide analogue therapy.

BACKGROUND & AIMS: Genome-wide association studies (GWAS) recently indicated that polymorphisms in the human leucocyte antigen (HLA)-DP genes were associated with risk of persistent hepatitis B virus (HBV) infection and clearance of HBV, but the effect of HLA-DP gene polymorphisms on the effect of antiviral therapy was unknown. We here investigated whether such polymorphisms were associated with decreases in HBsAg levels and seroclearance in patients who received long-term lamivudine (LAM) treatment. METHODS: Japanese patients (202) who were hepatitis B e antigen positive at baseline, received LAM as first-line treatment, and consented to HLA-DP genotyping (HLA-DPA1 rs3077 and HLA-DPB1 rs9277535) were categorized into two cohorts, viz., a cohort who achieved virological response without rescue therapy (cohort 1) and those who did so with rescue therapy (cohort 2). RESULTS: Serum HBsAg levels declined significantly between year 3 and 9 from baseline among cohort 1 patients possessing ≥2 A-alleles at rs3077 and rs9277535. The percentages of such patients in cohort 1 patients with decreases in HBsAg ≥0.5 log IU/ml were higher than those with <2 A-alleles (71.8% [28/39] vs. 38.9% [23/59]; P = 0.004). However, there was no significant difference in cumulative HBsAg seroclearance rates between patients with ≥2 and those with <2 A-alleles in cohort 1. In cohort 2, HBsAg seroclearance rates were higher in patients with ≥2 A-alleles than in those with <2 A-alleles (P = 0.003). CONCLUSION: We found an association between HLA-DP polymorphisms and decreases in HBsAg levels and seroclearance among HBeAg-positive patients treated with LAM.

Systematic investigation of contribution of genetic variation in the HLA-DP region to cervical cancer susceptibility.

Compared with the other human leukocyte antigen (HLA) genes, few studies have evaluated the role of HLA-DP genes in cervical cancer pathogenesis. A recent genome-wide association study (GWAS) in the Swedish population has identified a susceptibility locus for cervical cancer within the HLA-DP region. To further study this locus, we imputed classic HLA alleles using single-nucleotide polymorphism (SNP) data and analysed 449 genotyped and 3066 imputed SNPs in 1034 cervical cancer patients and 3948 controls. We confirmed that the strongest signal came from a SNP located at HLA-DPB2 [rs3117027, odds ratio (OR) = 1.29, 95% confidence interval (CI) = 1.16-1.43, P = 1.9 × 10(-6) for A allele] and that this effect is not driven by associations with classic HLA alleles. In silico analysis further revealed that this SNP is highly correlated with rs3129294 (D' = 1, r(2) = 0.95 in controls), which may have a putative regulatory function. We also identified an independent association at DPB1*0402, which conferred decreased risk of cervical cancer (OR = 0.75, 95% CI = 0.63-0.89, P = 7.0 × 10(-4)) and is independent of previously described associations with HLA-B*0702, DRB1*1501-DQB1*0602, and DRB1*1301-DQA1*0103-DQB1*0603. No association was found with the two SNPs (rs4282438 or rs9277952) that were recently identified within the HLA-DP region in a cervical cancer GWAS in the Chinese population. Our study provides the first systematic investigation of the association of genetic variants in the HLA-DP region with cervical cancer susceptibility and provides further insight into the contribution of polymorphisms in the HLA-DP region to risk of cervical cancer.