Association of PvuII and XbaI polymorphisms in estrogen receptor alpha gene with the risk of hepatitis B virus infection in the Guangxi Zhuang population

Background and objectiveAvailable evidence has suggested that estrogen receptor alpha (ESR1) is implicated in the pathogenic process of hepatitis B infection. Therefore, we evaluated the association of PvuII (rs2234693) and XbaI (rs9340799) in ESR1 and HBV infection in Guangxi Zhuang populations.MethodsA total of 389 subjects were divided into four groups: 112 patients with chronic hepatitis B (CHB), 65 patients with hepatitis B virus (HBV)-related liver cirrhosis (LC), 107 patients with HBV-related hepatocellular carcinoma (HCC), and 105 healthy controls. The polymerase chain reaction–restriction fragment length polymorphism strategy was used to detect ESR1 gene PvuII and XbaI polymorphisms.ResultsCompared with healthy controls, binary logistic regression analyses show that the CC genotype of PvuII was associated with a significantly increased susceptibility to CHB compared with the TT genotype (OR = 1.760, 95% CI 1.316–2.831; p = 0.044). The PvuII CC genotype was also associated with significantly increased risk of HBV-related LC (OR = 1.921, 95% CI 1.342–2.478; p = 0.043). Similarly, the subjects bearing the homozygous CC genotype of PvuII polymorphism also had more than a 1.7-fold increased risk for development of HCC (OR = 1.748, 95% CI 1.313–2.787; p = 0.010) compared with those bearing the TT genotype. Furthermore, the AC haplotype was associated with a significantly increased risk of HCC with an OR of 1.456 (p = 0.003). In contrast, there were no significant differences in the genotype and allele of XbaI polymorphisms in the ESR1 gene between the groups of patients and healthy controls. In addition, ESR1 polymorphisms were not significantly associated with susceptibility to HBV-related HCC when using CHB and LC patients as references.ConclusionWe conclude that the CC genotype of PvuII in ESR1 is associated with an increased risk of CHB, HBV-related LC and HCC in Guangxi Zhuang populations.     

Association of the gene polymorphisms in sodium taurocholate cotransporting polypeptide with the outcomes of hepatitis B infection in Chinese Han population

ObjectiveIn recent years, sodium taurocholate cotransporting polypeptide (NTCP) was newly identified as a hepatitis B virus (HBV) receptor, which partly shed light on the reason for HBV hepatotropism and its host specificity. However, the related researches were limited to in vitro or animal experiments. Therefore, this study aimed to investigate the association of NTCP polymorphisms with HBV natural course in humans.MethodsAccording to their serological and clinical characteristics, 933 Chinese Han individuals were divided into two major groups, 352 viral clearance controls and 581 persistently infected patients. The latter one included 186 hepatocellular carcinoma (HCC) and 395 non-HCC subjects. A total of five single nucleotide polymorphisms (SNPs) were selected from HapMap dataset and genotyped by high resolution melting (HRM) curve method.ResultsThe rs7154439 AA genotype was observed slightly more common in viral clearance group than in persistently infected group [16 (4.5%) subjects vs. 10 (1.7%) subjects. p = 0.008, adjusted odds ratio (AOR) = 0.33, 95% confidence interval (CI) = 0.15–0.75 in a codominant model; and p = 0.006, AOR = 0.32, 95% CI = 0.14–0.72 in a recessive model]. While the rs4646287 AA genotype was observed slightly more frequent in HCC group than in non-HCC group [6 (3.2%) subjects vs. 1 (0.3%) subject. p = 0.018, AOR = 15.74, 95% CI = 1.59–155.54 in a codominant model; and p = 0.018, AOR = 15.91, 95% CI = 1.61–157.01 in a recessive model]. There were no statistically significant differences of allele or haplotype distribution between any two groups.ConclusionsThis study suggests that polymorphisms in the NTCP region may be associated with the natural course of HBV infection. The rs7154439 AA genotype was associated with HBV clearance, while the rs4646287 AA genotype was associated with HCC occurrence. However, considering the sample size is relatively small, larger studies, especially through multicenter collaboration will be needed to fully validate the significance of these findings.     

Association of IPS1 polymorphisms with peginterferon efficacy in chronic hepatitis B with HBeAg-positive in the Chinese population

AimsTo investigate whether IPS1 polymorphisms affect peginterferon alpha (PEG-IFN) efficacy in chronic hepatitis B (CHB) patients using a tag- single nucleotide polymorphism (SNP) approach.MethodsA total of 212 hepatitis B e antigen (HBeAg)-positive patients treated with a 48 weeks of PEG-IFN monotherapy were enrolled initially and 127 patients were followed for 48 weeks posttreatment. Genotype analysis was performed for 10 tag-SNPs in IPS1.ResultsThe end of virological response (EVR) rate was 45.8% (97/212) and the sustained virological response (SVR) rate was 45.7% (58/127). Meanwhile, 35.4% (75/212) achieved HBeAg seroconversion at the end of treatment. In a multivariate analysis, the rs2464 CC genotype was independently associated with EVR (OR 2.21, 95% CI 1.23–3.98, P = 0.008) and SVR (OR 2.34, 95% CI 1.05–5.20, P = 0.037) after adjustment for sex, age, HBV genotype, baseline levels of HBV DNA and ALT. Meanwhile, rs2464 CC genotype were also independently associated with decline of HBsAg levels below 1500 IU/mL at 12 weeks of treatment (OR 2.52, 95% CI 1.01–6.29, P = 0.047). Furthermore, three SNPs were found to be independently associated with HBeAg seroconversion at the end of treatment. (1) The rs2326369 CC genotype was independently associated with no HBeAg seroconversion (OR 0.52, 95% CI 0.29–0.95, P = 0.034); (2) The rs6515831 TT genotype was independently associated with HBeAg seroconversion (OR 2.11, 95% CI 1.14–3.90, P = 0.017); (3) The rs2464 CC genotype was independently associated with HBeAg seroconversion (OR 2.36, 95% CI 1.26–4.42, P = 0.007).ConclusionsPolymorphisms in IPS1 are independently associated with treatment response to PEG-IFN among Chinese HBeAg-positive CHB patients.     

Replication of genome wide association studies on hepatocellular carcinoma susceptibility loci of STAT4 and HLA-DQ in a Korean population

A recent genome-wide association study (GWAS) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) identified two loci (rs7574865 in STAT4 and rs9275319 in HLA-DQ) in a Chinese population. We attempted to replicate the associations between the two SNP loci and the risk of HCC in a Korean population. The rs7574865 in STAT4 and rs9275319 in HLA-DQ were genotyped in a total of 3838 Korean subjects composed of 287 HBV-related hepatocellular carcinoma patients, 671 chronic hepatitis B virus (CHB) patients, and 2880 population controls using TaqMan genotyping assay. Gene expression was measured by microarray. A logistic regression analysis revealed that rs7574865 in STAT4 and rs9275319 in HLA-DQ were associated with the risk of CHB (OR = 1.25, P = 0.0002 and OR = 1.57, P = 1.44 × 10⁻¹⁰, respectively). However, these loci were no association with the risk of HBV-related HCC among CHB patients. In the gene expression analyses, although no significant differences in mRNA expression of nearby genes according to genotypes were detected, a significantly decreased mRNA expression in HCC subjects was observed in STAT4, HLA-DQA1, and HLA-DQB1. Although the genetic effects of two HCC susceptibility loci were not replicated, the two loci were found to exert susceptibility effects on the risk of CHB in a Korean population. In addition, the decreased mRNA expression of STAT4, HLA-DQA1, and HLA-DQB1 in HCC tissue might provide a clue to understanding their role in the progression to HCC.     

Genetic variations of PD1 and TIM3 are differentially and interactively associated with the development of cirrhosis and HCC in patients with chronic HBV infection

Cooperation or interaction of programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) molecules is more relevant than either molecule alone to immune dysfunction in chronic viral infection and cancers. This study simultaneously investigated polymorphisms at PD1 +8669 and TIM3 −1516 loci in 845 hepatitis B virus (HBV) chronically infected patients [151 asymptomatic carriers, 202 chronic hepatitis, 221 cirrhosis and 271 hepatocellular carcinoma (HCC)], 141 HBV infection resolvers and 318 healthy controls. Multivariate analysis showed that, in addition to gender, age, ALT, albumin and HBV DNA, PD1 +8669 genotype AA was associated with cirrhosis compared with patients without cirrhosis (OR, 2.410; P = 0.001). TIM3 −1516 genotypes GT + TT, together with gender, age, ALT, AST, direct bilirubin, albumin and HBeAg status, were associated with HCC compared with cirrhosis patients without HCC (OR, 2.142; P = 0.011). The combined carriage of PD1 +8669 AA/TIM3 −1516 GT or TT was higher in cirrhosis and HCC pooled patients than in patients without cirrhosis (OR, 2.326; P = 0.020) and in HCC patients than in cirrhosis patients (OR, 2.232; P = 0.013). These data suggest that PD1 and TIM3 polymorphisms may differentially and interactively predispose cirrhosis and HCC in chronic HBV infection.     

The effect of P2X7 receptor 1513 polymorphism on susceptibility to tuberculosis: A meta-analysis

Studies of the association between the purinergic receptor P2X, ligand-gated ion channel 7 (P2X7 receptor) gene 1513A/C polymorphism and susceptibility to tuberculosis have yielded inconsistent results. We performed this meta-analysis to help clarify these inconsistencies. After systematically searching PUBMED, MEDLINE, EMBASE and ISI Web of knowledge, two of the authors independently extracted relevant data and a meta-analysis was performed by using STATA11.0 software. A total number of nine studies involving 2195 cases and 2036 controls were identified. The results indicated that P2X7 receptor gene 1513C allele (OR 1.389, 95% CI 1.161–1.660, p < 0.001) and CC genotype (1.582, 95% CI 1.129–2.217, p = 0. 012) were significantly associated with increased susceptibility to tuberculosis. Subgroup analysis indicated that this SNP greatly contributed to susceptibility to tuberculosis in Asians. The C allele of P2X7 receptor gene 1513A/C polymorphism was also associated with increased susceptibility to pulmonary tuberculosis in Asians (C vs. A: OR 1.420, 95% CI 1.163–1.733, p = 0.001; (CC + AC) vs. AA: OR 1.522, 95% CI 1.186–1.953, p = 0.001). Greater association between P2X7 receptor gene 1513A/C polymorphism and susceptibility to extra-pulmonary tuberculosis with bigger ORs were found (C vs. A, OR 2.035, 95% CI 1.236–3.352, p = 0.005; CC vs. AA, OR 3.788, 95% CI 1.434–10.009, p = 0.007; AC vs. AA, OR 2.148, 95% CI 1.252–3.684, p = 0.005; (CC + AC) vs. AA, OR 2.386, 95% CI 1.302–4.374, p = 0.005; CC vs. (AC + AA), OR 2.692, 95% CI 1.242–5.836, p = 0. 012). This meta-analysis indicates that the C allele of P2X7 receptor gene 1513A/C polymorphism is a risk factor for pulmonary tuberculosis in Asians, while not in Africans or Latinos and a risk for extra-pulmonary tuberculosis. Further well-designed, large scale studies are required to confirm this conclusion.     

Protective effects of HLA-DPA1/DPB1 variants against Hepatitis B virus infection in an Indonesian population

Human leukocyte antigen (HLA) DPA1/DPB1 variants have been reported to influence Hepatitis B virus (HBV) infection. HLA-DPA1/DPB1 plays a pivotal role in antigen presentation to CD4⁺ helper T cells and influences the outcome of HBV infection. To investigate the influence of HLA-DP variants on the outcome of HBV infection in an Indonesian population where it has the third-highest prevalence of HBV infection worldwide, we performed a case–control study of 686 participants, including patients with HBV-related advanced or nonadvanced liver disease, patients with spontaneously resolved HBV, and healthy controls. Single-nucleotide polymorphisms in HLA-DPA1 (rs3077) and HLA-DPB1 (rs3135021, rs9277535, and rs228388) were genotyped using real-time TaqMan® genotyping assays. Because rs2281388 deviated from Hardy–Weinberg equilibrium, it was excluded from subsequent analyses. The results of logistic regression analyses showed that the HLA-DPB1 rs9277535 variants were associated with a reduced risk of persistent HBV infection (odds ratio [OR] 0.70, 95% confidence interval [95% CI] 0.52–0.96, P = 0.026, additive genetic model; OR 0.60, 95% CI 0.38–0.96, P = 0.033, dominant genetic model). The HLA-DPA1 rs3077 variant was associated with a protective effect increasing the spontaneously resolved HBV infection (OR 0.64, 95% CI 0.41–0.98, P = 0.039, dominant genetic model). By contrast, the HLA-DPB1 rs3135021 variant was not associated with the outcome of HBV infection, including susceptibility, spontaneously resolved, or disease progression. Combinations of haplotype markers were also associated with HBV susceptibility (CA for rs3077–rs9277535, OR 0.57, 95% CI 0.36–0.92, P = 0.021; GA for rs3135021–rs9277535, OR 0.56, 95% CI 0.36–0.86, P = 0.0087). In conclusion, these findings confirm that HLA-DPA1/DPB1 variants were associated with the outcomes of HBV infection in an Indonesian population.     

Strong influence of human leukocyte antigen-DP variants on response to hepatitis B vaccine in a Japanese population

Genome-wide association studies (GWASs) have reported that human leukocyte antigen (HLA) variants are associated with chronic hepatitis B, spontaneous hepatitis B virus (HBV) clearance, and response to hepatitis B vaccine. Single nucleotide polymorphisms (SNPs) in HLA-DP (rs9277535 and rs3077) and HLA-DQ (rs2856718 and rs7453920) have been repeatedly associated with chronic hepatitis B and spontaneous HBV clearance. However, the data on the SNPs associated with response to hepatitis B vaccine are inconclusive. The objective of this study was to determine whether these four HLA SNPs that have been identified as risk loci for chronic HBV infection are associated with response to hepatitis B vaccine in a Japanese population. We enrolled 278 medical students who received hepatitis B vaccination and measured anti-hepatitis B surface (HBs) antibody titers 1 month after a three-dose vaccination series. We found that rs9277535 and rs3077 in HLA-DP were strongly associated with response to hepatitis B vaccine (odds ratio [OR] = 0.31 and 0.32, P = 0.004 and 0.010, respectively). These two SNPs were significantly associated with anti-HBs titers in an allele-dependent manner. On the other hand, rs2856718 and rs7453920 in HLA-DQ were not associated with response to hepatitis B vaccine. These results indicate that rs9277535 and rs3077 in HLA-DP are the major determinants of response to hepatitis B vaccine, whereas rs2856718 and rs7453920 in HLA-DQ have little effect on the immune response to hepatitis B vaccine.     

Toll-like receptor 7 variations are associated with the susceptibility to HCV infection among Chinese females

Toll-like receptors 7 (TLR7) play a crucial role in provoking an immune response in HCV infection. We aimed to investigate whether single nucleotide polymorphisms (SNPs) of TLR7, including rs179009, rs179010 and rs179012, affect the outcomes of HCV infection among the Chinese population. A total of 1767 Chinese Han individuals were enrolled. The distribution of SNP frequencies among three groups with different outcomes of HCV infection was assessed, including healthy controls, cases with spontaneous clearance and cases with viral persistence. Then TLR7 mRNA expression and the production of IFN-α and IL-6 after TLR7 agonist Imiquimod stimulation in vitro were determined. Our results suggested that rs179009 GG genotype was significantly associated with a higher risk of the susceptibility to HCV infection among female subjects (OR = 2.42, 95% CI = 1.24–4.71, P = 0.01). Haplotype GCG was significantly associated with a high risk for HCV susceptibility (OR = 1.50, 95% CI = 1.11–2.03, P = 0.01) as compared with the reference haplotype ACG among females. In the functional research of rs179009, a lower IFN-α level was observed in GG genotype than in AA genotype (P = 0.032). Our data indicate that TLR7 rs179009 GG genotype and haplotype GCG were associated with an increased risk of the susceptibility to HCV infection among Chinese females, which may be due to the impaired IFN-α response.     

Association between SNPs in miRNA-machinery genes and chronic hepatitis B in the Chinese Han population

Single nucleotide polymorphisms (SNPs) in miRNA-machinery genes can influence their generation and maturation, then expression and structure. To explore the relationship between three SNPs (rs3757 in DGCR8, rs636832 in AGO1, rs7813 in GEMIN4) in miRNA-machinery genes and chronic hepatitis B, we genotyped the SNPs by high resolution melting method (HRM) in a case-control study of 332 unrelated chronic hepatitis B patients and 352 unrelated healthy controls in Western China. Interestingly, the rs636832 was significantly associated with the susceptibility of CHB (genotype: AA/GA/GG: p = 0.010; allele: A/G: OR = 0.727, 95% CI = 0.575–0.920, p = 0.008). The minor allele A of rs636832 was significantly associated with a decreased risk of CHB. Additionally, the dominant model AG + GG vs. AA showed a risk of 1.442-fold (p = 0.018) with CHB. Further exploration for the association between rs636832 and HBV-DNA load in 329 cases showed no significant difference (genotype: p = 0.321; allele: p = 0.148). Neither did the association between rs636832 and the status of HBsAg and HbeAg (HBsAg: genotype p = 0.337, allele p = 0.436; HBeAg: genotype p = 0.861, allele p = 0.822). Our study first provided the evidence that rs636832 in AGO1 was associated with chronic HBV infection susceptibility in Chinese Han population. Further epidemiological and functional studies in larger populations are warranted to verify our results.     

Toll-like receptor 1 and 10 polymorphisms,Helicobacter pylori susceptibility and risk of gastric lesions in a high-risk Chinese population

Genetic polymorphisms of Toll-like receptor (TLR) 1 and 10 may influence Helicobacter pylori (H. pylori) susceptibility. To evaluate associations between TLR1 and 10 polymorphisms, H. pylori infection, and precancerous gastric lesions, a population-based study was conducted in a high-risk Chinese population.Three single-nucleotide polymorphisms, TLR1 rs4833095, TLR10 rs10004195, and TLR10 rs4129009 were genotyped by TaqMan SNP genotyping assay in 2553 participants with diverse gastric lesions. The status of H. pylori infection was determined by ¹³C-urea breath test.TLR1 rs4833095 T and TLR10 rs10004195 T alleles were the minor alleles and showed in linkage disequilibrium (D′ = 0.98, r² = 0.73) in the Chinese population. A decreased risk of H. pylori infection was observed in subjects with TLR1 rs4833095 CT genotype [adjusted odds ratio (OR) = 0.80; 95% confidence interval (CI): 0.66–0.96] or T allele (OR = 0.82; 95%CI: 0.69–0.99). Moreover, subjects carrying TLR1 rs4833095 TT genotype were associated with reduced risks of chronic atrophic gastritis (CAG, OR = 0.66; 95%CI: 0.45–0.97) and intestinal metaplasia (IM, OR = 0.57; 95%CI: 0.36–0.90). The risk of CAG was also decreased in subjects carrying TLR10 rs10004195 T allele (OR = 0.75; 95%CI: 0.57–0.99). Furthermore, haplotype analysis indicated that haplotype TT of rs4833095 and rs10004195 had a protective effect on H. pylori infection (OR = 0.83; 95%CI: 0.72–0.96) or precancerous gastric lesions (OR = 0.78; 95%CI: 0.64–0.96 for CAG, and OR = 0.74; 95%CI: 0.57–0.96 for IM).These findings suggest that TLR1 rs4833095 and TLR10 rs10004195 may play crucial roles in H. pylori susceptibility and gastric pathogenesis.     

IFNL4 ss469415590 polymorphism contributes to treatment decisions in patients with chronic hepatitis C virus genotype 1b,but not 2a,infection

Recently, the dinucleotide variant ss469415590 (TT/ΔG) in a novel gene, interferon lambda 4 (IFNL4), was identified as a stronger predictor of hepatitis C virus (HCV) clearance in individuals of African ancestry compared with rs12979860. We aimed to determine whether this variant contributes to treatment decisions in a Chinese population. A total of 447 chronic hepatitis C (CHC) patients (including 328 treated with interferon alpha-2b and ribavirin), 129 individuals who had spontaneously cleared HCV (SHC), and 169 healthy controls were retrospectively investigated. ss469415590 genotyping was performed using a mass spectrometry method (SEQUENOM). A higher proportion of SHC individuals carried the TT/TT genotype compared with CHC patients (95.3% vs. 88.8%, P = 0.027). In patients with HCV genotype 1b, the ss469415590 variant was independently associated with sustained virologic response (SVR) (odds ratio [OR] = 3.247, 95% confidence interval [CI] = 1.038–10.159, P = 0.043) and on-treatment virological responses, including rapid (RVR), complete early (cEVR), early (EVR), and end-of-treatment (ETVR), with a minimal OR of 3.73. Especially for patients with high viral load (≥ 4 × 10⁵ IU/ml), ΔG allele carriers had a lower chance of achieving SVR compared with those carrying the TT/TT genotype (7.1% vs. 36.0%, P = 0.034, OR [95% CI] = 7.24 [1.02–318.45], negative predictive value = 92.9%). In patients with HCV genotype 2a, no significant association between the ss154949590 variant and the virological response was identified (P > 0.05). Additionally, we found that ss154949590 was in complete linkage disequilibrium with rs12979860. In conclusion, the IFNL4 ss154949590 TT/TT genotype favors spontaneous clearance of HCV. This same variant is associated with treatment-induced clearance in patients with genotype 1b, but not 2a. ss469415590 (or rs12979860) genotyping should be considered for patients with HCV genotype 1b and high viral load when making a choice between standard dual therapy and an IFN-free direct-acting antiviral regimen.     

Subgenotype D5, BCP and MHR mutations in hepatic complications among hepatitis B virus infected patients from Orissa,India

The study was undertaken to investigate the clinical implications of hepatitis B virus (HBV) genotypes, basal core promoter (BCP), precore (PC) and surface gene mutations in HBV infected patients from Orissa, southeastern India. HBV infections were identified by serology testing and HBV DNA amplification by polymerase chain reaction among the 152 patients. After sequencing, surface gene mutation were studied by sequence analysis as well as by using BLOSUM scores and BCP mutations were studied only by sequence analysis. A high proportion of HBV/D5 (66.0%) was found among the study samples having significant relation with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) patients (p < 0.05). The BCP mutation, TA (81.4%) and C1753/TA (75.0%) was found in significant proportion (p < 0.05) among HCC cases and in fact a gradual increase in these mutations were noted between inactive carriers (IC) to HCC group and also showed higher viral load. An increasing trend of major hydrophilic region (MHR) mutations in S gene was also observed from IC (56.0%) to chronic liver disease (CLD) (60.4%) to LC (72.4%) to HCC (95.0%) patients. In conclusion, our study suggests that the predominant HBV subgenotype HBV/D5 with high viral load and BCP mutations (double and triple) and high mutations in MHR region was significantly associated with advanced liver disease (LC and HCC) and might act as predictor of severe hepatic complications.     

Association of human leukocyte antigen DP/DQ gene polymorphisms with chronic hepatitis B in Chinese Han and Uygur populations

Several genome-wide association studies (GWAS) have shown that human leukocyte antigen (HLA) DP/DQ gene polymorphisms are associated with susceptibility to chronic hepatitis B virus (HBV) infection. We clarified the roles of the HLA-DP/DQ gene in HBV infection in different nationalities. Three single nucleotide polymorphisms (SNPs) in HLA-DP (rs9277471, rs9277535 and rs9277542) and the SNP rs9272346 in HLA-DQ were studied. In total, 779 patients were recruited to this study, including 400 Chinese Han and 399 Uygurs. The rs9277535 variant genotypes were directly associated with HBV persistence compared to healthy controls in an additive model of the Chinese Han population (odds ratio [OR] = 1.88, 95% confidence interval [CI] = 1.03–3.41, P = 0.040), and in a recessive model of the Chinese female population (OR = 2.02, 95% CI = 1.26–3.24, P = 0.003). In addition, rs9277471 and rs9277542 variant genotypes significantly decreased the risk of HBV infection compared to healthy controls in an additive model of the Chinese Han population (OR = 0.53, 95% CI = 0.29–0.98, P = 0.042; OR = 0.53, 95% CI = 0.29–0.97, P = 0.039) and in a dominant model of the Chinese female population (OR = 0.50, 95% CI = 0.31–0.80, P = 0.004; OR = 0.49, 95% CI = 0.31–0.79, P = 0.003). The GG genotype of rs9277346 was associated with HBV infection in the Chinese Han population (additive model: OR = 0.38, 95%CI = 017–0.82, P = 0.014; recessive model: OR = 0.41, 95% CI = 0.19–0.86, P = 0.019) and in males (additive model: OR = 0.31, 95% CI = 0.14–0.65, P = 0.002; dominant model: OR = 0.65, 95% CI = 0.43–0.97, P = 0.034; recessive model: OR = 0.36, 95% CI = 0.18–0.73, P = 0.005). In addition, allele G of rs9277346 was marginally related to a reduction in risk for HBV infection in the Uygur population. Our study suggests that HLA-DP/DQ polymorphisms can affect susceptibility and resistance to HBV infection in Chinese populations, and are possibly linked to race and sex.     

Annual influenza vaccination reduces total hospitalization in patients with chronic hepatitis B virus infection: A population-based analysis

BackgroundThis study evaluated hospitalization and mortality in patients with chronic hepatitis B virus infection (HBV (+)) and matched comparison patients after stratifying the patients according to annual influenza vaccination (Vaccine (+)).MethodsData from Taiwan's National Health Insurance program from 2000 to 2009 were used to identify HBV(+)/vaccine(+) (n = 4434), HBV(+)/Vaccine(−) (n = 3646), HBV(−)/Vaccine(+) (n = 8868), and HBV(−)/Vaccine(−) (n = 8868) cohorts. The risk of pneumonia/influenza, respiratory failure, intensive care, hospitalization, and mortality in the four cohorts was evaluated.ResultsThe total hospitalization rate was significantly lower in patients with chronic HBV infection who received an annual influenza vaccination than in chronic HBV-infected patients who did not receive an influenza vaccination (16.29 vs. 24.02 per 100 person-years), contributing to an adjusted hazard ratio (HR) of 0.56 (95% confidence interval (CI) = 0.50–0.62). The HBV(+)/Vaccine(+) cohort also had lower risks than the HBV(+)/Vaccine(−) cohort for pneumonia and influenza (adjusted HR = 0.79, 95% CI = 0.67–0.92), intensive care unit admission (adjusted HR = 0.33, 95% CI = 0.25–0.43), and mortality (adjusted HR = 0.19, 95% CI = 0.15–0.24).ConclusionsOur results suggest that annual influenza vaccination can reduce the risk of hospitalization and mortality in patients with chronic HBV infection.     

Association of genetic polymorphisms in CD8 + T cell inhibitory genes and susceptibility to and progression of chronic HBV infection

BackgroundPrevious studies have shown that multiple inhibitory genes play an important role in HBV-specific CD8 + T cell exhaustion and dysfunction in the setting of chronic HBV infection. Polymorphic variants of these genes are thought to be predisposing factors for HBV susceptibility, clearance, and disease progression. The aim of this retrospective study was to identify variants affecting chronic HBV infection in a Chinese Han population.MethodsWe chose 28 tgSNPs from HapMap data on 5 key genes. They were genotyped on a total of 858 chronic HBV patients, 429 patients who underwent spontaneous recovery, and 239 healthy controls. We evaluated the correlation between the polymorphisms and HBV susceptibility, spontaneous clearance, and disease progression.ResultsThe association of rs3827537 of BIM genotype TA and allele A was significantly different (P = 0.016, OR = 2.049; P = 0.031, OR = 1.925) between HBV patients and healthy controls. The rs36084323 of PD-1, as well as rs3766377, rs485618, rs4656942 of CD244 showed significant associations with the risk for HBV-related cirrhosis and hepatocellular carcinoma (HCC) (P = 0.009, OR = 0.482; P = 0.009, OR = 4.573; P = 0.015, OR = 0.580; P = 0.028, OR = 2.855). MDR analysis revealed that the four SNPs (rs36084323, rs3766377, rs485618, rs4656942) modulated the predisposition to cirrhosis and HCC in patients with chronic HBV infection (P = 0.006). Using a luciferase reporter assay, we demonstrated that various alleles of rs3766377 had differential effects, and rs3766377 and rs485618 might have interactive effects.ConclusionsThe present study reveals genetic associations among PD-1 and CD244 variants that may be involved in the development of cirrhosis and HCC in patients with chronic HBV infection. The BIM variant was associated with HBV susceptibility.     

Association of HLA-DP variants with the responsiveness to Hepatitis B virus vaccination in Korean Infants

Recently, HLA-DP single nucleotide polymorphisms (SNPs) have been reported to be related to responsiveness to hepatitis B virus (HBV) vaccination. The aim of this study was to investigate associations between HLA-DP SNPs and responsiveness to HBV vaccine in Korean infants. A total of 290 healthy Korean infants who were registered to Seoul Metropolitan Public Cord Blood Bank during the period of February 2007 to December 2011 were enrolled. Anti-HBs antibody level was analyzed after three doses of HBV vaccination. Genotyping of HLA-DPA1 SNPs (rs3077 and rs3830066) and HLA-DPB1 SNPs (rs7770370, rs7770501, rs3128961, and rs9277535) were performed by PCR-sequencing. HLA-A, -B, and –DRB1 genotyping was also performed by PCR-sequence-specific oligonucleotide probe kits. HLA-DPB1 SNPs (rs7770370, rs7770501, rs3128961, and rs9277535) were associated with HBV vaccine response. Allele frequencies of rs7770370 A, rs7770501 C, rs3128961 G, and rs9277535 A were significantly higher in responders than in non-responders (all p < 0.01). Anti-HBs antibody levels were different according to genotypes of DPB1 rs7770370, rs7770501, rs3128961, and rs9277535 (all p < 0.01). In multivariate analysis, HLA-DPB1 rs7770370 AA genotype was significantly associated with HBV vaccine response (relative risk, RR = 2.5, p = 0.033) and high-titer vaccine response (RR = 2.7, p < 0.001). In conclusion, HLA-DPB1 SNPs were significantly associated with responses to HBV vaccination in Korean infants.     

A trivial role of STAT4 variant in chronic hepatitis B induced hepatocellular carcinoma

Two polymorphisms in the STAT4 and HLA-DQ loci were more recently reported to associate with chronic hepatitis B (CHB) induced hepatocellular carcinoma (HCC). We utilised an independent Vietnamese cohort of clinically classified HBV patients of chronic hepatitis B carriers (n = 206), liver cirrhosis (n = 222) and hepatocellular carcinoma (n = 239) and assessed the influence of the reported variants. The STAT4 variant (rs7574865) was marginally associated with HCC susceptibility in CHB carriers in allelic and recessive genetic models (OR = 0.84, 95%CI = 0.7–0.99, P = 0.048 and OR = 0.7, 95%CI = 0.5–0.99, P = 0.047). No significant association between the studied variant with several clinical parameters such as liver enzymes (ALT, AST), total and direct bilirubin, AFP, HBV genotype and viral loads were observed. Our study highlights the reported variant to be a trivial factor and possibly other confounding factors may regulate STAT4 expression during HCC development.     

The −2518 bp promoter polymorphism at CCL2/MCP1 influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil

Mucosal leishmaniasis (ML) follows localized cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. Proinflammatory responses mediate CL self-healing but are exaggerated in ML. Proinflammatory monocyte chemoattractant protein 1 (MCP-1; encoded by CCL2) is associated with CL. We explore its role in CL/ML through analysis of the regulatory CCL2 ?2518 bp promoter polymorphism in CL/ML population samples and families from Brazil. Genotype frequencies were compared among ML/CL cases and control groups using logistic regression and the family-based association test (FBAT). MCP-1 was measured in plasma and macrophages. The GG recessive genotype at CCL2 ?2518 bp was more common in patients with ML (N = 67) than in neighborhood control (NC; N = 60) subjects (OR 1.78; 95% CI 1.01–3.14; P = 0.045), than in NC combined with leishmanin skin-test positive (N = 60) controls (OR 4.40; 95% CI 1.42–13.65; P = 0.010), and than in controls combined with CL (N = 60) patients (OR 2.78; 95% CI 1.13–6.85; P = 0.045). No associations were observed for CL compared to any groups. FBAT (91 ML and 223 CL cases in families) confirmed recessive association of ML with allele G (Z = 2.679; P = 0.007). Higher levels of MCP-1 occurred in plasma (P = 0.03) and macrophages (P < 0.0001) from GG compared to AA individuals. These results suggest that high MCP-1 increases risk of ML.     

Polymorphisms in the oligoadenylate synthetase gene cluster and its association with clinical outcomes of dengue virus infection

Oligoadenylate synthetases (OAS) play an important role in the immune response against dengue virus. Single nucleotide polymorphisms (SNPs) in the OAS genes are known to affect OAS activity and are associated with outcome of viral infections. Polymorphisms in the OAS1 (rs1131454 and rs10774671), OAS3 (rs2285932 and rs2072136) and OAS2 (rs15895 and rs1732778) genes were studied using PCR followed by restriction fragment length polymorphism methods in 109 patients hospitalized for dengue (DEN) and 105 healthy controls (HCs) who have no documented evidence of symptomatic dengue. The two locus haplotype of OAS2 G-G was significantly higher in all patient groups [DEN vs. HCs, P = 0.0041, P corrected (Pc) = 0.012, Odds ratio (OR) 1.73 95% CI 1.16–2.59] while the four locus haplotype of OAS3-OAS2 C-G-A-G was significantly lower in all dengue patient groups [DEN vs. HCs, P = 0.0054, Pc = 0.0486, OR 0.09, 95% CI 0.00–0.64] compared to controls. When the six locus haplotypes involving OAS1, OAS3 and OAS2 polymorphisms were analyzed and compared, the frequency of the haplotype A-A-C-A-G-G was significantly higher [P = 0.0267, Pc = 0.486, OR 2.34, 95% CI 1.08–4.91] and the frequency of the haplotype A-A-C-G-G-A was significantly lower in DHF cases [P = 0.014, Pc = 0.252, OR 0.12, 95% CI 0.01–0.85] compared to healthy controls. The results suggest that OAS1-OAS3-OAS2 haplotypes are associated with differential susceptibility to clinical outcomes of dengue infection.