The -94Ins/DelATTG polymorphism in NFκB1 promoter modulates chronic hepatitis C and liver disease progression

Infection with Hepatitis C Virus (HCV) is one of the most important risk factor of hepatocellular carcinoma (HCC). HCV is suspected to induce HCC primarily through chronic inflammation and promotion of cirrhosis, a well-known pre-neoplastic condition. The NF-κB pathway is a key regulator of immune and inflammatory processes and plays a pivotal role in oncogenesis. Genetic variations affecting the pathway may alter NF-κB activity in response to HCV infection and contribute to liver tumorigenesis. The present study aims to evaluate the association between -94Ins/DelATTG (rs28362491) polymorphism in NF-κB1 gene promoter region and 2758G > A (rs696) single nucleotide polymorphism in the 3ʹUTR region of NFκBIA and the outcomes of HCV infection.In this case–control study, 559 subjects (343 patients with HCV infection including 237 mild chronic hepatitis patients and 106 patients with Advanced Liver Disease (AdLD), 78 individuals who naturally cleared HCV and 138 healthy subjects) were genotyped for the NFκB1 and NFκBIA SNPs using PCR-RFLP. Logistic regression was used to assess the association between polymorphisms and the outcome and progression of the infection.Variation at rs696 was not associated with HCV resolution or progression (P > 0.05). By contrast, the Ins/Ins genotype was associated with a 4-fold increase of AdLD risk when compared to mild chronic hepatitis C (OR = 4.69; 95% CI, 2.15–10.19; P = 0.0001) and the risk was more pronounced when compared to healthy controls (OR = 5.02; 95% CI, 2.30–10.98; P = 0.00005). Furthermore, carriage of Ins allele at rs28362491 was significantly associated with higher viral loads (P = 0.003).Our results suggest that variation in NFκB1 gene promoter modulates the progression of chronic hepatitis C toward advanced liver disease.     

Impacts of human leukocyte antigen DQ genetic polymorphisms and their interactions with hepatitis B virus mutations on the risks of viral persistence,liver cirrhosis,and hepatocellular carcinoma

Human leukocyte antigen (HLA)-DQ genetic polymorphisms have been associated with chronic hepatitis B virus (HBV) outcomes. We aimed to determine impacts of HLA-DQ polymorphisms and their interactions with HBV mutations on the risks of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). rs2856718 (A > G) and rs9275319 (A > G) were genotyped in 1342 healthy controls, 327 HBV surface antigen (HBsAg) seroclearance subjects, 611 asymptomatic HBsAg carriers (ASCs), 1144 chronic hepatitis B (CHB) patients, 734 LC patients, and 1531 HCC patients using quantitative PCR. HBV mutations were detected by direct sequencing. Logistic regression analyses were utilized to assess the factors and/or multiplicative interactions significantly associated with liver diseases. rs9275319 variant genotypes were inversely associated with HBV persistence compared to HBV natural clearance subjects. rs2856718 variant genotypes significantly increased LC risk compared to ASCs plus CHB patients (GG vs. AA: odds ratio [OR], 1.52, 95% confidence interval [CI], 1.17–1.97 and AG + GG vs. AA: OR, 1.27; 95% CI, 1.04–1.54) and decreased HCC risk compared to HCC-free HBV-infected subjects (AG vs. AA: OR, 0.76; 95% CI, 0.65–0.89 and AG + GG vs. AA: OR, 0.78, 95% CI, 0.68–0.90). rs2856718 variant genotypes were significantly associated with an increased frequency of HBV A1726C mutation, a LC-risk, HCC-protective mutation, in genotype C. A rs9275319 variant genotype (GG) was significantly associated with an increased frequency of preS1 start codon mutation, an HCC-risk mutation, in genotype C. The interaction of rs2856718 AG + GG genotype with T1753V, a HCC-risk mutation, significantly reduced LC risk, with an OR of 0.26 (95% CI, 0.09–0.78); whereas the interaction of rs2856718 AG genotype with C1673T, a LC-risk mutation, significantly increased HCC risk, with an OR of 2.80 (95% CI, 1.02–7.66) in genotype C HBV-infected subjects. Conclusively, the HLA-DQ polymorphisms affect the risks of LC and HCC differently in chronic HBV-infected subjects, possibly via interacting with the HBV mutations.     

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.     

Common polymorphic effectors of immunity against hepatitis B and C modulate susceptibility to infection and spontaneous clearance in a Moroccan population

Chronic diseases caused by hepatitis B and C viruses may evolve towards major complications as liver cirrhosis and cancer. Fortunately, only subsets among acutely infected individuals develop a persistent disease suggesting that genetic susceptibility may influence the establishment of chronicity. In the present study we aim to explore variants distribution in genes encoding for important immune response effectors in chronic hepatitis B and C. We intend to identify common features and to establish connections between single nucleotide polymorphisms (SNPs) predisposing to both chronic hepatitis and spontaneous clearance in a Moroccan population. Ten SNPs mapping on seven candidate genes (CD209, TGFβ-1, CCR5, CCL2, CXCL12, SUMO1 and UBC9) were studied in 544 Moroccan subjects grouped in chronically infected patients, spontaneously resolved individuals, liver disease progressors and healthy controls. Among significant associations found between virus infections and genetic variants, we report for the first time an association of rs4804803 (CD209) A and G variants with susceptibility to HBV infection and spontaneous clearance (p < 0.001, OR = 3.53, 95% CI 2.155; 5.908, and p < 0.001, OR = 7.75, 95% CI 4.646–13.114, respectively). Other important, albeit previously unknown, association was found between SUMO1 rs10185956T variant and spontaneous clearance of HCV infection (p = 0.002, OR = 2.71, 95% CI 1.332–5.869). Our observation, that deserves further confirmation with other SNPs and populations, underlines the involvement of selected immune polymorphisms, among which those in CD209, in the natural history of both chronic hepatitis B and C.     

PNPLA3基因多态性与原发性肝癌遗传易感性的相关性研究

目的：评估PNPLA3 I148M基因多态性与原发性肝细胞癌（HCC）相关性,并探讨其机制。方法：本研究纳入HCC患者67例和健康对照组69例,对照组无肝癌家族史及肝病病史。通过聚合酶链反应（PCR）及基因测序法检测PNPLA3 rs738409基因表型,通过Hardy-weinbeurg遗传平衡定律分析HCC组与对照组各基因型是否具有群体代表。通过χ2检验分析HCC组rs738409各基因型的频率分布有无差异。结果：对HCC组及对照组经吻合度检验,各组基因多态性分布均符合Hardy-Weinberg（H-W）平衡法则（P〉0.05）。HCC组与对照组148 GG、148 CG、148 CC基因型频率分布差异均有统计学意义（χ2=6.30,P〈0.05）。结论：rs738409基因表型与原发性肝癌发病风险具有相关性。     

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.     

HCV F protein amplifies the predictions of IL-28B and CTLA-4 polymorphisms about the susceptibility and outcomes of HCV infection in Southeast China

Cytotoxic T lymphocyte associated antigen-4(CTLA-4) is an inhibitory receptor with great value in the progression of hepatitis C virus (HCV) infection related diseases. To determine the potential associations of IL-28B rs12979860 and CTLA-4 rs231775, rs3087243 and rs5742909 polymorphisms with the generation of HCV F protein, susceptibility and outcomes of HCV infection, a total of 375 healthy controls, 219 HCV spontaneous recovered patients and 600 chronic HCV patients from Southeast China were recruited and genotyped in this study. And the relative mRNA levels of CTLA-4 in T cells were detected. Logistic regression analysis showed that rs231775 A allele was associated with significantly higher rate of spontaneous viral clearance in anti-HCV F antibody negative patients (adjusted OR = 0.512, P = 0.008), but allele A was related to higher mRNA level of CTLA-4 with the generation of HCV F protein. And rs5742909 T allele added up to the risk of HCV infection chronicity significantly in patients with the presence of HCV F protein (adjusted OR = 2.698, P = 0.003). Also, the rs5742909 CC genotype, along with the presence of HCV F protein, indicated a significantly higher CTLA-4 level than that in anti-HCV F antibody negative patients. The AG+AA genotype of rs3087243 significantly increased the susceptibility to HCV infection in subjects over 56 years old (adjusted OR = 1.595, P = 0.011). Genotype–genotype interaction between IL-28B rs12979860 and CTLA-4 rs3087243 was found to be significantly associated with increased susceptibility to HCV infection (adjusted OR = 1.509, P = 0.005). Haplotype analysis in CTLA-4 also showed significant association with the generation of HCV F protein. All these results indicated the importance of IL-28B and CTLA-4 polymorphisms and their associations with HCV F protein in the risk and chronicity of HCV infection in Chinese Han population in Southeast China.     

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.     

Toll-like receptor 8 (TLR8) polymorphisms are associated with non-progression of chronic hepatitis C in HIV/HCV coinfected patients

Toll-like receptor 8 (TLR8) polymorphisms have been related to hepatitis C virus (HCV) infection. The aim was to estimate the association of TLR8 polymorphisms with HCV-related outcomes in HIV/HCV coinfected patients. We performed a cross-sectional study of 220 patients who underwent a liver biopsy. TLR8 polymorphisms were genotyped using GoldenGate® assay. The outcome variables were non-fibrosis (F0), mild-inflammation (A0/A1), and non-steatosis [fatty hepatocytes (FH) < 10%]. Logistic regression analysis was used to compare the outcome variables according to TLR8 polymorphisms. Four polymorphisms were analyzed (rs1013151, rs5744069, rs17256081 and rs3764880rs1013151). Female patients had higher frequency of TLR8 major alleles at rs17256081 and rs101315, and minor alleles at rs3764880 and rs5744069. Male patients had higher frequency of TLR8 minor alleles except for rs3764880, where major alleles were higher (p < 0.01). Two TLR8 polymorphisms (rs1013151 and rs5744069) were significantly associated with non-fibrosis (F0) [adjusted odds ratio (aOR) = 4.42 (95% of confidence interval (95%CI) = 1.54; 12.68) (p = 0.006) and aOR = 4.76 (95%CI = 1.69; 13.37) (p = 0.003); respectively]. When data were stratified by gender, rs1013151 and rs5744069 polymorphisms remained significant for male patients [adjusted odds ratio (aOR) = 4.49 (95%CI = 1.08; 18.62) (p = 0.039) and aOR = 6.17 (95%CI = 1.45; 26.20) (p = 0.014); respectively]. When data were stratified by major HCV genotypes, patients infected with HCV genotype 1 (GT1) had significant values for both rs1013151 and rs5744069 polymorphisms [aOR = 5.79 (95%CI = 1.44; 23.32) (p = 0.013) and aOR = 8.01 (95%CI = 2.16; 35.65) (p = 0.005); respectively]. Finally, none of the TLR8 polymorphisms were significantly associated with mild-inflammation or non-steatosis. In conclusion, TLR8 polymorphisms seem to be related to non-progression of liver fibrosis in HIV/HCV coinfected patients, particularly in males and those patients infected with GT1.     

Genetic polymorphisms of the IFNλ genes are associated with biochemical features in Han Chinese with HCV infection from Yunnan Province,China

Hepatitis C virus (HCV) is the pathogenic factor for hepatitis C disease, which could lead to chronic or serious hepatic diseases. Previous studies have identified that the IL28B gene polymorphisms were associated with therapeutic effect and viral clearness of HCV patients. We aimed to test whether genetic polymorphisms of three IFNλ genes (IL28A, IL28B and IL29) are associated with HCV infection in Han Chinese. We collected whole blood of 261 HCV infectious patients without any therapy and 265 matched normal controls from Yunnan Province. Among these subjects, 28.4% (74/261) of HCV patients and 26.8% (71/265) of controls were male. Ten SNPs (rs8099917, rs10853728, rs11883177, rs12980602, rs4803224, rs11671087, rs11665818, rs8108008, rs7248931, and rs30461), which covered the whole region of the IL28A, IL28B, and IL29 genes, were genotyped. Our results showed that there was no association between genotypes and alleles of the IFNλ gene polymorphisms and HCV infection. One haplotype (TGCTGTGGAT), which was consisted of ten SNPs, showed a significantly higher frequency in HCV patients (11/522 = 2.1%) than in controls (1/530 = 0.2%) (P = 0.003). We performed association analyses for biochemical features and genotype of each SNP, and found that HCV patients with certain genotypes of some SNPs had a higher level of the ALT/AST ratio and total blood bilirubin (TBIL) compared to healthy controls. Our results suggested the IFNλ gene polymorphisms might be associated with clinical features of HCV patients from Yunnan Province, China.     

Vitamin D level and vitamin D receptor genetic variations contribute to HCV infection susceptibility and chronicity in a Chinese population

Vitamin D and vitamin D receptor (VDR) are involved in multiple immune-mediated disorders including chronic hepatitis C virus (HCV) infection. The aim of this study was to determine the association between plasma vitamin D level, VDR genetic polymorphisms and risk of HCV infection susceptibility and chronicity. Seven single nucleotide polymorphisms (SNPs) in VDR gene were genotyped and plasma 25-hydroxyvitamin D [25(OH)D] levels were measured in a Han Chinese population of 898 HCV persistent infection cases, 558 spontaneous clearance subjects and 1136 uninfected controls with high risk of HCV infection. In this case–control study, the average plasma 25(OH)D level in persistent infection patients was significantly lower than that in spontaneous clearance cases (P = 0.039) and controls (P = 0.005). Logistic analyses indicated that rs7975232-C, rs2239185-T and rs11574129-T alleles were significantly associated with a decreased risk of HCV infection susceptibility (all P_Bonferroni < 0.05, in additive/dominant models; P_trend = 9.000 × 10^− 4, combined effects in a locus-dosage manner). The protective effects of three favorable alleles were more evident among males, females and subjects aged ≤ 50 years (all P < 0.05). Haplotype analyses suggested that compared with the most frequent haplotype A_rs7975232T_rs731236C_rs11574129, CTT was correlated with a reduced risk of HCV infection susceptibility (P = 2.200 × 10^− 3). These findings implied that low vitamin D levels might be associated with an increased risk for HCV infection and chronicity, and favorable VDR variants (rs7975232-C, rs2239185-T and rs11574129-T) might contribute to a decreased susceptibility to HCV infection in a high-risk Chinese population.     

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 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.     

Sex-specific association of estrogen receptor 2 polymorphisms with hepatitis C virus infection outcomes in a high-risk Chinese Han population

Hepatitis C virus (HCV) has different clinical and biological characteristics in women versus men, which suggests the potential involvement of estrogen. Estrogen signaling is mediated by the estrogen receptor, and genetic variations in the estrogen receptor gene might affect the pathology of HCV infection. We performed logistic regression analysis to explore the associations between rs1256049, rs4986938 and rs944459 polymorphisms of the estrogen receptor 2 gene (ESR2) and HCV infection outcomes. The variant A allele of rs4986938 was associated with an increased HCV infection susceptibility in the males (additive model: adjusted OR = 1.493, P = 0.010) and a significantly reduced risk of HCV infection in the female subgroup (GA vs. GG: adjusted OR = 0.710, P = 0.012; dominant model: adjusted OR = 0.686, P = 0.004; additive model: adjusted OR = 0.703, P = 0.002). In addition, females carrying the rs4986938 AA genotype appeared to clear HCV spontaneously more readily (adjusted OR = 0.237, P = 0.011), and additive model analyses showed that each additional allele contributed a decreased risk of approximately 34% for HCV chronicity (adjusted OR = 0.659, P = 0.006). Furthermore, a significant multiplicative interaction between the combined rs1256049 and rs4986938 genotypes was found to decrease HCV infection risk (adjusted OR = 0.583, P = 3.000 × 10⁻⁴). The area under the curve, based on the model and including age, gender, HCV genotypes and the three SNPs, was significantly related to the clearance of HCV (P = 0.003). We provide here the first report that rs4986938 in the ESR2 gene played a potential sex-specific role in the etiology of HCV infection in a high-risk Chinese Han population, suggesting that ESR2 is a candidate susceptibility gene for HCV infection and viral clearance.     

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.     

Trends in mortality burden of hepatocellular carcinoma,cirrhosis, and fulminant hepatitis before and after roll-out of the first pilot vaccination program against hepatitis B in Peru: An analysis of death certificate data

The first pilot vaccination program against hepatitis B in Peru was implemented in the hyperendemic Abancay province in 1991. To assess the impact of vaccination on mortality rates of hepatitis B-related hepatocellular carcinoma (HCC), cirrhosis, and fulminant hepatitis, we compared mortality trends before (1960–1990) and after (1991–2012) roll-out of the vaccination program, using death certificate data from the Municipalidad Provincial de Abancay. Our results showed that, following program roll-out, the overall mortality rates (per 100,000 population) decreased from 9.20 to 3.30 for HCC (95% CI, 1.28–10.48%; P < 0.014), from 16.0 to 6.3 for cirrhosis (95% CI, 3.20–16.10%; P < 0.004), and from 34.80 to 1.28 for fulminant hepatitis (95% CI, 16.70–50.30%; P < 0.001). The absolute number of deaths attributable to cirrhosis (10 [8.80%] vs. 0.0%; P < 0.001) and fulminant hepatitis (83 [40.0%] vs. 5 [19.20%]; P < 0.026) decreased in 5–14-year-old children following vaccination. These findings showed reduced mortality rates of hepatitis B-related liver diseases, particularly cirrhosis and fulminant hepatitis in children under 15 years, following implementation of the vaccination program against hepatitis B.     

Influence of HLA-G polymorphisms in human immunodeficiency virus infection and hepatitis C virus co-infection in Brazilian and Italian individuals

ObjectiveThis study aimed to investigate the role of Human Leukocyte Antigen (HLA)-G in the susceptibility to HIV-1 infection through the analysis of the HLA-G 3′ untranslated region (UTR) polymorphisms 14 bp insertion/deletion (rs66554220) and +3142C>G (rs1063320).DesignWe analyzed 582 HIV-1 infected patients and 626 uninfected individuals from Brazil and Italy in a case-control study.MethodsHLA-G polymorphisms were genotyped using PCR, PCR-RFLP assays or direct sequencing. All analyses were stratified by ethnicity. Genotypic, allelic and diplotypic frequencies were compared between HIV-1 infected subjects and controls using Chi-square or Fischer exact tests. Also, haplotypic frequencies were estimated using MLocus software.ResultsAfrican-derived HIV-infected individuals presented a higher frequency of the 14 bp insertion allele as compared to non-infected individuals (0.468 versus 0.373, respectively; p_Bonf = 0.010). A higher frequency of the 14 bp insertion +3142G (insG) haplotype (0.456 versus 0.346, p < 0.001) and the insG/insG diplotype (OR = 1.88, 95%CI = 1.08–3.23, p = 0.021) was observed among African-derived patients as compared to uninfected controls. Also, we observed a higher frequency of the ins/ins genotype among African-derived HIV patients co-infected with HCV (OR = 2.78, 95%CI = 1.20–6.49, p = 0.008).ConclusionsOur data point out to an increased frequency of alleles and genotypes associated with low HLA-G expression among African-derived patients, suggesting a potential role for HLA-G in the susceptibility to HIV-1 infection and HCV co-infection in those individuals.     

Role of IL28B genotype in the liver stiffness increase in untreated patients with chronic hepatitis C

The role of interleukin (IL)28B has been deepened in the treatment response to pegylated-interferon in patients affected by chronic hepatitis C (CHC). However, recently the IL28B genotypes were also related to hepatic fibrosis progression in untreated patients, using the liver biopsy. The aim of this prospective and longitudinal study was to assess the role of different IL28B genotypes in the liver stiffness progression in a cohort of untreated subjects affected by CHC.We included in this analysis all untreated patients affected by CHC and followed for at least 5 years with the annual evaluation of liver stiffness using Fibroscan®. All enrolled subjects were genotyped for rs8099917 and rs12979860 IL28B polymorphisms.In the study period, 266 patients were considered. After 5 years we observed the following median stiffness increases: 6.7 kPa [5.1–7.8] in TT/CC, 4.9 kPa [4.1–5.0] in TT/TC, 3.4 kPa [3.2–3.8] in TG/TC and 1.7 kPa [1.2–1.9] in GG/TT. These values were statistically significant in all groups (p < 0.001). In the multivariate analysis resulted as predictive factors of liver stiffness progression the following: IL28B TT/CC genotype (OR = 4.571; 95%IC = 2.381–12.994; p < 0.001) and IL28B GG/TT genotype (OR = 0.510; 95%IC = 0.289–0.712; p = 0.007). In this study we evidenced that IL28B genotypes were associated with a different level of liver stiffness increase after 5 years and could be used to select the patients who should be treated with priority.     

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.     

Impact of polymorphisms in the HCP5 and HLA-C,and ZNRD1 genes on HIV viral load

AIMSSingle nucleotide polymorphisms (SNPs) in the human leucocyte antigen (HLA) complex P5 (HCP5), HLA-C, and near the zinc ribbon domain containing 1 (ZNRD1) have been shown to influence viral load (VL) set point in HIV-infected individuals with a known seroconversion onset. We aimed to determine the influence of HCP5 rs2395029, HLA-C rs9264942, and ZNRD1 rs3869068 on VL in antiretroviral-naïve individuals and on time to the first VL < 51 copies/ml and on CD4⁺ T-cell recovery after initiation of combination antiretroviral therapy (cART).Material and methodsWe genotyped the rs2395029 (A > C), rs9264942 (T > C), and rs3869068 (C > T) SNPs in 1897 Caucasians from The Danish HIV Cohort Study — a prospective, nationwide, population-based study of HIV-infected individuals in Denmark. General linear models evaluated the effect of SNPs on VL in antiretroviral-naïve individuals 0–18 months after diagnosis and on CD4⁺ T-cell recovery during cART. Cox proportional hazard regression analysis assessed the association with time to first VL < 51 copies/ml. All models were assuming additive genetic effects.ResultsThe rs2395029, rs9264942, and rs3869068 minor alleles were associated with lower VL in antiretroviral-naïve individuals (rs2395029: [mean VL (copies/ml)], A/A: 70,795 [61,660–79,433], A/C: 33,884 [19,498–58,884], P = 0.002; rs9264942: TT: 81,283 [67,608–97,724], T/C: 63,096 [54,954–75,858], CC: 38,905 [25,119–58,884], P < 0.0001; rs3869068, CC: 72,444 [63,096–83,176], C/T: 45,709 [33,113–64,565], TT: 58,884 [20,417–169,824], P = 0.01). Moreover, the C-alleles of rs2395029 and rs9264942 were associated with shorter time to VL < 51 copies/ml: (HR [95% confidence interval], 1.67 [1.09–1.72], P = 0.008; 1.16 [1.06–1.28], P = 0.002; 1.30 [1.08–1.53], P = 0.005, respectively, adjusted for last VL before cART). None of the SNPs predicted CD4⁺ T-cell recovery during cART.ConclusionsThe minor alleles of rs2395029, rs9264942, and rs3689068 associate with lower VL among antiretroviral-naïve individuals and with shorter time to first VL < 51 copies/ml during cART even after adjustment for VL before cART.