Short Communication: Does Interleukin-28B Single Nucleotide Polymorphisms Influence the Natural History of Hepatitis B?

Abstract Single nucleotide polymorphisms (SNP) nearby the IL28B gene have been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in both monoinfected and HIV-coinfected patients. However, its impact on spontaneous clearance of HBV (the pathogenesis of which is also related to interferon) is less known. A case-control study was performed. Cases were 49 HIV(+) patients with chronic hepatitis B (HBsAg(+) for more than 6 months) who had been genotyped for the rs12979860 SNP (protective CC genotype). One control for each case was chosen among HIV patients with anti-HBs and anti-HBc. Controls were matched for gender and coinfection with HCV. Most patients were male (90%) and the median (IQR) age was 42.6 (39-46.7) years. Eighteen (36.7%) were also coinfected by HCV. Among HBsAg(+) patients, 19 (41.3%) were HBeAg(+) and 13 (26.5%) were also infected with hepatitis delta (HDV). No differences were found in the distribution of the CC genotype between patients with chronic hepatitis B and those who spontaneously cured hepatitis B: 59.2% vs. 44.9%; p=0.3. Thus, the interleukin-28B (IL-28B) genotype does not seem to have a role in the development of chronic hepatitis B among HIV-infected patients.     

Association Between Catalase Gene Polymorphisms and Risk of Chronic Hepatitis B,Hepatitis B Virus-Related Liver Cirrhosis and Hepatocellular Carcinoma in Guangxi Population: A Case–Control Study

Reactive oxygen species (ROS) play critical roles in hepatocarcinogenesis. The catalase (CAT) enzyme is involved in the repair of ROS. Therefore, we investigate the association between CAT gene polymorphisms and the risk of hepatocellular carcinoma (HCC).A total of 715 subjects were divided into 4 groups: 111 chronic hepatitis B (CHB) patients, 90 hepatitis B virus (HBV)-related liver cirrhosis (LC) patients, 266 HBV-HCC patients, and 248 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism strategy was used to detect CAT gene rs1001179, rs769217, and rs7943316 polymorphisms.Binary logistic regression analyses adjusting for sex, age, ethnicity, smoking and alcohol consumption, and body mass index suggested that subjects carrying the rs769217 T allele were at marginally increased risk of CHB, LC, and HCC, with adjusted odds ratios (ORs) of 1.51 (95% confidence interval [CI] = 1.04–2.20, P = 0.029), 1.48 (95% CI = 1.03–2.14, P = 0.035), and 1.51 (95% CI = 1.14–1.98, P = 0.004), respectively. Similarly, those individuals carrying the rs769217 TT genotype had a moderately increased risk of CHB, LC, and HCC, with adjusted ORs of 2.11 (95% CI = 1.05–4.22, P = 0.035), 2.00 (95% CI, 1.01–3.95, P = 0.047), and 1.93 (95% CI = 1.14–3.28, P = 0.015), respectively. Moreover, subjects carrying the rs769217 CT genotype and at least 1 copy of the T allele (dominant model) were 1.78 times and 1.83 times more likely to develop HCC, respectively (OR = 1.78, 95% CI = 1.16–2.73, P = 0.009 and OR = 1.83, 95% CI = 1.23–2.71, P = 0.003). This association between CAT rs769217 T alleles and HCC risk is significantly strengthened among men, nonsmokers, nondrinkers, and among individuals <50 years of age. Furthermore, we found 1 high-risk haplotype GTA for CHB (OR = 1.45, 95% CI = 1.05–2.01) and 1 protective haplotype GCA for HCC risk (OR = 0.67, 95% CI = 0.52–0.87). We did not found any significant difference in CAT rs1001179 and rs7943316 polymorphisms between controls and cases.Our findings suggest that the CAT rs769217 T allele is associated with increased risk of CHB, HBV-LC, and HBV-HCC in Guangxi population.     

The IFN-λ Genetic Polymorphism Association With the Viral Clearance Induced by Hepatitis C Virus Treatment in Pakistani Patients

Background

Polymorphisms in the interferon λ (INF λ) genes on chromosome 19 have been associated with clearance of hepatitis C virus (HCV) induced by interferon and ribavirin therapy however there is no such data available for Pakistani patients with HCV infection.

Objectives

In this study, the effects of single nucleotide polymorphisms (SNPs) have been investigated in response to treatment with interferon-α and ribavirin in a cohort of 75 HCV genotype 3a patients.

Patients and Methods

A total number of 50 SNPs from the Interferon λ region on chromosome 19 were genotyped to investigate allelic associations with the treatment response in HCV type 3a patients. Thirteen SNPs were associated with HCV clearance, with the most significant alleles being RS8109886 (Fisher’s P = 0.0001), RS8113007 (Fisher’s P = 0.0001) and RS12979860 (Fisher’s P = 0.0002).

Results

These SNPs were found to be the most suitable SNPs for predicting treatment response in the present study. These findings support those reported previously. This could be used to improve HCV treatment strategies and suggest that Pakistani patients should be genotyped for the relevant SNPs to identify the patients who are more likely to respond to interferon and ribavirin therapy.

Conclusions

This therapy is costly and can be accompanied by several adverse side-effects, hence pre-treatment prediction of patients who are most likely to benefit would have both economic and patient benefits in the long term.     

High Risk of Hepatitis B Virus Reactivation in Nucleos(t)ide Analogue-Induced Hepatitis B e Antigen Seroconverters Older Than 40 Years

Background

A recent study showed that chronic hepatitis B virus (HBV) carriers with nucleos(t)ide analogue (NA)-induced hepatitis B antigen (HBeAg) seroconversion occurring before the age of 30 years have a higher risk of HBV reactivation.

Aim

To compare the risk of HBV reactivation and HBeAg seroreversion between patients with spontaneous and NA-induced HBeAg seroconversion.

Methods

A total of 135 and 251 non-cirrhotic patients with NA-induced and spontaneous HBeAg seroconversion, respectively, were analyzed.

Results

NA-induced HBeAg seroconverters faced higher risks of HBV reactivation and HBeAg seroreversion than spontaneous HBeAg seroconverters (P < 0.001). In spontaneous HBeAg seroconverters, age at HBeAg seroconversion, sex, HBV DNA levels before HBeAg seroconversion, HBV genotype C, and pre-S deletions were independent predictors of HBV reactivation. In NA-induced HBeAg seroconverters, only age at baseline was an independent predictor of HBV reactivation. To determine whether the difference in the incidence of HBV reactivation or HBeAg seroreversion between two groups was age-specific, we analyzed these patients according to their age at HBeAg seroconversion (20–29, 30–39, and ≥40 years). Our data showed that NA-induced HBeAg seroconversion was an independent predictor of HBV reactivation and HBeAg seroreversion than spontaneous HBeAg seroconversion in patients older than 40 years at HBeAg seroconversion, but not in patients between 20–29 and 30–39 years of age.

Conclusions

NA-induced HBeAg seroconverters are associated with higher risks of HBV reactivation and HBeAg seroreversion compared to spontaneous HBeAg seroconverters, especially in patients who are older than 40 years at HBeAg seroconversion.     

Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Tunisian Adults’ Asthma

Introduction

Several studies have shown a strong correlation between the serum vitamin D level and asthma severity and deficits in lung function.

Objective

Study the relationship between vitamin D and the severity of asthma by targeting five SNPs of vitamin D metabolism gene pathway in a Tunisian adult asthmatics population.

Methods

Our case–control study includes 154 adult asthmatic patients and 154 healthy Tunisian subjects. We genotyped many variants in three human genes encoding key components of the vitamin D metabolism, CYP2R1, CYP27B1, GC. The GC gene rs4588 and rs7041 polymorphisms were analysed using the PCR-RFLP method, while rs10741657 and rs12794714 for CYP2R1 gene and rs10877012 of CYP27B1 gene were investigated using TaqMan PCR genotyping techniques.

Results

We found that the presence of at least one copy of the rs12794714 A, allele was associated with lower risk of developing asthma (OR 0.61). Further, the rs12794714 is a protector factor against asthma severity (OR 0.5). However, the presence of rs10877012 TG genotype is a risk factor related to asthma severity (OR 1.89). When we classified the population according to sex, our results showed that rs10877012 TT genotype was a risk factor for women subjects (OR 6.7). Moreover, the expression of TT genotype was associated with a higher risk of asthma in non-smoker patients (OR 7.13). We found a significant lower VD serum levels in asthmatics than controls but no impact of the polymorphisms on VD levels.

Conclusions

We found that rs12794714 and rs10877012 SNPs were associated with asthma risk.

     

Clinical Expression of ‘Silent’ Hepatitis B Virus Infection in a Patient with Visceral Leishmaniasis

A 69-year-old male was hospitalized in January 1999 because of viszeral leishmaniasis. He had also suffered from anti-hepatitis C virus (HCV)-positive chronic hepatitis for years. All serum hepatitis B virus (HBV) antigens and antibodies were negative except for anti-HBc. The patient was treated with amphotericin B cholesteryl sulfate (2 mg/kg twice a day for 7 days, iv). Fever disappeared on the 3rd day of treatment, the clinical condition improved rapidly and the patient recovered. In May 1999 the patient developed iteric HBsAg-negative acute hepatitis (aspartate aminotransferase 722 U/l; alanine aminotransferase 988 U/l). Anti-HBc IgM was positive and HBV-DNA was detected in serum by PCR. Anti-HAV IgM was negative. A serum sample obtained on presentation and stored at −80°C was retrospectively tested and found positive for HBV-DNA. In July 1999, complete remission of acute hepatitis and seroconversion to anti-HBs was observed. We suppose that a moderate depression of the immune system, probably associated with leishmaniasis, may have enhanced HBV replication in the patient who had an HBsAg-negative ‘silent’ HBV infection. Restoration of the immune system after successful antiprotozoan therapy might have induced cell-mediated necrosis of the HBV-infected hepatocytes and seroconversion to anti-HBs. Received: June 6, 2000 · Revision accepted: February 16, 2001     

Significant Differences in the Interleukin-1ß and Interleukin-1 Receptor Antagonist Gene Polymorphisms in a Hungarian Population with Inflammatory Bowel Disease

Background: There is growing evidence of the importance of genetic predisposition and the activation of the mucosal immune system in the pathogenesis of inflammatory bowel disease. Thus, genes involved in the regulation of inflammation are receiving increased attention. We have studied whether Crohn's disease (CD) or ulcerative colitis (UC) is associated with certain allelic combinations of IL1B/IL1RA gene polymorphisms in a different European population than the ones studied so far. Methods: Ninety-six patients with UC, 97 with CD, and 132 healthy individuals (HC) were typed for the polymorphic regions in exon 5 of the IL1B gene and in intron 2 of the IL1RA gene, using polymerase chain reaction-based methods. Results: In CD homozygotes for allele 1 in IL1B gene polymorphism were more often present (72% versus 28%; P = 0.01) in the subgroup of patients carrying at least one copy of allele 2 in IL1RA gene polymorphism. This association was not found in HC (HC versus CD; P = 0.03) or UC. However, in UC patients with pancolitis a similar trend was observed (75% versus 25%). Several genotype combinations characterized by the presence of allele 2 of the IL1RA gene polymorphism were more common in CD (P = 0.001) and UC (P = 0.049) than in HC. Conclusions: Our data support the concept that CD and severe UC have a genetic disequilibrium in the distribution of IL1B and IL1RA gene polymorphisms. These findings together with functional studies will contribute to the understanding of the pathogenesis of the chronicity of inflammation in these diseases.     

Investigation of Transforming Growth Factor-β1 Gene Polymorphisms Among Iranian Patients With Chronic Hepatitis C

Background

Chronic hepatitis C infection is caused by the hepatitis C virus (HCV), and its clinical complications include liver cirrhosis, liver failure, and hepatocellular carcinoma.Transforming growth factor-β1 (TGF-β1) is an important cytokine in cell growthand differentiation, angiogenesis, extracellular matrix formation, immune responseregulation, and cancer development and progression.

Objectives

The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in TGF-β1 and chronic HCV infection among patients referred to the Taleghani Hospital, Tehran, Iran between 2008 and 2010.

Patients and Methods

In this case-control study, samples were collected using a convenience sampling method. We genotyped 164 HCV patients and 169 healthy controls for 3 SNPs in the TGF-β1 gene (-509 promoter, codon 10, and codon 25). We determined the SNP genotypes by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. To confirm the PCR-RFLP genotyping results, 10% of the samples were re-genotyped using a direct sequencing method.

Results

There were no significant differences in the allelic frequency distribution of SNPs at -509 C/T, +869 C/T, or +915 G/C between HCV patients and the healthy controls. Genotyping results for all three polymorphic sites were similar with no statistically significant differences between the groups.

Conclusions

Most of the Iranian patients (over 85%), both healthy controls and HCV patients, had the GG genotype at the +915 G/C position, resulting in a high level of TGF-β1 production. Therefore, we concluded that the SNPs investigated by us cannot be considered as prognostic factors for HCV infection in our population, despite being reported as prognostic markers in other populations. Moreover, there is a possibility that most of the population is susceptible to HCV infection.     

Quantitation of Hepatitis C Virus RNA in Plasma and Peripheral Blood Mononuclear Cells of Patients with Chronic Hepatitis Treated with Interferon-α

We quantified hepatitis C virus (HCV) RNA at different times in plasma and peripheral blood mononuclear cells (PBMC) in 51 patients with chronic hepatitis C undergoing interferon-_2a (IFN-_2a) therapy. HCV RNA loads in plasma correlated with those in PBMC before and during the treatment (P < 0.001). After treatment, a sustained response was observed in 19 patients (SR), a response followed by relapse in 9 (RR), and non response in 23 (NR). By univariate analysis PBMC HCV RNA load before treatment was lower in SR than in RR and NR (P = 0.003). In the 9 RR, HCV RNA disappeared in PBMC before or at the same time as in plasma and again became detectable in plasma and PBMC simultaneously or earlier in plasma. These results indicate that quantitation of HCV RNA in PBMC is not a useful parameter for the follow-up of treated patients.     

Clinical Outcomes of Hepatitis B Virus–Related Hepatocellular Carcinoma Patients with Undetectable Serum HBV DNA Levels

Digestive Diseases and Sciences - Some hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients show undetectable serum HBV DNA levels at HCC diagnosis. The risk of HBV reactivation...     

The Expression of Hypoxia-Inducible Factor-1α in Hepatitis B Virus-Related Hepatocellular Carcinoma: Correlation with Patients’ Prognosis and Hepatitis B Virus X Protein

Hypoxia inducible factor-1α (HIF-1α) was well correlated with carcinogenesis and tumor progression in many kinds of cancer. In this study, high expression of HIF-1α was found in 37 of the 72 (51.39%) tumor specimens, and significantly correlated with venous invasion and lymphonode invasion. Patients with high expression of HIF-1α had a significantly shorter overall survival rate and disease-free survival rate than those with low expression. Multivariate analysis showed high HIF-1α expression was a borderline independent factor of overall survival. HIF-1α expression was also found to be significantly correlated with the expression of hepatitis B virus X protein (HBx), and over-expressed HBx upregulated HIF-1α protein expression in vitro. These results suggested that HIF-1α, which was partially regulated by HBx, might be a prognostic marker of HBV-related HCC patients. Dr. Huahong Xie, Dr. Jiugang Song, and Dr. Kaige Liu contributed equally to this study.