The Associations Between Polymorphisms Of APOBEC3F And Hepatitis Virus B Infection

BackgroundHepatitis B virus infection is one of the most serious public health problems throughout the world and also one of the most common chronic hepatitis viruses which resulted in a wide range of diseases, including asymptomatic carriers, a potential of hepatitis, acute hepatitis, chronic hepatitis, fulminant hepatitis, even hepatic cirrhosis and hepatocellular carcinoma. Chronic hepatitis B is the most common of infectious diseases in China. There are1.3to2.0million people that10%or15%of population for chronic hepatitis B carries, which more than23million people for chronic activities hepatitis and annually chronic hepatitis B patients would occurred hepatic cirrhosis and hepatocellular carcinoma that respectively accounted for2%and1%according to estimated China crowd. This situation would cause a great of threat for human health and brings a large of spirit burden and the economic burden for patients. Researchers make a great deal of research and exploration for long time, then some progresses has been made and have a better understanding such as pathogenesis, treatment and prevention to chronic hepatitis B. But detailed pathogenesis remains controversial. In recent years, the hepatitis B virus basic research although have larger developments, but did not bring qualitative change to the clinical treatment.Hepatitis B virus infection could cause latent hepatitis, acute hepatitis, chronic hepatitis, fulminant hepatitis, even hepatic cirrhosis and hepatocellular carcinoma, such a broad spectrum of disease, as well as different disease processes and clinical outcomes, existing research that the reason related to three factors:(1) environmental factors including the overall health status of the exposed population, the vaccination status;(2) viral factors including the amount of virus, viral genotype, and the virus itself variability caused by virus genome differences;(3)host factors including infection by age and gender, whether the merger HCV, HDV, HIV and other viral infections, and host genetic susceptibility to human.With the continuous development of human genome research, in order to further elucidate the pathogenesis of hepatic cirrhosis, some researchers proceed from hepatitis B virus infection genetic susceptibility research based on virological and immunological studies, then a large number of disease related genes and genetic susceptibility mechanism have been discovered and elucidated, then hepatitis B host genetic susceptibility research would continue to be reported in China and abroad. Now, the research that the human gene is related to HBV infection is focused on the human leukocyte antigen (HLA), interferon (INF), tumor necrosis factor TNF (TNF), interleukin (IL) gene.Human leucocyte antigen(HLA) that is produced by major histocompatibility complex was associated with the outcome of HBV persistent infection in patients. These HLA-Ⅱ class alleles were related to the positive chronic outcome when the body was infected by HBV:HLA-DQA1*0302, HLA-DQA1*0501, HLA-DQB1*0201, HLA-DQB1*0301, HLA-DQB1*11, HLA-DQB1*15, HLA-DRB1*0301, HLA-DRB1*0401, HLA-DRB1*0701, HLA-DRB1*1001, HLA-DRB1*1201, HLA-DRB1*1501, HLA-DRB1*06, HLA-DRB1*08, HLA-DRB1*16, the haplotype consisting of HLA-DQA1*0501/HLA-DQB1*0301and HLA-DQB1*1102, the haplotypes of contains HLA-DR*7,et al. These HLA-Ⅱ class alleles were related to the negative chronic outcome when the body was infected by HBV: HLA-DRB1*0403, HLA-DR*0406, HLA-DR*07, HLA-DRB1*1101, HLA-DRB1*1104, HLA-DR*13, HLA-DR*15, HLA-DQA1*0201, HLA-DQA1*0301, HLA-DQB1*0303, HLA-DQB1*0402, HLA-DQB1*0503, the haplotype consisting of HLA-DRB1*04and HLA-DQA1*0301, the haplotype consisting of HLA-DRB1*15/*16and HLA-DQA1*0102, the haplotype consisting of HLA-DRB1*01and HLA-DQA1*0104,et al.Tumor necrosis factor-a (TNF-a) that was involved in non-cytotoxic anti-virus mechanism is an important cytokine. The relation was controversial that between TNF-α promoter-308G/A and-238G/A with the state of hepatitis B virus persistent infection. There was an research has been confirmed that TNF-α-863C/C and TNF-α-857C/C are susceptibility genes of HBV infection.As the TNF-α, IFN-γ played a role that can clear the hepatitis B virus in the body by non-cytotoxic effect. There was association between IFN-γ gene polymorphism and the SR of interferon treatment in CHB patients. This study suggested the possibility that IFN-y gene polymorphism(intron1at position+874) might be important in determining an individual’s sustained efficacy of interferon, especially "TT" genetype. Another research suggested an association between the genetic ability to produce low levels of IFN-y and the susceptibility to develop chronic HBV infection.Interleukin which is a lymphocyte factor can activate the cellular immune. Studies have found that some SNPs affect persistent HBV infection. These sites include:IL-6promoter-572G/C, IL-10promoter-592A/C, IL-10promoter-819T/C, IL-10promoter-1082G/A, IL-10promoter-137G/C, IL-10promoter-607C/A, IL-18promoter-656G/T, IL-la-889C/T, IL-1β-511C/T, IL-1β+3953C/T, et al.In addition, some studies have found that other types of genes related to the genetic susceptibility of hepatitis B. These sites include:MIF-173C/C, KIR2DS2, KIR2DS3, KIR2DS1, KIR3DS1, KIR2DL5, ER-α-29T/T, MBP codon-54, VDR-Taq Ⅰ-T/T, VDR-Fok Ⅰ-C/C, VDR-BsmI, et al.HBV does not directly damage the liver cells, it damages the infected liver cells when cleaning the virus through immune response. In recent years, the researchers found that a new host cell factor of mediated innate immunity which called apolipoprotein B mRNA-editing enzymecatalyitc polypeptide-like3family (APOBEC3) what play a unique anti-virus functions in the body resist viral infection process. The family include:APOBEC3A～G. The human immune proteins APOBEC3G and APOBEC3F induce destructive G-to-A changes in the HIV genome, referred to as’hypermutation’. These two proteins co-express in human cells, co-localize to mRNA processing bodies and might co-package into HIV virus. Therefore they are expected to also co-mutate the HIV genome. Although HBV is a DNA virus, it has a similar copy process with retroviral. At the same time, some researchers confirmed the rs8177832locus APOBEC3G gene polymorphism and HBV replication related. The protein gene sequence of APOBEC3F is similar to APOBEC3G. So we were analyzing the association of APOBEC3F polymorphism with the infection of hepatitis B virus in Chinese population.Methods A total of179patients with hepatitis B (119males and60females) who visited the clinics for treatment of liver disease at Nanfang Hospital between2011and2012were enrolled in this study.224non-B hepatitis patients (123males and101females) served as a control group.Clinical data collected each case subjects (including the case and control groups). Each of the cases of venous whole blood sample collected under sterile conditions. Genomic DNA was isolated from whole blood using the DNA blood protocol (CWBIO) according to the manufacturer’s instructions. The extracted DNA was stored in refrigerator at-20℃.The fourth exon gene fragments of the APOBEC3F was amplified by PCR. Then we sequencing and detection of the gene polymorphism for this fragments.Comparison of the age of different groups were performed using the Mann-Whitney U-t test. Comparison of the allele and genotype frequencies of different groups were performed using the chi-square test or the Fisher exact test. APOBEC3F allele frequencies were tested for the Hardy-Weinberg equilibrium for both patients and controls using the chi-square test. The significance level was set at a P value of0.05. Statistical analysis using SPSS16.0software.ResultsAge distribution between the case and control groups showed no significant difference (t=-0.858, P=0.391). Gender distribution was no significant difference between the case and control groups (χ2=2.646, P=0.104). This shows that the two groups were balanced comparable.We investigated the distribution of-498\-532\-552polymorphisms in179HBV-infected patients (case) and224non-B hepatitis patients (control).There were no polymorphisms.The frequencies of T allele of-536in patients with HBV infection (264,71.7%) were lower than controls (410,91.5%), while the frequencies of C allele of-536in case groups (94,28.3%) were higher than controls (38,8.5%).(χ2=45.906, OR=0.260,95%CI (0.173,0.391), P=0.000<0.05)There was no statistically significant that the frequencies of allele of-536in different age groups and gender groups. There was no statistical significance of the frequency of-536allele between the HBeAg-positive group and HBeAg-negative group (χ2=0.001, P=0.979). But the frequencies of-536C allele in HBeAg-positive group and HBeAg-negative group were markedly higher than control group(χ2=22.695, P=0.000;χ2=35.685, P=0.000).ConclusionC allele of APOBEC3F-4exon-536can increase the risk of HBV infection. But this might not be associated with HBV persistent infection in patients in this study. The gene frequencies of APOBEC3F-498\-532\-552were the same in the different populations in existing researches.