Association Of Polymorphisms Of TNF-a And IL-10 Genes With Outcomes Of Hepatitis B Virus Infection

Hepatitis B virus (HBV) infection is one of the most important chronic viral diseases in the world, which threats the people's health and quality of life.The clinical outcomes of HBV infection are extremely varied, from asymptomatic HBV carriers or cryptic hepatitis, to acute hepatitis, chronic hepatitis, liver cirrhosis or primary hepatocellular carcinoma. What produces the differences in infection, severity, and outcome? At present, most studies about reasons for this variation focus on viral load, genotype, and genetic divergence due to viral gene mutations. In fact, many investigations suggested that HBV was not a direct cytopathic disease. The injury was mediated by the immune response. The variable patterns and clinical outcomes of the infection were mainly determined by host immunological factors and genetic factors as well as the virological factors.Cytokine plays an important role in defense against viral infection, indirectly through determination of the predominant pattern of the host response, and directly through inhibition of viral replication. T cells are involved in the pathogenesis of HBV hepatitis, playing a crucial role in the control of HBV and liver injury during HBV hepatitis. Adoptive transfer experiment in an HBV transgenic mouse model has demonstrated the role of virus specific CD8+ T cells in the elimination of HBV. Moreover, there are several lines of evidences suggesting an important role of CD4+ helper T (Th) cell in the elimination of HBV. One is the significant over expression of HLA-DR13 allele in patients with a self-limiting disease compared to patients who develop chronic disease.The Th cells include Th0, Th1 and Th2 cells. Th1/Th2 cytokine level is different in different phases of hepatitis B virus infection. Thl cytokines (TNF-α, IL-2 and IFN-γ) promote cellular immunity,assist HBVs CTL and benefit clearing virus. And Th2 cytokines (IL-10, IL-6 and IL-4) have inhibitory activity against Th1 cells, and they can inhibit cell immunity, enhance humoral immunity, and are related to tissue damage. TNF-αand IL-10 are two important cytokines of Th1/Th2, and their promoter single nucleotide polymorphism may influence their expressions, induce the imbalance of Th1/Th2 cytokines, and they may be associated with outcomes of hepatitis B virus infection.Objective: To investigate the genotype distribution with tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) promoter single nucleotide polymorphisms (SNP) in Han nationality of Hebei Province with different outcomes of hepatitis B virus (HBV) infection; To explore whether their polymorphisms are associated with the clinical types of patients with chronic HBV infection. Methods: The research enrolled 57 patients with self-limited infections, 51 patients with asymptomatic carriers, 61 patients with chronic hepatitis and 82 patients with Liver cirrhosis. The single nucleotide polymorphisms (SNPs) within TNF-a-238(G/A), -308(G/A) and IL-10-819(C/T) genes in the promoter region were detected by using an allele specific primer-polymerase chain reaction (AS-PCR), to draw one case of every genotype detected by sequence analysis, explore the association of genetic polymorphism by chi-square test with SPSS 10.0 software.Results:1 The frequency of TNF-a-238GG genotype in patients with chronic hepatitis(78.7%)and liver cirrhosis(76.2%)was significantly less than that in subjects with HBV carriers(88.2%) and self-limited HBV infection(87.5%),P<0.05; The frequencies of the G allele in subjects with HBV carriers (94.1%) and self-limited HBV infection (92.9%) were significantly higher than patients with chronic hepatitis (88.6%) and liver cirrhosis (86.9%), P<0.05; There was no significant difference in G allele frequency between HBV carriers and self-limited HBV infection subjects, or between patients with chronic hepatitis and Liver cirrhosis.2 The frequency of TNF-a-308GG genotype was 90.2% in patients with chronic hepatitis, 70.1% in patients with liver cirrhosis, 87.7% in patients with self-limited HBV infection and 90.2% in HBV carriers, respectively. The frequency of the G allele was 95.1% in patients with chronic hepatitis, 94.4% in patients with liver cirrhosis, 93.0% in patients with self-limited HBV infection and 95.1% in HBV carriers. There was no significant difference in G allele frequency between the above four groups (P>0.05).3 The frequencies of IL-10-819 TT genotype in chronic hepatitis (55.7%) and in liver cirrhosis (59.3%) were much higher than in patients with self-limited HBV infection (35.1%) and HBV carriers (37.2%), P<0.05. The frequencies of the T allele in patients with chronic hepatitis (70.5%) and liver cirrhosis (71.6%) were significantly higher than patients with self-limited HBV infection (57.0%) and HBV carriers (58.9%), P<0.05. There was no significant difference in T allele frequency between HBV carriers and self-limited HBV infection subjects, or between patients with chronic hepatitis and Liver cirrhosis.4 Distribution IL-10 -819 allele genotype in different patient groups: its distribution in patients with chronic hepatitis (28.1%) and liver cirrhosis (39.7%) were much higher than patients with self-limited HBV infection (16.5%) and HBV carriers (15.7%), P<0.05. Its distribution in patients with chronic hepatitis (35.5%) was much higher than the other three groups, P<0.05.Conclusions:1 The single nucleotide polymorphisms (SNPs) of cytokines in the promoter region could be detected by AS-PCR. 2 There are significant evidences that genotype distribution and allele frequencies of TNF-a-238 associate with different outcomes of HBV infection.3 There is no association between the genetic polymorphism of TNFa-308 and the different outcomes of HBV infection.4 There are significant evidences that genotype distribution and allele frequencies of IL-10-819 associate with the HBV infection.