Association between polymorphisms of HLA-DRB1 gene and TNF-alpha gene with susceptibility and/or disease progression of chronic hepatitis B infection in Thai population

Abstract

Chronic hepatitis B virus (HBV) infection is caused of liver disease and liver cancer. However, the factor which determined the different outcome in an individual patient remains unclear. The evidence in twin studies supporting genetic factors was associated with HBV infection. In addition, considerable evidence suggests that host genetic factor play an important role in the pathogenesis and clinical outcome of the disease in several ethic groups. The aim of this study was to identify the polymorphisms of HLA-DRB1 gene and TNF-[alpha] gene and to determine the association with susceptibility and/or disease progression of chronic hepatitis B infection in Thai population. Population-based case-control study included 150 chronic HBV patients (100 patients without HCC and 50 patients with HCC) and 100 patients who transient from HBV infection to serve as control with similar ethic and geographic background. HLA-DRB1 gene and TNF-[alpha] gene polymorphisms were identified by PCR-sequence specific primer (SSP) and PCR-restriction fragment length polymorphism (RFLP), respectively. The result of this study demonstrated that HLA-DRB1*1301-2 phenotype in the transient HBV patients was significantly higher than chronic HBV patients (OR=0.04, 95%CI=0.00-0.26, p.=0.0004) and-863A allele of TNF-[alpha] gene was increased in chronic HBV patients compared with transient HBV patients (OR= 1.63, 95%CI=1-2.65, p=0.0495). Interestingly, HLA-DRB1*1301-2 show a strong association with the clearance of HBV which similar to another study in several ethic groups. Moreover, we also found an association between TNF-[alpha] and the progression of chronic HBV infection. The present study showed that the frequencies of the-863A allele and-238A allele was significantly increased in chronic HBV patients with HCC compared with chronic HBV patients without HCC (OR=2.17, 95%CI=1.03-4.59, p=0.0414 and OR=3.69, 95%CI=0.94-15.42, p=0.046, respectively). The effect of the-863A allele and-238A allele were similar to autosomal dominant mode of inheritance. Haplotype analysis revealed that the homozygosity of the significantly most common haplotype (CGG/CGG) was a protective marker for HCC (OR=0.37, 95%CI=0.17-0.79, P=0.009) supporting the positive association of-863A and-238A genotype. No significant association in HLA-DR12 and TNF-[alpha] gene polymorphisms at position 308(G/A) were found between chronic HBV patients and recovered patients. In conclusion, our study showed that HLA-DRB1*1301-2 is a host factor that might be a protective allele in chronic hepatitis B infection. Furthermore, the 863A allele and-238A allele of TNF-[alpha] gene were identified as a genetic marker for hepatocellular carcinoma development in patient with chronic HBV infection in Thai population.