Tumor necrosis factor gene polymorphisms and clearance or progression of hepatitis B virus infection

Objectives: We evaluated the influence of tumor necrosis factor-alpha (TNF-alpha) promoter gene polymorphisms on clearance of hepatitis B virus (HBV) and outcome of HBV chronic hepatitis. Methods: Four TNF-alpha promoter polymorphisms (T-1031C, C-863A, G-308A, and G-238A) were evaluated by direct sequencing in 184 chronic HBV carriers hepatitis B surface antigen (HBsAg) positive and 96 controls with documented sero-clearance (HBsAg negativity, positivity for anti-HBs and anti-HBc IgG). Frequencies of single-nucleotide polymorphisms (SNPs) and haplotypes in the control group were compared with those of the chronic carrier group and with clinically defined subgroups of the latter: asymptomatic carriers, patients with compensated hepatitis, decompensated cirrhotics, and patients with hepatocellular carcinoma. Furthermore, subgroups of chronic carriers were compared among them. Results: In the chronic carrier group, the -308G allele was more frequent in those with a family history of HBV infection (96% vs 88% of those with non-familial transmission). The G/G genotype at position -308 was found in all chronic carriers with decompensated cirrhosis but in only 78% of controls (P=0.01) and was more frequent in decompensated cirrhotics than in the other subgroups. The distribution of TNF-alpha gene polymorphisms in the carrier group was not significantly different from that in the sero-clearance control group. TNF-alpha SNPs at positions -1031/-863 and -863/-238 were in linkage disequilibrium. The TCGG haplotype (-T1031, -C863, -G308, -G238) was significantly associated with end-stage liver disease. Conclusions: The TNF-alpha promoter polymorphisms do not appear to be determinant of HBV sero-clearance in southern Italians. The genotype -308G/G and haplotype TCGG are associated with an unfavorable prognosis in patients with chronic HBV infection.