Association of Toll-like receptor 4 (TLR4) gene polymorphisms with remission of chronic hepatitis B infections in female patients

Background and Aims: Polymorphisms within the TLR4 gene are thought to influence the clinical course and outcome of HBV infections. They were shown to be associated with delayed progression of liver fibrosis and a reduced risk of development of hepatocellular carcinoma. We investigated the association of the occurrence of the TLR4 single nucleotide polymorphism (SNP) rs4986790 (A>G) and the polymorphism in 3'-untranslated region rs913930 (T>C) with spontaneous clearance of HBV infections.

Methods: 519 patients with chronic hepatitis B (CHB group) and 169 subjects with spontaneous HBsAg clearance (SC group) were enrolled (595 Caucasians, 73 Asians and 20 Africans). In the CHB group, 26.4% (137/519) of the patients were HBeAg-positive and 47.6% (180/378) of the HBeAg-negative patients were inactive carriers. Genomic DNA was extracted from peripheral blood samples. The two SNPs were genotyped by polymerase chain reaction and melting curve analysis. Statistical analysis was made using Chi-square test and logistic regression analysis.

Results: The genotype distributions of the two SNPs did not differed significantly between the CHB and SC groups. However, among female subjects, the presence of at least one minor allele was significantly more frequent in the SC group as compared to the CHB group (34.7% vs. 21%, p = 0.015), whereas this was not significantly different among male subjects. In the CHB group, the rs913930 CC genotype was significantly less frequent among the HBeAg positive patients as compared to the wild-type TT (15.7% vs. 31.1%, p = 0.028). In the regression analysis adjusted for age and gender, rs913930 CC was associated with a lower risk of HBeAg-positive HBV infection when compared to TT genotype (OR = 0.460, 95% CI = 0.226 – 0.936, p = 0.032). For the rs4986790 SNP, there was no association found with regard to HBeAg status. However, the presence of at least one minor allele of these two SNPs was significantly associated with HBeAg-negative status among female patients (OR = 0.406, 95% CI = 0.198 – 0.835, p = 0.014), but not among male patients.

Conclusions: TLR4 polymorphisms at rs4986790 and rs913930 appear to be associated with remission of chronic HBV infections in females and could therefore have an impact on disease progression and outcome. Further studies are needed to confirm these results and elucidate the impact of these polymorphisms on the course and clinical outcome of HBV infection.