Effects of TBK1 genetic polymorphisms and their interactions with hepatitis B virus mutations on the risk of hepatocellular carcinoma in Han Chinese population: a case-control study.

BACKGROUND

TANK-binding kinase 1 (TBK1) plays a critical role in driving inflammation and carcinogenesis. We aimed to investigate whether TBK1 single nucleotide polymorphisms (SNPs) were associated with the selection of hepatitis B virus (HBV) mutations, and to explore their interaction in modulating the risk of hepatocellular carcinoma (HCC).

METHODS

Four TBK1 SNPs (rs12313449, rs73122364, rs7486100, and rs11175413) were genotyped in 3405 participants using quantitative PCR. HBV mutations were determined by Sanger sequencing. Interactions of TBK1 polymorphisms and HBV mutations were examined on both additive and multiplicative scales. A dual-luciferase assay was performed to assess the transcriptional activity of fragments containing rs12313449, rs73122364, rs7486100, and rs11175413 polymorphic genotypes. We evaluated the association between TBK1 SNPs and HCC prognosis in 397 surgically treated HCC patients.

RESULTS

Variant genotypes of rs12313449, rs73122364, and rs7486100 were associated with an increased risk of HCC. In genotype C HBV-infected subjects, GA and AA genotypes at rs12313449, AT and TT genotypes at rs73122364, and TA and AA genotypes at rs7486100 were associated with a higher prevalence of HBV mutations including T1753A/C, A1762T/G1764A, G1896A, and preS deletion, which increase HCC risk. The interactions of variant genotypes of rs12313449, rs73122364, and rs7486100 with T1753A/C, A1762T/G1764A, and G1896A were significantly associated with an increased HCC risk. TBK1 promoter with rs12313449-A showed a higher activity than that with rs12313449-G and was more strongly up-regulated by TNF-α and IL-6 stimulation. GA and AA genotypes at rs12313449 were associated with worse overall survival and recurrence-free survival and were unfavorable prognostic factors for HCC.

CONCLUSIONS

TBK1 genetic polymorphisms may facilitate immune selection of HCC-associated HBV mutations and are associated with HCC development, possibly through synergistic interactions with specific HCC-associated HBV mutations.