Associations of pri-miR-34b/c and pre-miR-196a2 Polymorphisms and Their Multiplicative Interactions with Hepatitis B Virus Mutations with Hepatocellular Carcinoma Risk

Abstract

BackgroundGenetic polymorphisms of pri-miR-34b/c and pre-miR-196a2 have been reported to be associated with the susceptibility to cancers. However, the effect of these polymorphisms and their interactions with hepatitis B virus (HBV) mutations on the development of hepatocellular carcinoma (HCC) remains largely unknown. We hypothesized that these polymorphisms might interact with the HBV mutations and play a role in hepatocarcinogenesis.Methods Pri-miR-34b/c rs4938723 (T>C) and pre-miR-196a2 rs11614913 (T>C) were genotyped in 3,325 subjects including 1,021 HBV-HCC patients using quantitative PCR. HBV mutations were determined by direct sequencing. Contributions of the polymorphisms and their multiplicative interactions with gender or HCC-related HBV mutations to HCC risk were assessed using multivariate regression analyses.Resultsrs4938723 CC genotype was significantly associated with HCC risk compared to HBV natural clearance subjects, adjusted for age and gender (adjusted odds ratio [AOR] = 2.01, 95% confidence interval [CI] = 1.16–3.49). rs4938723 variant genotypes in dominant model significantly increased HCC risk in women, compared to female healthy controls (AOR = 1.85, 95% CI = 1.20–2.84) or female HCC-free subjects (AOR = 1.62, 95% CI = 1.14–2.31). rs4938723 CC genotype and rs11614913 TC genotype were significantly associated with increased frequencies of the HCC-related HBV mutations T1674C/G and G1896A, respectively. rs11614913 was not significantly associated with HCC risk, but its CC genotype significantly enhanced the effect of rs4938723 in women. In multivariate regression analyses, rs4938723 in dominant model increased HCC risk (AOR = 1.62, 95% CI = 1.05–2.49), whereas its multiplicative interaction with C1730G, a HBV mutation inversely associated with HCC risk, reduced HCC risk (AOR = 0.34, 95% CI = 0.15–0.81); rs11614913 strengthened the G1896A effect but attenuated the A3120G/T effect on HCC risk.Conclusionsrs4938723 might be a genetic risk factor of HCC but its effect on HCC is significantly affected by the HBV mutations. rs11614913 might not be a HCC susceptible factor but it might affect the effects of the HBV mutations or rs4938723 on HCC risk.

A single nucleotide polymorphism in the promoter region (rs10877887) of let-7 is associated with hepatocellular carcinoma in a Chinese population

“…Recent studies have indicated the role of an increasing number of genes in the molecular mechanism of hepatocarcinogenesis. miRNA, a family of small noncoding RNA, often reported to be up-or down-regulated in tumors, also plays a role in tumorigenesis (Farazi et al, 2011;Han et al, 2013). Whereas miR-9 is up-regulated in several forms of cancer including Hodgkin lymphoma, the miR-34 family members are important tumor-suppressors, with multiple targets in key cancer pathways (Jansson and Lund, 2012).…”

Associations Between Three Common MicroRNA Polymorphisms and Hepatocellular Carcinoma Risk in Chinese

“…However, the results are inconsistent. A recent study indicated that polymorphism of miR-196a2C>T might not be a HCC susceptible factor of HCC, but could affect the effects of the HBV mutations (Han et al, 2013). The inconsistency of these studies may be explained by differences in population background, source of control subjects, sample size, and also by chance, and therefore these results are greatly needed to confirm by further studies.…”

Genetic variations in microRNA genes and susceptibility to hepatocellular carcinoma

“…A previous study indicated that the miR-499A>G polymorphism is strongly affected by HBV mutations (Han et al, 2013), indicating that HBV mutation has a synergistic effect with miR-499A>G polymorphism on the risk of HCC.…”