Association of miRNA-122-binding site polymorphism at the interleukin-1 α gene and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk

Abstract

This study was designed to investigate the contribution of miRNA-122-binding site polymorphism at the IL-1A gene and its multiplicative interactions with hepatitis B virus (HBV) mutations in the risk of hepatocellular carcinoma (HCC). A total of 1021 healthy controls, 302 HBV surface antigen (HBsAg) seroclearance subjects, and 2011 HBsAg-positive subjects (including 1021 HCC patients) were enrolled in this study. Quantitative PCR was used to genotype rs3783553. HBV mutations were determined by direct sequencing. Multivariate logistic regression analyses were performed to test the associations of rs3783553, mutations, and their interactions with the risk of HCC. No significant association was found between rs3783553 and the risk of HCC among healthy controls, HBsAg seroclearance subjects, HBsAg-positive subjects without HCC, and all controls. Additionally, rs3783553 was not significantly associated with chronic HBV infection, liver cirrhosis, HBV e antigen seroconversion, abnormal alanine aminotransferase, and high viral load (>10⁴ copies/ml). However, the TTCA insertion allele of rs3783553 was significantly associated with an increased frequency of HBV C7A mutation compared with homozygous TTCA deletion carriers [(del/ins+ ins/ins) vs. del/del, adjusted odds ratio (OR)=1.48, 95% confidence interval (CI)=1.09-2.02, P=0.013]. Multiplicative interaction of rs3783553 with HBV preS deletion significantly reduced the risk of HCC in males, with an adjusted OR of 0.64 (95% CI=0.42-0.98; P=0.041) after age and HBV genotype were adjusted. Although rs3783553 did not significantly affect genetic susceptibility to HBV-related HCC, its variant allele may predispose the host to selecting HBV C7A mutation during evolution and significantly reduce the risk of HCC caused by HBV preS deletion. This study provides an insight into the complex host-virus interaction in HBV-induced hepatocarcinogenesis and is helpful in determining HBsAg-positive subjects who are likely to develop HCC.

Keywords

miRNA-122-binding site / IL-1A / rs3783553 / hepatitis B virus (HBV) mutations / hepatocellular carcinoma (HCC) / interaction

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Acknowledgements

This study was funded by The National Outstanding Youth Fund (81025015) and Creative Research Group (30921006) from National Natural Scientific Foundation of China, Science and Technology Commission of Shanghai Municipality Fund (12ZR1453600, 12ZR1429300), and Shanghai Health Bureau Fund (20114066).

Abbreviations

ALT	alanine aminotransferase
ANOVA	analysis of variance
anti-HBc	antibody to HBc
anti-HCV	antibody to HCV
ASC	asymptomatic HBsAg carriers
CHB	chronic hepatitis B
CI	confidence interval
HBsAg	HBV surface antigen
HBV	hepatitis B virus
HCC	hepatocellular carcinoma
HCV	hepatitis C virus
HDV	hepatitis delta virus
HWE	HardyWeinberg equilibrium
IL-1	interleukin-1
LC	liver cirrhosis
miRNA	mircoRNA
mRNA	messenger RNA
OR	odds ratio
qPCR	quantitative PCR
3′UTR	3′ untranslated region

Compliance with ethics guidelines

Yan Du, Xue Han, Rui Pu, Jiaxin Xie, Yuwei Zhang, and Guangwen Cao declare that they have no conflict of interest. This study was approved by the ethics committee of the Second Military Medical University, and the study protocol is in accordance with the Declaration of Helsinki [revised in 2000 (5)]. All participants provided written informed consents.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg