Correlation Between MiR-146a, MiR-196a2 And MiR-499 Gene Polymorphisms And Genetic Susceptibility To Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors worldwide.It has a high rate of incidence and mortality rate and it is estimated that there were 782,000 new cases in 2012(5.6%of the total number of new hepatocellular carcinoma cases).More than 50%of cases occur in China.According to 1997 epidemiology of cancer incidence,the mortality was about 20.37/100,000 in China,including 29.01/100,000 for male and 11.21/100,000 for female,ranked as the second of cancer related death.The death rate was in the second place within the total mortality of malignancy in the male population followed by gastric cancer,and in the third place in the female population followed by gastric cancer and esophageal cancer.HCC has already threatened the lives of our country.A large number of reports have confirmed that multivariate,multi-stage,multi-gene interaction led to HCC.Given that there is a great variation in population to develop HCC,genetic polymorphisms and their interaction with environment are likely involved in the development of HCC.MicroRNA(miRNA)is a non-coding RNA,which is about 22nt and widely existed in all kinds of organisms from virus to human,and it is widely involved in many kinds of life activities,including development,proliferation,apoptosis and carcinogenesis.Previous studies have indicated that many miRNAs play an important role in carcinogenesis by regulating the expression of oncogenes and tumor suppressors.Many studies on the association between microRNAs(miRNAs)and hepatocellular carcinoma have reported that miRNAs may play an important role in cancer initiation,progression,outgrowth,and drug resistance.A large number of studies have shown that genetic variation of the key parts of the gene will have a major impact on the gene structural,expression and molecular regulatory functions,and further lead to changes in the regulation of the biological function.Single nucleotide polymorphism(SNP)is one of the most common human genetic variants,which mainly refers to the DNA sequence polymorphism caused by a single nucleotide variation at the genomic level.Numerous studies show that genetic variation affects the cancer genetic susceptibility of individuals.The SNPs were able to change the structure or expression of the gene,which affects the regulation of genes.If the presence of important functional SNPs occured in the sequence of pri-miRNA(primaiy miRNA),it may affect the generation of the pre-miRNA(precursor miRNA)and leading to structural or expression abnormalities in mature miRNAs.Several key regulatory genes involved in the generation of mature miRNAs.miRNAs are involved in the development and progression of hepatocellular carcinoma by binding to the 3'untranslate region of the gene and causing the degradation or inhibition of translation of the target gene mRNA.Therefore,when SNPs are located on mature miRNAs,they directly participate in the regulation of target genes,leading to the occurrence of hepatocellular carcinoma.Studies have shown that miR-146a rs2910164(C/G),miR-196a2 rs11614913(C/T)and miR-499 rs3746444(T/C)singly or jointly can contribute to many kinds of malignant tumors.Similarly,some research reported the association between them and genetic susceptibility to HCC,but the results are conflicting and inconclusive.In our study,we investigated the role of miR-146a rs2910164(C/G),miR-196a2 rs11614913(C/T)and miR-499 rs3746444(T/C)with the risk of hepatocellular carcinoma in a Chinese population.Hepatocellular carcinoma patients(175)and healthy controls(302)were recruited between April 2013 and March 2015.Genotype analysis of miR-146a,miR-196a2,and miR-499 polymorphisms was carried out by polymerase chain reaction-restriction fragment length polymorphism.There was a significant difference between the genotype distribution of miR-146a in hepatocellular carcinoma patients and controls(?2=17.23,P<0.001).In the co-dominant model,genotypes of CG and GG in miR-146a rs2910164 significantly elevated the risk of hepatocellular carcinoma compared with the CC genotype,with adjusted ORs(95%CI)of 3.05(1.07-8.70)and 4.96(1.64-14.97),respectively.In the recessive model,the GG genotype had a 3.75-fold risk of hepatocellular carcinoma compared with the CG+GG genotype,with an adjusted OR(95%CI)of 3.75(1.39-10.11).However,no significant association was observed between miR-196a2 and miR-499 variants and risk of hepatocellular carcinoma in the co-dominant,dominant,and recessive models.In the co-dominant model,the miR-146a CG and GG genotypes greatly significantly increased the risk of HCC in subjects with HBV infection with adjusted ORs(95%CI)of 2.02(1.05-5.707)and 3.12(1.66-10.77),respectively.In the dominant model,CG+GG genotype had a 1.91-fold risk of hepatocellular carcinoma compared with the CC genotype,with an adjusted OR(95%CI)of 1.91(1.85-3.38).In the recessive model,the GG genotype had a 1.54-fold risk of hepatocellular carcinoma compared with the CG+GG genotype,with an adjusted OR(95%CI)of 1.54(1.15-6.08).However,there was no significant association between miR-146a C>G polymorphisms and HCC risk in patients with HCV infection or no HBV and HCV infection.Our study revealed that the GG and CG genotypes of miR-146a increased the risk of hepatocellular carcinoma in the Chinese population,especially in the patients with HBV infection.While,there was no association between miR-196a2(C/T)and miR-499(T/C)polymorphisms with HCC genetic susceptibility.Background:Hepatocellular carcinoma(HCC)is one of the most common malignant tumors worldwide.It has a high rate of incidence and mortality rate.A large number of reports have confirmed that multivariate,multi-stage,multi-gene interaction led to HCC.Given that there is a great variation in population to develop HCC.Previous studies have indicated that many miRNAs play an important role in carcinogenesis by regulating the expression of oncogenes and tumor suppressors.If the presence of important functional single nucleotide polymorphisms(SNPs)occured in the sequence of pri-miRNA(primaiy miRNA),it may affect the generation of the pre-miRNA(precursor miRNA)and leading to structural or expression abnormalities in mature miRNAs.Several key regulatory genes involved in the generation of mature miRNAs.MiRNAs are involved in the development and progression of HCC by binding to the 3'untranslate region of the gene and causing the degradation or inhibition of translation of the target mRNA.Therefore,when SNPs are located on mature miRNAs,they directly participate in the regulation of target genes,leading to the development of HCC.Extensive studies have attempted to investigate the association between miR-146a rs2910164(C/G)and HCC susceptibility.However,the results are still inconsistent and uncertain.Objective:To comprehensively evaluated the relationship between miR-146a rs2910164 polymorphism and HCC genetic susceptibility.Methods:Computer retrieval Pubmed,Web of science,Cochrane,Wanfang medical databases and Google Scholar.Search deadline is October 31st 2016.The case-control studies about the association between miR-146a polymorphism and susceptibility to hepatocellular carcinoma published in Chinese or English were incorporated.Quality criteria were used to assess the quality of the literature,and then data were extracted.Stata 12.0 software for statistical analysis was used to detect the heterogeneity of the literature.If I2<50%or P>0.10,a fixed effect model is appropriate.If I>50%or P<0.10,a random effect model is suitable.The relationship between miR-146a rs2910164(C/G)and HCC genetic susceptibility was systematically analyzed.Results:18 studies(5610 cases and 7531 controls)were enrolled for meta-analysis.No significant association between miR-146a rs2910164 polymorphism and HCC susceptibility was observed.The OR,95%CI and P value were listed in the five genetic models re,spectively:the allele model:C vs G(OR=0.99,95%CI=0.88-1.06,P=0.440),the heterozygous model CG vs GG(OR=0.99,95%CI=0.90-1.10,P=0.898),the homozygote model:CC vs GG(OR=0.91,95%CI=0.75-1.10,P=0.314),the dominant model:CC+CG vs GG(OR=0.97,95%CI=0.79-1.19,P=0.759),and the recessive model CG+GG vs CC(OR=1.05,95%CI=0.94-1.18,P=0.405).The subgroup analyzes of enthnicity,source of control and HWE were performed in five genetic models,respectively.Only in the PB subgroup of the recessive model,significantly increased risks for HCC were observed(OR=1.20,95%CI=1.02-1.40,P=0.024).There was no association between miR-146a rs2910164(C/G)and HCC susceptibility in the other subgroups.Stratified analysis of HBV infection revealed that miR-146a rs2910164(C/G)increased the risk of HCC with HBV-positive(OR=1.26,95%CI=1.10-1.49,P=0.001).Conclusions:Our results show that there is no significant association between miR-146a rs2910164(C/G)and HCC risk,but it may increase the risk of HBV-positive HCC.Well-designed studies with larger sample sizes and more ethnic groups are needed to further validate the reliability of the results.