Association Of HIF-1Gene Polymorphisms With Susceptibility To HBV-related Liver Disease

Objectives Hypoxia inducible factor-1（HIF-1）, as a main nucleartranscription factor in the hypoxic condition, play a critical role in the process ofhuman response to hypoxia. In our experiment, we detected the polymorphismsof HIF-1a rs11549465、rs11549467, to explore genetype distribution and theassociation between HIF-1a gene polymorphisms and HBV-related hepatitis,liver cirrhosis and hepatocelluar carcinoma risk in Guangxi population.Methods We filtrated442patients with HBV-related liver diseases as casegroups, including153patients with chronic hepatitis B (CHB group),132patients with liver cirrhosis (LC group) and157patients with hepatocellularcarcinoma (HCC group). A total of173healthy individuals were chosen ascontrol group. Polymerase chain reaction-restriction fragment lengthpolymorphism (PCR-RFLP) was applied to detect frequencies of the genotypeand allele of rs11549465and rs11549467sites of HIF-1a, and then the resultswere validated by direct DNA sequencing method. χ2test was used to examineHardy-Weinberg equilibrium of the two SNPs, and logistic regression wasutilized to evaluate odds ratio (OR) and95%confidence interval (95%CI),adjusted for sex and age, exploring the relationship of HIF-1a gene polymorphisms and HBV-related hepatitis, liver cirrhosis and HCC susceptibility.SHEsis software was for the haplotye analysis.Results1. No statistically significant differences were found in gender compositionbetween control group and CHB, LC, HCC group (P>0.05). However, Thedifferences of age composition were found between control group and LC group,control group and HCC group, CHB group and LC group, CHB group and HCCgroup(P<0.05). HCC group of HIF-1a rs11549465was out of Hardy-Weinbergequilibrium (P<0.05), and the other group were all in Hardy-Weinbergequilibrium (P>0.05).2. CC, CT and TT genotypes were detected in HIF-1rs11549465. TreatingCC genotype as reference, there was no significant difference in the distributionof CT and TT genotype frequencies among the control group, CHB, LC andHCC group were not significant (P>0.05). Treating C allele as reference, nosignificant difference was found in the distribution of T allele among all groups(P>0.05).3. There were GG, GA and AA genotypes in HIF-1rs11549467. Comparingwith GG genotype, there was no significant difference in the distribution of GAand AA genotype frequencies among the control group, CHB, LC and HCCgroup were not significant (P>0.05). Comparing with G allele, no significantdifference was found in the distribution of A allele among all groups (P>0.05).4. The genotype and allele frequencies of HIF-1a rs11549465andrs11549467were found no association between men and women of Guangxipopulations among the control group, CHB, LC and HCC group by analysis ofgender stratification.5. We conducted haplotype analysis for HIF-1a rs11549465and rs11549467.The results shows that statistical differences were found in CA andCG haplotype carriers between control group and HCC group P=0.025，OR=0.416；P=0.008，OR=2.327）. There were also significant differences in CGand TG haplotype carriers between CHB group and HCC group（P=0.007，OR=2.408；P=0.020，OR=0.315）.Conclusion1. The HIF-1a rs11549465polymorphism might decrease the risk of thedevelopment from CHB to HCC in Guangxi populations. There was noassociation between the polymorphism of rs11549467and HBV-related hepatitis,liver cirrhosis and hepatocelluar carcinoma risk.2. Haplotypes were integrated to analyze for HIF-1a rs11549465andrs11549467. The risk suffering from HCC of the CA haplotype carriers reduced,indicating CA haplotype might be a protective factor for HCC. And the risksuffering from HCC of the CG haplotype carriers increased, indicating CGhaplotype might be a risk factor for HCC. The risk of the CG haplotype carrierswas increased and TG haplotype carriers decreased between CHB group andHCC group, indicating CG might be a risk and TG might be a protective factorin the development from CHB to HCC.