Genetic Polymorphisms Of Glutathione S-transferases M1 And T1 Associated With Susceptibility To Hepatitis B-related Cirrhosis And Hepatocellular Carcinoma

Chronic infection with hepatitis B virus (HBV) is the most important cause of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in China, where the predominant mode of HBV transmission is perinatal. Although the relative risk is about 20 for HBV surface antigen (HBsAg) carriers compared with noncarriers, only a fraction of HBsAg carriers eventually develop LC and HCC. The age at onset of HCC also varies over a wide range among HBsAg carriers.The glutathione S-transferases (GSTs) are known to catalyze the conjugation of glutathione (GSH) with different species of electrophilic compounds. GSTs are an important part of the cellular detoxification system and, perhaps, evolved to protect cells against reactive oxygen metabolites. The GSTM1/ GSTTl is polymorphic in humans. GSTM1 has been shown to be polymorphic and is absent in 35 - 60% of individuals. Similarly, GSTTl is also polymorphic and is absent in 10 - 65% of human populations. The lack of GSTM1 activity is due to the inherited homozygous deletion of the genes, and GSTM1 deficiency has been linked with risk for various cancers. Less is known about the association between GSTTl and cancer risk, but persons with the GSTTl null type show reduced ability to detoxify metabolites of 1,3-butadiene and ethylene oxide.Persistent HBV infection can cause genomic damage directly, through amechanism of chromosomal integration, or indirectly, through increased oxidative stress and free-radical generation during the course of chronic hepatitis.We conducted a multicenter case-control study to examine whether this polymorphism influences risk for LC and HCC among HBsAg carriers. We specifically investigated whether this association varied by age at onset of HCC and the status of glutathione S- transferases genes GSTMl and GSTTl.Objective: To investigate the association of genetic polymorphisms in glutathione S-transferases(GST) Ml, Tl with hepatitis B-related cirrhosis and hepatocellular carcinoma.Methods: Genomic DNA was isolated from peripheral blood from HBsAg carriers, including HCC( n = 87 ), liver cirrhosis (n = 53 ) and chronic hepatitis B( n = 57 ) .GSTMl, Tl Genotypes were detected by multiplex PCR.Results: 1 , The association of genetic polymorphisms in GSTMl, Tl with hepatitis B-related cirrhosis : The allelic frequencies of GSTMl in LC patients were not significantly different from those of CHB patients when odds ratios were only adjusted for age and gender (P=0.225, OR =1.71 95%CI=0.734-4.013 ). The distribution of the null genotype of GSTT1 polymorphism did not differ significantly between patients and controls (p=0.363 , OR =1.493 95%CI=0.648-3.452) . To investigate whether profiles of GST genotypes may be associated with the risk of LC, we also compared the risk of LC associated with combinations of genotypes. The reference group consisted of individuals with putative low-risk genotypes, i.e. the presence of GSTMl and GSTT1 genotypes. There were no significant differences among the combination of genotypes.2, The association of genetic polymorphisms in GSTMl, Tl with hepatitis B-related hepatocellular carcinoma. The frequency of the GSTMl null genotype in patients with HCC (63.64%) showed a statistically significant increase compared to the control group frequency (43.40 %). The GSTMl null genotype was associated with a 2.160 -fold increased risk of HCC (OR =2.160 95%CI=1.972-4.271). The number ofGSTT1 null individuals was also higher among HCC cases, but this increase did not reach statistical significance (OR =1.262 95%CI=0.675-4.491).3 , The GSTM1-null genotype was associated with a increased risk for early-onset HCC.Conclusion: Our findings suggest that the GSTM1 null genotype has an increased susceptibility to HCC, especially of early-onset HCC in HBV-related LC patients.