Research Of Genetic Polymorphism Of GSTs And Liver Injury Induced By Anti-tuberculosis Drugs

Objective: The purpose of this study is to find out the correlation between genotypes of glutathione-s-transferase and liver injury.The results may be helpful for the prevention and treatment of liver damage induced by anti-tuberculosis,and it may provide reference for individualized treatment of tuberculosis.Method: This project consists of a retrospective study and a prospective study.The former was performed on 239 patients received anti-TB treatment recommended by WHO during January2018-June 2018.Univariate analysis and multi-factor logistic regression analysis were used to analyze the relationship between the liver injury and factors like gender,age,weight,nation,use of liver protection drug and does of anti-TB drugs.Prospective study was conducted on 94 pulmonary tuberculosis patients treated during February 2019-October 2019,genotypes of GSTs(GSTM1,GSTT1,GSTP1)and blood concentrations of anti-TB drugs were detected for those patients.We investigate whether the GSTs genotype is a risk factor for liver damage occurrence through three aspects,including the correlation between the occurrence of liver damage and GSTs genotypes,the correlation between blood drug concentration and GSTs genotypes,the correlation between change of liver function values and GSTs genotypes.Results:1.The retrospective analysis shows that liver injury incidence is different among diverse nation groups(P = 0.018),especially in patients between Tibetan and han Chinese population(P = 0.005).2.Research on relationship between liver injury and glutathione-s-transferase(GSTM1,GSTT1,GSTP1)genotypes’ results show that liver injury incidence among GSTP1 rs1695 A > G genotype AA type,AG and GG three groups exist significant difference(P = 0.013),the liver damage between AA and AG + GG two groups exists significant difference(P = 0.008).There was no significant difference of liver injury incidence between the two groups of AA type and AG+GG type of rs1695 in Tibetan patients(P=0.254),while,there was a significant difference in han Chinese patients(P=0.035).3.The results of the study on the correlation between the GSTM1 genotype and the changes of liver function test indicators(ALT,AST,ALP,TBIL)value show that the changes of AST value tested after 4 weeks of antituberculous are significantly different between GSTM1 non-null and GSTM1 null groups(P=0.02).The change of TBIL value is significantly different between GSTM1 non-null and GSTM1 null groups after 4 weeks of treatment(P=0.022).There is a significant difference in TBIL value changes between GSTM1 non-null and GSTM1 null genotypes after 12 weeks of antituberculous(P=0.024).4.Study on the correlation between the GSTT1 genotype and the changes in liver function test indicates that the ALT value changing is significantly different between the two groups of GSTT1 non-null and GSTT1 null genotypes after 4 weeks of treatment(P=0.034).Changing of ALT value after 8 weeks of administration were significantly different between the two genotypes(P=0.033).5.Study on the correlation between GSTP1 gene polymorphism and the changes of liver function shows that the changes of AST value after 12 weeks of antituberculous were significantly different among the rs1695 AA,AG and GG groups(P=0.027).The changes of TBIL value were significantly different among the three genotypes after 2 weeks of antituberculous(P=0.012),8 weeks of antituberculous(P=0.001),16 weeks of antituberculous(P=0.010)and 24 weeks of antituberculous(P=0.014).Changes of ALP values are significantly different between the three genotypes after 8 weeks(P=0.035)and 16 weeks of antituberculous(P=0.043).6.Study on the correlation between genotypes of GSTs and blood concentrations of anti-TB drugs suggest that the blood concentration of pyrazinamide is significantly different between genotypes of GSTP1 rs1695 A>G and AG+GG(P=0.027)when the same dose of pyrazinamide haved.Conclusion:1.The occurrence of drug-induced liver injury caused by anti-tuberculosis drugs was significantly different between Tibetan and Han.2.Rs1695 A>G mutation may increase the risk of liver damage of Chinese Han.3.There exist close relationship between the rs1695 mutation and the value change of TBIL and ALP of patients treated with anti-TB drugs.4.The blood concentration of pyrazinamide of the A genotype of rs1695 is higher than that of G genotype.