Relationship Between Xanthine Oxidase Gene Polymorphism And Adverse Reactions Induced By Anti-tuberculosis Drugs

Objectives:To investigate the relationship of the xanthine oxidase gene polymorphism with liver damage and hyperuricemia during anti-tuberculosis treatment,in order to provide the genetic evidence for formulating individualized therapy plans and preventing the occurrence of adverse reactions caused by anti-tuberculosis treatment.Methods:The TB patients who met the conditions from June 2018 to March 2019 in the First Affiliated Hospital of Dali University were selected as subjects.According to the criteria for adverse reactions,they were divided into normal liver control group and liver injury case group,normal uric acid level control group and high uric acid.The peripheral blood of patients was collected and DNA was extracted,and genotyping was performed by direct sequencing by polymerase chain reaction.The goodness of fit?~2test was used to analyze whether the genotype distribution of each SNP locus was consistent with the Hardy-Weinberg genetic balance.The frequency distribution of genotypes and alleles of each SNP locus in case group and control group was assessed by Chi-square test.Logistic binary regression analysis was used to evaluate the risk factors for adverse reactions after anti-tuberculosis treatment while P<0.05 was considered statistically significant.Linkage disequilibrium of polymorphic loci was analyzed by SHEsis online software,the haplotypes were constructed and analyzed by Phase 2.1.Results:1.A total of 183 patients with tuberculosis were enrolled in this study,and 21 patients developed liver injury during anti-tuberculosis treatment,with an incidence of 11.48%.156patients with tuberculosis who were included in the analysis of hyperuricemia,70 patients had hyperuricemia,with an incidence of 44.87%.The results of univariate analysis showed that the gender,age,body mass index(BMI),smoking history and drinking history were not significantly different between the case group and the control group(P>0.05).2.The result of genotyping in the polymorphic sites of xanthine oxidase gene(rs1884725,rs2295475,rs45612839,rs45523133,rs206812,rs206813,rs7575607)by the direct sequencing of polymerase chain reaction shows that,allele A/G polymorphisms were detected in rs1884725,rs2295475,rs206812,rs45523133 and rs7575607.The mutation frequencies were:20.49%,42.07%,35.52%,3.83%,24.04%,respectively;No allele mutation was detected in rs45612839;there is an allele C/T polymorphism was detected in rs206813with a mutation frequency of 4.10%.3.There was no significant difference in the distribution of genotypes and alleles of 6single nucleotide polymorphism loci between case group and the control group(P>0.05).4.The haplotypes of xanthine oxidase gene polymorphisms(rs1884725,rs2295475,rs45523133,rs206812,rs206813,rs7575607)were constructed by Phase 2.1 software.The results showed that the frequency of G-G-G-A-T-A haplotype(In the order of rs1884725-rs2295475-rs45523133-rs206812-rs206813-rs7575607)was significantly higher in the liver injury group than in the control group,suggesting that G-G-G-A-T-A haplotype carrying the rs206812 and rs7575607 mutant alleles increased the risk of liver injury by 2.445times(OR=2.445,95%CI:1.058～5.652,P=0.032);The frequency of G-G-G-A-T-G(In the order of rs1884725-rs2295475-rs45523133-rs206812-rs206813-rs7575607)haplotype was significantly higher in the hyperuricemia group caused by anti-tuberculosis drugs than in the control group,suggesting that haplotype G-G-G-A-T-G individuals carrying the rs206812mutation allele had an increased risk of hyperuricemia by 3.981 times when receiving antituberculosis drugs(OR=3.981,95%CI:1.041～15.227,P=0.030).Conclusion:1.During the treatment of antituberculosis drugs,the single nucleotide polymorphism site rs1884725,rs2295475,rs45523133,rs206812,rs206813,rs7575607 of xanthine oxidase gene were not obviously associated with the occurrence of liver injury and hyperuricemia caused by anti-tuberculosis treatment.2.The G-G-G-A-T-A haplotype of the xanthine oxidase gene may increase the risk of liver damage in patients receiving anti-tuberculosis treatment;G-G-G-A-T-G haplotype may increase the risk of developing hyperuricemia in patients during anti-tuberculosis treatment.