Association Study Of ABO Blood Group,HMOX1 And HPX Gene Polymorphism With Antituberculosis Drug-induced Liver Injury

Part 1 Association study of ABO Blood Group and Antituberculosis Drug-induced Liver InjuryObjective: Antituberculosis drug-induced liver injury(ATLI)is a serious adverse drug reaction,and its pathogenic mechanism is still largely unknown.Rifampin(RIF)has been reported to cause hemolysis due to the production of drug-dependent antibodies,and hemolysis results in an increased level of free heme,which affects the function of hepatocytes.Blood group determinants can act as specific receptor sites for drugantibody complexes,causing erythrocyte destruction in the presence of RIF.RIFinduced immune hemolysis may be a potential mechanism for ATLI.Thus,the study aimed to explore the role of ABO blood group systems in Chinese ATLI patients.Methods: A 1:4 matched case-control study was conducted among 146 ATLI cases and 584 controls.Multivariable conditional logistic regression and Cox proportional regression were used to estimate the association between ABO blood group and risk of ATLI by odds ratio(OR),hazards ratio(HR)and 95% confidence intervals(CIs),and liver disease history and taking hepatoprotectant were used as covariates.Results: Patients in the A,B,AB,and non-O blood groups had a significantly higher risk of ATLI than those in the O blood group(OR=1.832,95%CI:1.126-2.983,P=0.015;OR=1.751,95%CI:1.044-2.937,P=0.034;OR=2.059,95%CI:1.077-3.938,P=0.029;OR=1.822,95%CI:1.173-2.831,P=0.007,respectively).After considering the time of ATLI occurrence,similar results were found in the A,B,AB and non-O blood groups(HR=1.676,95%CI:1.072-2.620,P=0.024;HR=1.620,95%CI:1.016-2.584,P=0.043;HR=2.010,95%CI:1.130-3.576,P=0.018;HR=1.701,95%CI:1.138-2.542,P=0.010,respectively).Furthermore,subgroup analysis also detected a significant association between ABO blood group and ATLI in patients taking RIF(P<0.05).However,no significant difference was observed in patients not taking RIF(P>0.05).Conclusion: Based on the present matched case-control study,the ABO blood group may be associated with susceptibility to ATLI in the Chinese antituberculosis population,especially in patients with blood groups A,B and AB who are taking RIF.Part 2 Association of genetic polymorphisms of HMOX1,HPX genes and Anti-tuberculosis Drug-induced Liver InjuryObjective: rifampin can lead to hemolytic reaction.After exposed to rifampin,human erythrocytes will spontaneously die or apoptosis,which can lead to the accumulation of heme in the blood.Then the body starts its compensatory detoxification system,mainly HMOX1 catabolizes heme into non-toxic substances.The combination of HPX and heme can reduce the toxicity of free heme and the hemopexin-heme complex is cleared through receptor-mediated endocytosis,mainly by macrophages and hepatocytes expressing the scavenger receptor LRP1(low-density lipoprotein receptorrelated protein 1).When a large amount of free heme protein or heme is accumulated,the heme detoxification system of heme metabolism system will exceed its load,resulting in hepatotoxicity.HMOX1 and HPX are important enzymes and proteins in heme metabolism and detoxification.The enzyme activity of HMOX1 is regulated by HMOX1 gene polymorphism.This study explored the genetic susceptibility of ATLI to HMOX1 and HPX genes.Methods: In the present study,eight tag SNPs of HMOX1 and HPX genes were selected based on the strategy of candidate genome,and the genotypes of eight SNPs of all subjects were tested by Taq Man genotyping technique.Multivariable conditional logistic regression and Cox proportional regression were used to estimate the association between polymorphism of HMOX1,HPX genes and risk of ATLI by odds ratio(OR),hazards ratio(HR)and 95% confidence intervals(CIs),and liver disease history and hepatoprotectant use were used as covariates.Results: Based on 146 ATLI cases and 584 normal controls,and adjusting for the history of liver disease and use of hepatoprotectant,no significant differences were detected between the genotype distribution of HMOX1 and HPX genes and ATLI(P>0.05).Hierarchical analysis showed that HMOX1-rs1807714 GA/AA genotype(dominant model,OR=0.509,95%CI:0.275-0.943,P=0.032),HMOX1-rs1807714 A allele(dominant model,OR=0.604,95%CI:0.373-0.978,P=0.040)had a decreased risk of ATLI.HPX-rs2682099 AA was the risk factor of ATLI in moderate and severe ATLI(recessive model,OR=4.724,95%CI:1.239-18.006,P=0.023).HMOX1-rs1807714 A allele(OR=0.668,95%CI:0.461-0.966,P=0.032)had a lower risk of ATLI.Among the haplotypes of HMOX1-rs56375085-rs1807714,C-A haplotype had a lower risk of ATLI than C-G haplotype(OR=0.698,95%CI:0.488-0.997,P=0.048).Taking the generic risk genotypes as reference,rs4758417 AA-rs3761439 AA genotype and rs4758417 AG-rs3761439 AG genotype had a higher risk of ATLI.Conclusion: HMOX1-rs1807714 A was associated with lower risk of ATLI in moderate and severe ATLI population.,HPX-rs2682099 AA was associated with higher risk of ATLI in moderate and severe ATLI population.HMOX1-rs1807714 AA was detected to be associated with decreased risk of ATLI in the population of Hepatocellular Injury.Among the haplotypes composed of HMOX1-rs56375085-rs1807714,C-A haplotype has lower ATLI risk than C-G haplotype.HPX-rs4758417AA-HMOX1-rs3761439AA genotype and HPX-rs4758417AG-HMOX1-rs3761439 AG genotypes had increased risk of ATLI.