Correlation Of Adverse Reactions Caused By Gene Polymorphism And Anti-TB Drugs

Objective: To study the clinical characteristics,predisposing factor and the clinicaltreatment effect to antituberculosis drug-induced hepatotoxicity(ATDH).Method: An retrospectively analysis was conducted in tuberculosis(TB) patientsbetween2008and2012in Beijing Chest Hosptal. The clinical characteristics andcorrelative factors were recorded.Results: All1620TB patients who received the anti-tb drugs from2008to2012,94(5.8%)patients had ATDILI. More than fifty percent of the patients withhepatotoxicity occurred in the beginning of chemotherapy within four weeks.Theduration of the hepatotoxity more than one month accounted for55.3%，the longestduration is four month. The incidence of ATDILI in the patients treated with HRZ69.1%（68/94）regime was higher than that in the patients treated with HR16.0%（15/94）orR3.2%（3/94）. In average level, it takes about28days to turn to normal, the lastedrecovery case took78days. All the cases completed the therapy successfully.Conclusion:The incidence of ATDILI in our material is nearly5.8%. The regime ofATDILI in the patients treated with HRZ was the highest group, The mean recovery timeof the hepatotoxicity is about one month. Objective:To evaluate whether the gene polymorphism of drug metabolizing emzymes(DME),including NAT2, CYP2E1，MnSOD and NOS2A, are associated with antituberculosisdrug-induced hepatitis.Method:52patients who received standard first-line quadruple drug therapy with ATDILI arecase group,107patients received the same therapy without ATDILI are control group.Their genotypes were determined using a polymerase chain reaction and directsequencing method to study the susceptibility between the gene polymorphisim andATDILI.Results:1. Compared fast/media/slow acetylator genotypes of the NAT2gene, slow acetylatorgenotype（OR:3.209，P=0.005） had a significantly higher risk of ATDILI than rapid(OR:0.413，P=0.019) and media（OR:1.056，P=0.873） acetylator genotypes. Moreover,the OR of rapid acetylator, less than1, is an antagonistic action in the ATDILI. Thegenotype of NAT2*5/*7、NAT2*6/*6with a higher OR than other genotypes,4.24（P=0.0249）、3.264（P=0.038）respectively are more likely toATDILI.2. Compared three genotypes of nat2gene,(C1/C1,C1/C2,C2/C2). C1/C1genotype(OR:1.896,P>0.05）had a higher risk of ATDILI than the genotypes C1/C2（OR:0.468,P>0.05）,C2/C2（OR:1.249, P>0.05）. The patients with slow acetylator genotype ofNAT2combined with CYP2E1C1/C1genotype(OR:6.967,P=0.001) had higher risk ofATDILI than the patients only with slow acetylator genotype of NAT2(OR:3.209,P=0.005) or with CYP2E1C1/C1(OR:1.896,P=0.081). 3Compared three genotype TT,TC,CC of the MnSOD gene, CC genotype of MnSODgene (OR:4.006, P=0.024) had a significantly higher risk of ATDILI than47TT(OR:0.952,P>0.05) and47TC(OR:0.679,P>0.05). The patients with slow acetylator genotypeof NAT2combined with47CC of MnSOD gene (OR:9.500,P=0.021) had higher risk ofATDILI than the patients only with slow acetylator genotype of NAT2(OR:3.209,P=0.005) or with the47CC of MnSOD gene(OR:4.006,P=0.024).Combined withthe rapid or media acetylator genotype,47CC genotype of MnSOD still have a relativehigh OR:4.222.(P<0.05)4. Compared three genotype (TT,TC,CC) of the NOS2A gene in1281+1205position,the5CC genotype (OR:3.712, P=0.005)had a significantly higher risk of ATDILI than1281+1205TT(OR:0.754,P>0.05)and1281+1205TC（OR:0.644,P>0.05）. The patientswith slow acetylator genotype of NAT2combined with1281+1205CC of NOS2A gene(OR:8.896,P=0.003) had higher risk of ATDILI than the patients only with slowacetylator genotype of NAT2(OR:3.209,P=0.005) or with the1281+1205CC of NOS2Agene(OR:3.712, P=0.005).With the rapid or media acetylator genotype,47CC genotypeof MnSOD still have a relative high OR:4.222,P<0.05.And the descending order of ORvalue is CC>CT>TT, when combined with the same slow acetylator genotype.5. After adjustment for age, sex and other genotype, the slow acetylator genotype ofNAT2, the47CC of MnSOD and the1281+1205CC of NOS2A remained an independentrisk factor for ATDILI. OR were4.012（P<0.05）、4.412（P<0.05）、9.125（P<0.05）,respectively.Conclusion:The fast/slow acetylators of NAT2, especially,the genotype NAT2*4/*4，NAT2*5/*6，NAT2*6/*6and the47CC of MnSOD and the1281+1205CC of NOS2A werefignificantly with higher risk of developing ATDILI. The gene polymorphism ofCYP2E1had no association with susceptibility to antituberculosis drug-induced hepatitis.Although there is no statistical difference between CYP2E1genetic polymorphism andthe susceptibility to ATDILI, the C1/C1genotype of CYP2E1obviously increase theincidence of ATDILI of SA genotype. Objective: To investigate the ototoxicity effects of long-term use of aminoglycosides inthe treatment of pulmonary tuberculosis and to screen the sensitive mitochondrial DNAmutation relative to aminoglycoside-induced and nonsyndromic hearing loss.Method: Patients treated for tuberculosis with streptomycin， amikacin orcapreomycin were recruited. These86subjects test clinical symptoms, pure tone hearingthreshold and genetic evaluation of mitochondrial12S rRNA to see the susceptibilitybwtween the mutation and the ototoxicity..Results: The study samples consisted of53males and33females. The age of allparticipants ranged from15years old to65years, with the median age of36years.Molecular analysis of12S rRNA gene identified11variants, while none of the subjectscarry variants of A1555G or C1494T in12S rRNA.4variants of6times conferredincreased sensitivity to aminoglycosides or nonsyndromic deafness were detected:A827G, T961linsC, T1095C and a new mutation T1541C may related toaminoglycosides-induced hearing loss variants T1541C. The patient who carry thismutaion have an irreversible moderate degree hearing loss.Conclusion: Therefore, our data demonstrated that mitochondrial12S rRNA typicmanifestation associated with aminoglycoside ototoxicity. Besides A1555G andC1494T,there may be some other mitochondrial DNA variants(A827G,T961insC,T1095C and T1541C)associated with the hearing loss.