Relationships of CYP450,GSTs,and UGT gene polymorphisms with anti-tuberculosis drug-induced liver injury

SUN Shufeng; LI Biao; CHONG Yingzhi; DU Ying

doi:10.3969/j.issn.1002-266X.2017.39.002

Abstract：Objective To investigate the correlations of drug metabolic enzymes cytochrome P450 (CYP450),gluta-thione S-transferases (GSTs),and uridine diphosphate glycosyltransferase (UGT)gene single nucleotide polymorphisms (SNPs)with anti-tuberculosis drug-induced liver injury (ADLI). Methods We selected 207 cases of Han tuberculosis (TB)patients who experienced liver injury within 6 months of anti-TB chemotherapy treatment as the case group and 207 cases of TB patients with no abnormal liver function as the control group. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP)was employed to identify the SNPs of CYP1A2734C/ A,CYP3A418B-20232G/ A, CYP3A53-6986A/ G,CYP2C19681G/ A,GSTA1 -69C/ T,and GSTM3 deletion mutation,and UGT2B7-268A/ G and UGT2B7802C/ T. We adopted univariate and multivariate logistic regression methods to discuss the relationships of CYP450,GSTs,and UGT gene SNPs with ADLI. Multifactor dimensionality reduction (MDR)method was used to explore the interaction between ADLI and SNPs. Results Univariate and multivariate logistic regression analysis showed that the genotype AA of CYP1A2734C/ A,the genotype GA of CYP3A418B-20232G/ A,the genotype AG of UGT2B7-268A/ G,and the genotype TT of UGT2B7802C/ T were the protective genotypes of ADLI,and the mutant genotypes AG and GG of CYP3A53-6986A/ G and the genotype TT of GSTA1-69C/ T were the risk genotypes of ADLI. After adjusting the effects of other gene SNPs,we found that CYP3A418B-20232G/ A,CYP3A53-6986A/ G,UGT2B7-268A/ G,and UGT2B7802C/ T were related to the occurrence of ADLI. A best model consisted of three factors UGT2B7 -268A/ G,CYP3A418B-20232G,and CYP3A53-6986G,with the sample accuracy of 61. 29% and the cross-validation consistency of 10 / 10,was obtained by MDR,and the high risk genotype combination could increase risk of ADLI. Conclusions CYP3A418B-20232G/ A,CYP3A53-6986A/ G,UGT2B7-268A/ G,and UGT2B7802C/ T gene SNPs are related to the occurrence of ADLI. Multifactor dimensionality reduction analysis shows that there are gene-gene interactions and the combination of UGT2B7-268A/ G,CYP3A418B-20232G/ A,and CYP3A53-6986A/ G can increase the risk of ADLI.