Genetic Polymorphisms of Glutathione S-Transferase P1 (GSTP1) and the Incidence of Anti-Tuberculosis Drug-Induced Hepatotoxicity.
BACKGROUND
Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most common adverse effects associated with tuberculosis (TB) therapy. Animal studies have demonstrated important roles of glutathione S-transferases in the prevention of chemical-induced hepatotoxicity. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of glutathione S-transferase P1 (GSTP1) and ATDH in TB patients.


METHODS
We used two independent samples for this genetic association study. In the initial prospective study, 322 newly diagnosed TB patients were followed up for three months after initiating anti-TB therapy. In an independent retrospective study, 115 ATDH patients and 116 patients without ATDH were selected to verify the results of the prospective study. Tag-SNPs of GSTP1 were genotyped either with the MassARRAY platform or the improved multiple ligase detection reaction (iMLDR) method. The associations between SNPs and ATDH were analyzed by logistic regression analysis adjusting for confounding factors.


RESULTS
Of the 322 patients recruited in the prospective cohort, 35 were excluded during the 3 months of follow-up, and 30 were diagnosed with ATDH and were considered as the ATDH group. The remaining 257 subjects without ATDH were considered as the non-ATDH group. After correction for potential confounding factors, significant differences were found for rs1695 (A>G) under an allelic model (OR = 3.876, 95%CI: 1.258011.905; P = 0.018). In the retrospective study, rs1695 allele A also had a higher risk of ATDH (OR = 2.10, 95%CI: 1.17-3.76; P = 0.012). We only found rs4147581AA genotype under a dominant model was related to ATDH in the prospective study (OR = 2.578, 95%CI: 1.076-6.173; P = 0.034).


CONCLUSIONS
This is the first study to suggest that GSTP1 genotyping can be an important tool for identifying patients who are susceptible to ATDH. This result should be verified in independent large sample studies and also in other ethnic populations.
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Shouquan
S
Wu
Physical Examination Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
You-Juan
YJ
Wang
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Xiaoyan
X
Tang
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Yu
Y
Wang
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Jingcan
J
Wu
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Guiyi
G
Ji
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Miaomiao
M
Zhang
Division of Geriatrics, Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
Guo
G
Chen
Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Qianqian
Q
Liu
Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, BC, Canada.
Andrew J
AJ
Sandford
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Jian-Qing
JQ
He
D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics
D000995:Antitubercular Agents; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi