Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury: a meta-analysis.
BACKGROUND
Although some case-control studies have investigated the association between drug-metabolising enzyme (DME) gene polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury (ATLI), their results are conflicting, mainly due to limited power.


OBJECTIVE
To review the literature systematically, by means of a meta-analytical review, to evaluate the putative association and provide a quantitative summary estimate on the association with ATLI.


METHODS
We searched the databases of MEDLINE, PubMed, EMBASE and CBMdisc from 1966 to May 2007 using 'DME', 'hepatotoxicity', 'genetic polymorphism', 'genetic susceptibility' in combination with 'antitubercular agents', performed a manual search of citations from relevant original studies and review articles, and corresponded with authors.


RESULTS
Nine eligible articles were included in this meta-analysis, including five on N-acetyltransferase 2 (NAT2), four on cytochrome P450 2E1 (CYP2E1) and two on glutathione S-transferase (GST) studies, separately. The overall ORs of ATLI risk associated with NAT2 homozygous variant genotype (mt/mt), CYP2E1 homozygous wild genotype (*1A/*1A), GSTM1 homozygous null genotype (null/null) and GSTT1 homozygous null genotype (null/null) were respectively 1.93 (95%CI 0.81-4.62), 2.22 (95%CI 1.06-4.66), 2.62 (95%CI 1.45-4.75) and 1.18 (95%CI 0.61-2.29). In addition, the OR for Asian ATLI associated with the NAT2 homozygous variant (mt/mt) and the combined genotype (w/w + w/mt) was 2.52 (95%CI 1.49-4.26).


CONCLUSIONS
NAT2 mt/mt, CYP2E1*1A/*1A and GSTM1 null/null were observed to increase the risk of ATLI in tuberculosis patients. Our results support the hypothesis that NAT2 mt, CYP2E1*1A and GSTM1 null have a modest effect on genetic susceptibility to ATLI, but no significant evidence for GSTT1 null/null.
Sun
F
F
Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
Chen
Y
Y
Xiang
Y
Y
Zhan
S
S
D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics*; D012306:Risk; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000235:genetics
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; D019363:Cytochrome P-450 CYP1A1; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; C478900:NAT2 protein, human