CYP genetic variants and toxicity related to anti-tubercular agents: a systematic review and meta-analysis

Abstract

BackgroundTreatment with anti-tuberculosis drugs may cause patients to experience serious adverse effects. Genetic factors, such as polymorphisms of CYP genes, may increase the likelihood of a patient experiencing such adverse drug reactions. In this systematic review and meta-analysis, we synthesised evidence for associations between CYP genetic variants and anti-tuberculosis drug-related toxicity outcomes.MethodsWe searched MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science to identify relevant studies. We performed meta-analyses to obtain an effect estimate for each genetic variant on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies.ResultsWe included data from 28 distinct cohorts of patients in the review. We identified many areas of concern with regard to the quality of included studies. Patients with homozygous mutant-type or heterozygous genotype at the CYP2E1 RsaI polymorphism were significantly less likely to experience hepatotoxicity than patients with homozygous wild-type genotype (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.56–1.00; p = 0.047, I2 = 58.2%). No significant differences were observed for the CYP2E1 DraI and PstI polymorphisms. For the 96-bp deletion-insertion single-nucleotide polymorphism (SNP) of the CYP2E1 gene, homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (OR = 8.20, 95% CI 1.38–48.68, I2 = 0%); no significant difference was observed for heterozygous genotype compared with homozygous wild-type (OR = 0.77, 95% CI 0.19–3.21, I2 = 0%).ConclusionsGenerally, we identified that coverage of the association between SNPs of CYP genes and anti-tuberculosis drug-related toxicity outcomes is incomplete. We observed significant associations between the RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene and anti-tuberculosis drug-related hepatotoxicity. We were unable to comment on the impact of ethnicity on the investigated associations, as information on participants’ ethnicity was sparsely reported in the included studies.Systematic review registrationPROSPERO registration number: CRD42017068448.Electronic supplementary materialThe online version of this article (10.1186/s13643-018-0861-z) contains supplementary material, which is available to authorized users.

Genetic polymorphism related to ethambutol outcomes and susceptibility to toxicity

“…EMB binds to TetR, a transcriptional regulator that enhances the INH sensitivity of the inhA gene and leads to increases in the killing effect of INH, thus increasing INH toxicity (Zhu et al, 2019). Genetic polymorphisms in drug metabolic enzyme-encoded genes, such as GST, CYP, and UGT, could affect the risk of EMB hepatotoxicity (Li et al, 2013;Richardson et al, 2018;Sun et al, 2019). Meta-analysis study which conducted on various middle-and high income countries prove that there are significant association between RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 Frontiers in Genetics frontiersin.org gene to the hepatotoxicity (Richardson et al, 2018).…”

“…Genetic polymorphisms in drug metabolic enzyme-encoded genes, such as GST, CYP, and UGT, could affect the risk of EMB hepatotoxicity (Li et al, 2013;Richardson et al, 2018;Sun et al, 2019). Meta-analysis study which conducted on various middle-and high income countries prove that there are significant association between RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 Frontiers in Genetics frontiersin.org gene to the hepatotoxicity (Richardson et al, 2018). The results of a study on the GSTM1 gene polymorphism (null genotype) showed that the polymorphism was associated with hepatotoxic risk in the EMB-containing regimen, while the non-EMB-containing regimen showed insignificant results.…”

Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment—A Study from Patients of Portuguese Health Centers

“…For these genes, conflicting results have been published. Considering recent meta-analyses, two support the roles of CYP2E1, GSTM1, and GSTT1 in AT-DILI [ 19 , 20 ], one does not implicate GSTT1 [ 21 ], and in another CYP2E1 could only be implicated in East Asian populations [ 18 ]. In a trans-ethnic meta-analysis from Nicoletti et al, CYP2E1 was not associated with AT-DILI [ 46 ].…”

“…The cytochrome P450 2E1 (CYP2E1) is a phase I metabolizing enzyme that converts INH subproducts hydrazine and acetyl hydrazine into reactive hepatotoxic metabolites [ 17 ]. The SNP rs2031920, a 2Kb gene upstream variant, has been associated with higher enzymatic activity [ 18 , 19 ]. Glutathione S-Transferases (GSTs) are phase II metabolizing enzymes with an important role in the detoxification of metabolites resulting from the biotransformation of xenobiotics by phase I enzymes [ 17 ].…”

Influence of HNF4α and HNF4α-AS1 gene variants on the risk of anti-tuberculosis drugs-induced hepatotoxicity

“…Accumulating evidence indicates that lncRNA polymorphisms may also be potential biomarkers used for early diagnosis, monitoring therapy response, and prognostic assessment including for TB (45,46). Since results of current pharmacogenomics studies on ATDH are still lacking consistency according to different races, drug dosages, and treatment protocol, the results may not be representative of a Chinese population infected with TB (31,32,(47)(48)(49). Considering China's heavy burden of TB, further pharmacogenetic studies aiming to identify novel potential targets are needed in order to provide a better understanding of the potential mechanism of ATDH and optimize treatment outcomes.…”