Influence of genetic variants on toxicity to anti-tubercular agents: a systematic review and meta-analysis (protocol)

Richardson, Marty; Kirkham, Jamie J; Dwan, Kerry; Sloan, Derek J.; Davies, Geraint R.; Jorgensen, Andrea

doi:10.1186/s13643-017-0533-4

Cited by 13 publications

(24 citation statements)

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“…Genetic polymorphisms of NAT2 , CYP2E1 and the GST family are the most studied in relation to ATDH, for they may affect the metabolism and elimination of isoniazid, or are involved in oxidant-antioxidant balance in liver cells after exposure to anti-TB drugs 12 . We previously demonstrated that CYP2E1, GSTP1 and CYP2B6 were associated with susceptibility to ATDH by a meta-analysis and a case-control study 15,30,31 .…”

Section: Discussionmentioning

confidence: 99%

“…Genetic variants in drug metabolizing enzymes such as N-acetyltransferase 2 ( NAT2 ), cytochrome P450 2E1 ( CYP2E1 ) and glutathione S-transferases ( GSTM1, GSTT1 ), have been the most widely studied in respect to ATDH susceptibility in the Chinese population 9–11 , as well as other populations 12 . However, these genetic biomarkers have shown poor reproducibility in some studies.…”

Section: Introductionmentioning

confidence: 99%

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Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Wang

Xiang

Huang

et al. 2019

Sci Rep

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A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population. Subjects with or without hepatotoxicity during anti-TB treatment were recruited. DNA was extracted from peripheral blood and genotypes of the selected single nucleotide polymorphisms (SNPs) were determined by using the improved multiplex ligation detection reaction technique. Three genetic models (additive, dominant, and recessive) as well as haplotype, SNP-SNP interaction analyses were used to evaluate the genetic risk of ATDH. A total of 502 subjects (203 ATDH and 299 non-ATDH) were enrolled. The results showed that the minor allele of rs7643645 and the H0010001 haplotype in PXR were associated with decreased risk of ATDH, suggesting that drug-metabolizing enzymes regulated by PXR are involved in the pathogenesis of ATDH. More studies are required to verify this result.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Wang

Xiang

Huang

et al. 2019

Sci Rep

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“…The current study forms part of a series of systematic reviews and meta-analyses evaluating the influence of different genetic variants on toxicity to anti-TB agents, the protocol for which has been published (PROSPERO registration number: CRD42017068448) (13). This review has been conducted in accordance with the PRISMA statement (14); a completed copy of the PRISMA checklist is provided in Additional file 1.…”

Section: Methodsmentioning

confidence: 99%

Association of variants within the GST and other genes with anti-tubercular agents related toxicity: a systematic review and meta-analysis

Richardson

Kirkham

Dwan

et al. 2019

Preprint

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Background Individuals receiving treatment with anti-tuberculosis (TB) drugs may experience serious side-effects, such as anti-TB drug-induced hepatotoxicity (ATDH). Genetic variants, such as polymorphisms of the GST gene and other genes, may increase the risk of experiencing such toxicity events. This systematic review and meta-analysis provides a comprehensive evaluation of the evidence base for associations between variants of the GST gene and other genes and toxicity outcomes related to anti-TB drugs. Methods We searched for relevant studies in MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science. We pooled effect estimates for each genotype on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies. Results We included data from 28 distinct cohorts of patients in the review. The methodological quality of included studies was variable, with several important areas of concern. For GSTM1, patients with the homozygous null genotype were significantly more likely to experience hepatotoxicity than patients with heterozygous or homozygous present genotype (odds ratio [OR]=1.44, 95% confidence interval [CI] 1.15, 1.82). Moderate heterogeneity was observed in this analysis (I2=51.2%). No significant difference was observed for the GSTT1 null polymorphism. For the rs3814057 polymorphism of the PXR gene, both heterozygous genotype and homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (heterozygous versus homozygous wild-type: OR=1.98, 95% CI 1.06, 3.69; I2=0%; homozygous mutant-type versus homozygous wild-type: OR=2.18, 95% CI 1.07, 4.44; I2=0%). Conclusions We found that it is challenging to perform robust synthesis of the evidence base for associations between GST and other genetic variants and toxicity related to anti-TB drugs. We identified significant associations between the GSTM1 null and PXR rs3814057 polymorphisms and ATDH. To the best of our knowledge, no meta-analyses on genetic variants other than variants of the NAT2, CYP2E1, GSTM1 and GSTT1 genes have been published. Our results therefore add to the existing understanding of the association between genetic variants and hepatotoxicity.

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“…The current study forms part of a series of systematic reviews and meta-analyses evaluating the influence of different genetic variants on toxicity to anti-TB agents, the protocol for which has been published (PROSPERO registration number: CRD42017068448) [ 18 ]. This review has been conducted in accordance with the PRISMA statement [ 19 ]; a completed copy of the PRISMA checklist is provided in Additional file 1 .…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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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.

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Influence of genetic variants on toxicity to anti-tubercular agents: a systematic review and meta-analysis (protocol)

Cited by 13 publications

References 45 publications

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Association of variants within the GST and other genes with anti-tubercular agents related toxicity: a systematic review and meta-analysis

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

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