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

Richardson, Marty ORCID: 0000-0002-7097-8704, Kirkham, Jamie ORCID: 0000-0003-2579-9325, Dwan, Kerry ORCID: 0000-0001-6918-1215, Sloan, Derek ORCID: 0000-0002-7888-5449, Davies, Geraint ORCID: 0000-0002-3819-490X and Jorgensen, Andrea ORCID: 0000-0002-6977-9337 (2019) Association of variants within the <i>GST</i> and other genes with anti-tubercular agents related toxicity: a systematic review and meta-analysis. bioRxiv. 515817-.

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Abstract

<h4>Background</h4> 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. <h4>Methods</h4> 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. <h4>Results</h4> 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 (I 2 =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; I 2 =0%; homozygous mutant-type versus homozygous wild-type: OR=2.18, 95% CI 1.07, 4.44; I 2 =0%). <h4>Conclusions</h4> 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.

Item Type:	Article
Uncontrolled Keywords:	Rare Diseases, Clinical Research, Tuberculosis, Digestive Diseases, Liver Disease, Genetics, 2.1 Biological and endogenous factors, 2 Aetiology, 3 Good Health and Well Being
Depositing User:	Symplectic Admin
Date Deposited:	16 Jan 2019 16:23
Last Modified:	14 Mar 2024 17:34
DOI:	10.1101/515817
Related URLs:	Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3031394