Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

Abstract

Anti-tuberculosis drug-induced hepatitis (ATD-induced hepatitis) has been linked to polymorphisms in genes encoding drug metabolizing enzymes. N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferase (loci GSTM1 and GSTT1) are involved in the metabolism of isoniazid, the most toxic drug for the treatment of tuberculosis (TB). This study was designed to determine the frequency and to evaluate whether polymorphisms at CYP2E1, GSTM1 and GSTT1 genes are associated with drug response, as well as to identify clinical risk factors for ATD-induced hepatitis. A total of 245 Brazilian patients undergoing treatment for TB were genotyped using polymerase chain reaction and restriction fragment length polymorphism and sequencing methods. The frequencies of the CYP2E1 polymorphic alleles RsaI, PstI and DraI are 8%, 8.5% and 12%, respectively. GSTM1 and GSTT1 genes are deleted in 42.9% and 12.4% of the population, respectively. Fifteen patients (6.1%) developed hepatotoxicity. Clinical (HIV, female sex and extrapulmonary TB) and genetic characteristics (CYP2E1 without any mutations, having NAT2 slow acetylator profile) are at higher risk of developing ATD-induced hepatitis in this population. Genotyping for GSTM1 and GSTT1 showed no influence on drug response.

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

“…Thirty-eight articles (29 distinct patient cohorts) investigated the association between GSTM1/GSTT1 or other genetic variants and anti-TB drug-related toxicity. In this review, we include data from 35 articles (22–56), which included 28 distinct patient cohorts. We did not include data from two articles (57, 58) as the data presented were unclear and we were unable to clarify the data with the authors.…”

“…Twenty-four articles provided a rationale for the choice of genes and SNPs to be investigated. Eleven articles (7, 22, 30, 43, 44, 46, 48, 50, 54–56) did not provide such information; however, none of these articles limited their reporting to only statistically significant associations. Consequently, there is no evidence to suggest that selective reporting of genes and SNPs is an issue of concern for the included studies.…”

“…Twenty-two articles employed a case–control design (7, 24, 25, 27, 29–38, 40, 44, 45, 48–52), and 13 articles employed a prospective cohort design (22, 23, 26, 28, 41–43, 46, 47, 53–56). Only one (29) of the 22 articles describing case-control studies reported that the two groups were genotyped in mixed batches.…”

“…Sixteen articles made a specific assumption regarding the underlying mode of inheritance (22, 24, 27–29, 32, 33, 36, 38, 41, 44, 45, 47, 49, 54, 55). Of these, only four provided a rationale for this assumption (28, 44, 45, 54); for the remaining 12 articles, there is a risk of selective reporting where several analyses under different modes of inheritance may have been conducted, with only the most statistically significant being reported (18).…”

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

“…Twenty articles provided justification for the choice of gene and SNP to be investigated. For the 12 articles [ 31 , 33 , 36 , 44 , 46 , 48 , 52 , 54 – 56 , 58 , 59 ] that did not provide justification for each investigated gene and SNP, no articles limited their reporting to only statistically significant associations. Therefore, selective reporting of genes and SNPs does not appear to be an issue of concern.…”