CYP2E1 VNTR genotyping associated to anti–tuberculosis drug-induced hepatotoxicity

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Tuberculosis (TB) remains a major worldwide health problem with an estimated of 9.0 million of newcases and 1.5 million of deaths in 2013. Anti–TB drug-induced hepatotoxicity (ATDH) is considered the mostserious and prevalent adverse drug reaction in TB treatment. Isoniazid (INH), one of the first-line drugs againstTB, is more commonly associated to ATDH and, it is well known that the enzyme Citochrome P450 2E1 (CYP2E1)is involved in INH metabolism. It has been found that variable number tandem repeat (VNTR) polymorphicsequences in the promoter region regulate negatively CYP2E1 gene transcription: consequently, it could be putin relationship with adverse TB-drugs reactions.In this report we for the first time show advanced investigations regarding the association between CYP2E1-VNTR and ATDH; the study started last year also thank to a small grant by CUIA but was widely extended withother funds. We studied genotypic frequency distributions of the CYP2E1-VNTR (using PCR-RFLP methodology)in a cohort 294 TB patients treated with anti-TB drugs: 167 were Argentines (130 controls without ATDH and 37cases with ATDH) and 127 were Bolivians (83 controls without ATDH and 44 cases with ATDH). Chi-squared testwas used to compare proportions: a value of P<0.05 was considered to be statistically significant.In the Argentine population, we observed that the A2/A4 genotype frequency was significantly higher in casesthan in controls (P=0.048). In contrast, no significant differences were observed in Bolivian population betweencontrols and cases regarding to distribution of VNTR genotypes.Our preliminary results showed that the presence of A4 allele of CYP2E1-VNTR could be associated to ATDH, atleast in the Argentine population. These results are in agreement with previously reported data which proposedthat the transcriptional activity of A4 allele was higher than that of A2 allele since the transcriptionalsuppression of A4 was weaker than that of A2.It will be necessary to increase the number of cases in both populations to confirm this possible and interestingassociation. The CYP2E1 VNTR genotype, in fact, promises to be an attractive marker that could be used to predict or prevent ATDH like the acetylator profile.
Original languageEnglish
Title of host publicationGiornate del CUIA in Argentina 9-24 aprile 2015: contributi scientifici e biografia dei relatori
Pages31-32
Number of pages2
Publication statusPublished - 2015

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