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

Abstract

Tuberculosis (TB) remains a major worldwide health problem with an estimated of 9.0 million of new cases and 1.5 million of deaths in 2013. Anti–TB drug-induced hepatotoxicity (ATDH) is considered the most serious and prevalent adverse drug reaction in TB treatment. Isoniazid (INH), one of the first-line drugs against TB, 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) polymorphic sequences in the promoter region regulate negatively CYP2E1 gene transcription: consequently, it could be put in 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 with other 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 37 cases with ATDH) and 127 were Bolivians (83 controls without ATDH and 44 cases with ATDH). Chi-squared test was 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 cases than in controls (P=0.048). In contrast, no significant differences were observed in Bolivian population between controls 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, at least in the Argentine population. These results are in agreement with previously reported data which proposed that the transcriptional activity of A4 allele was higher than that of A2 allele since the transcriptional suppression 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 interesting association. 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.