title: N-acetyltransferase and cytochrome P450 2E1 gene polymorphisms and susceptibility to antituberculosis drug hepatotoxicity in an Indian population.
abstract: Background. Antituberculosis drug hepatotoxicity (ATDH) is common in India. Isoniazid, a constituent of most anti- tuberculosis drug regimens, is metabolized by N-acetyltransferase (NAT2) and cytochrome P450 2E1 (CYP2E1) enzymes. We therefore studied the association of some single-nucleotide polymorphisms (SNPs) in these enzyme genes with ATDH. Methods. Allelic and genotypic frequencies at three SNP loci in the NAT2 gene (rs1799929, rs1799930 and rs1799931) and one locus (rs2031920) in the CYP2E1 gene were studied using restriction fragment length polymorphism in 33 patients who developed ATDH following an isoniazid- containing antituberculosis drug regimen and 173 healthy blood donors. After confirming adherence of the control data to the Hardy-Weinberg equilibrium model, genotype and allele frequencies in the two groups were compared. Results. For SNP rs1799930 in the NAT2 gene, 7 (21%), 21 (64%) and 5 (15%) patients, and 93 (54%), 62 (36%) and 18 (10%) controls had GG, GA and AA genotypes, respectively (p=0.003; odds ratio [OR] for GA v. GG=4.50 [95% CI 1.80-11.22] and for AA v. GG=3.69 [1.05-12.93]). Allele frequency for G nucleotides for this SNP was 0.53 among patients and 0.72 among controls (OR 2.24 [1.31-3.84], p=0.007). The allele and genotype frequencies of the other NAT2 SNPs and the CYP2E1 SNP showed no significant difference between cases and controls. All the 33 patients and 151 (87%) of 173 controls had mutant allele at one or more of the three NAT2 SNP loci (p=0.03). The presence of two or more mutant alleles, a marker of slow acetylator status, was more frequent in patients (23/33 [70%]) than in controls (73/173 [42%]; OR 3.23 [95% CI 1.45-7.19], p=0.004). Conclusion. In India, the risk of ATDH is increased in persons with 'A' allele at SNP rs1799930 in the NAT2 gene, but is not associated with rs2031920 polymorphism in the CYP2E1 gene.
authors.affiliation: Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, Uttar Pradesh, India, Department of Gastroenterology.
authors.forename: Swapnil
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, Uttar Pradesh, India, Department of Gastroenterology.
authors.forename: Sunilbaran
authors.initials: S
authors.lastname: Daschakraborty
authors.affiliation: Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, Uttar Pradesh, India, Department of Gastroenterology.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Shukla
authors.affiliation: Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, Uttar Pradesh, India, Department of Gastroenterology.
authors.forename: Prerna
authors.initials: P
authors.lastname: Kapoor
authors.affiliation: Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, Uttar Pradesh, India, Department of Gastroenterology.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Aggarwal
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007194:India; D008111:Liver Function Tests; D008297:Male; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012306:Risk
chemical_list: D000995:Antitubercular Agents; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase