tagSNP rs1495741 as a useful molecular marker to predict antituberculosis drug-induced hepatotoxicity.
It has been widely reported that the slow acetylator phenotype of N-acetyltransferase 2 (NAT2) is associated with the development of antituberculosis drug-induced hepatotoxicity (ATDH). The aim of this report was to evaluate the level of agreement and accuracy of two recently recommended markers, the two-single nucleotide polymorphisms (SNP) (C282T and T341C) and tagSNP of NAT2 (rs1495741) genotypes, to predict the seven-SNP-inferred NAT2 phenotype in Bolivian and Argentinian tuberculosis (TB)-patient populations. In addition, we analyzed the association of these markers with ATDH.



We examined 331 TB patients who had been treated with anti-TB drugs. TagSNP of NAT2 genotyping was determined using PCR-restriction fragment length polymorphisms. The seven SNPs of NAT2 were determined using sequencing. Concordance analysis was carried out using Kendall's tau-b coefficient (w) and the degree of agreement with Cohen's κ coefficient (κ). Receiver operating characteristic receiver operating characteristic curves were obtained to measure the specificity and sensitivity of the method. A binary logistic regression was performed to identify variables associated with the development of ATDH.



Both predictors showed a remarkable concordance (>95.0%) and an almost perfect agreement (κ>0.945; P<0.0001) with the predicted acetylator profile. However, the sensitivity of the tagSNP genotypes to predict the NAT2 acetylator phenotype was lower in the Bolivian population (92.3%) compared with the Argentinian population (100.0%).



A nearly perfect agreement between both predictors and the predicted acetylation profile was observed with very high levels of sensitivity (>97%) and specificity (>98.0%). Furthermore, and as expected, both the two-SNP (C282T, T341C) and tagSNP were found to be independent variables in predicting ATDH with the same strength as seven-SNP of NAT2.
aHemostasis and Thrombosis Laboratory bPneumotisiology Division cIntensive Care Department of Critical Infected Patient (D.A.I.P.I.C.), Hospital of Infectious Diseases 'F. J. Muñiz' dLaboratory for Biological and Artificial Learning, Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Buenos Aires City, Argentina.
Julián G
JG
Chamorro
Jorge P
JP
Castagnino
Rosa M
RM
Musella
Mabel
M
Nogueras
Ana
A
Frías
Mabel
M
Visca
Omar
O
Aidar
Lucas
L
Costa
Gabriela F
GF
de Larrañaga
D000107:Acetylation; D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000209:etiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009161:Mycobacterium / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human