Genetic Landscape of NAT2 in the Moroccan Population: Implications for Isoniazid Pharmacogenetics in Tuberculosis

The NAT2 gene encodes N-acetyltransferase 2, an enzyme critically involved in the biotransformation of numerous xenobiotics and aromatic amines, including isoniazid, a cornerstone drug in tuberculosis therapy. Genetic polymorphisms in NAT2 lead to variable acetylation rates, clinically categorized as poor, intermediate, or rapid metabolizer phenotypes influencing drug efficacy and toxicity. This study aims to characterize the NAT2 polymorphisms in 240 Moroccan individuals using pre-existing clinical exome sequencing data. A total of fourteen variants were identified in the NAT2 coding region, with the most frequent being c.341 T>C (50%), c.803G>A (48.95%), c.481C>T (48.33%), and c.282C>T (29.16%). Diplotype-based phenotype prediction showed that 148 individuals (61.67%) were poor metabolizers, 71 (29.58%) intermediate metabolizers, and 14 (5.83%) rapid metabolizers. Seven individuals could not be classified due to the presence of variants with unreported diplotype-phenotype correlations. These findings provide a comprehensive pharmacogenetic profile of NAT2 in the Moroccan population and support the implementation of diplotype-guided isoniazid dosing strategies in tuberculosis-endemic settings.