https://doi.org/10.4081/monaldi.2024.3181
A study of N-acetyltransferase 2 gene polymorphisms in the Indian population and its relationship with serum isoniazid concentrations in a cohort of tuberculosis patients
Submitted: August 20, 2024
Accepted: October 16, 2024
Published: December 19, 2024
Accepted: October 16, 2024
Abstract Views: 48
PDF_EARLY VIEW: 13
SUPPLEMENTARY MATERIAL: 5
SUPPLEMENTARY MATERIAL: 5
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
The N-acetyltransferase 2 (NAT2) gene exhibits substantial genetic diversity, leading to distinct acetylator phenotypes among individuals. In this study, we determine NAT2 gene polymorphisms in tuberculosis (TB) patients and analyze serum isoniazid (INH) concentrations across the various genotypes. An observational prospective cohort study involving 217 patients with pulmonary or extrapulmonary TB was carried out. The NAT2 genotypes were identified using real-time polymerase chain reaction technology. INH concentrations at baseline and 2 hours post-dosing were estimated using high-performance liquid chromatography. The association between the acetylator status and INH concentrations was evaluated using odds ratios (OR) and the occurrence of adverse events across the different patient genotypes was also assessed. The genotype frequency of fast, intermediate, and slow acetylators was 7.37%, 39.17%, and 53.46%, respectively, while allele frequency was 27% for fast acetylators and 73% for slow acetylators. All the alleles followed the Hardy-Weinberg equilibrium. Patients with slow acetylator status had significantly increased serum INH concentrations 2 hours post-drug administration, followed by intermediate acetylators as compared to fast acetylators. 69 (31.8%) patients developed adverse drug reactions post-therapy. Patients with slow acetylator status had the highest (OR: 9.66) risk of developing drug-induced hepatoxicity, especially those with raised serum INH concentrations (OR: 1.34). Understanding the correlation between genetics and serum antitubercular drug levels in antitubercular drug-induced hepatotoxicity will provide valuable information to the medical community, minimizing the risk of adverse reactions and hospitalizations.
Governement of India. RNTCP guidelines. Available from: https://tbcindia.mohfw.gov.in/guidelines/.
Tostmann A, Boeree MJ, Aarnoutse RE, et al. Anti-tuberculosis drug-induced hepatotoxicity: concise up-to-date review. J Gastroenterol Hepatol 2008;23:192-202.
DOI: https://doi.org/10.1111/j.1440-1746.2007.05207.x
Dooley KE, Miyahara S, von Groote-Bidlingmaier F, et al. Early bactericidal activity of different Isoniazid doses for drug-resistant tuberculosis (in hindsight): a randomized, open-label clinical trial. Am J Respir Crit Care Med 2020;201:1416-24.
DOI: https://doi.org/10.1164/rccm.201910-1960OC
Kinzig-Schippers M, Tomalik-Scharte D, Jetter A, et al. Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733-8.
DOI: https://doi.org/10.1128/AAC.49.5.1733-1738.2005
Pasipanodya JG, Srivastava S, Gumbo T. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy. Clin Infect Dis 2012;55:169-77.
DOI: https://doi.org/10.1093/cid/cis353
Babalik A, Mannix S, Francis D, et al. Therapeutic drug monitoring in the treatment of active tuberculosis. Can Respir J 2011;18:225-9.
DOI: https://doi.org/10.1155/2011/307150
Seifart HI, Parkin DP, Botha FJ, et al. Population screening for isoniazid acetylator phenotype. Pharmacoepidemiol Drug Saf 2001;10:127-34.
DOI: https://doi.org/10.1002/pds.570
Mushiroda T, Yanai H, Yoshiyama T, et al. Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients. Hum Genome Var 2016;3:16014.
DOI: https://doi.org/10.1038/hgv.2016.14
Matsumoto T, Ohno M, Azuma J. Future of pharmacogenetics-based therapy for tuberculosis. Pharmacogenomics 2014;15:601-7.
DOI: https://doi.org/10.2217/pgs.14.38
Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs 2014;74:839-54. Erratum in: Drugs 2014;74:2061.
DOI: https://doi.org/10.1007/s40265-014-0222-8
Gutiérrez-Virgen JE, Piña-Pozas M, Hernández-Tobías EA, et al. NAT2 global landscape: genetic diversity and acetylation statuses from a systematic review. Plos One 2023;18:e0283726.
DOI: https://doi.org/10.1371/journal.pone.0283726
Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935-52.
DOI: https://doi.org/10.1164/rccm.200510-1666ST
Nahid P, Dorman SE, Alipanah N, et al. Official American thoracic society/centres for disease control and prevention/infectious diseases society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016;63:e147-95.
DOI: https://doi.org/10.1093/cid/ciw376
WHO. WHO consolidated guidelines on tuberculosis: Module 4: Treatment - Drug-susceptible tuberculosis treatment. Available from: https://www.who.int/publications/i/item/9789240048126.
Hemanth Kumar AK, Ramesh K, Kannan T, et al. N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis. Indian J Med Res 2017;145:118-23.
DOI: https://doi.org/10.4103/ijmr.IJMR_2013_15
Sabbagh A, Langaney A, Darlu P, et al. Worldwide distribution of NAT2 diversity: implications for NAT2 evolutionary history. BMC Genet 2008;9:21.
DOI: https://doi.org/10.1186/1471-2156-9-21
Garte S, Gaspari L, Alexandrie AK, et al. Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev 2001;10:1239-48.
Hamdy SI, Hiratsuka M, Narahara K, et al. Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR-1 in the Egyptian population. Br J Clin Pharmacol 2003;55:560-9.
DOI: https://doi.org/10.1046/j.1365-2125.2003.01786.x
Yadav D, Kumar R, Dixit RK, et al. Association of Nat2 gene polymorphism with antitubercular drug-induced hepatotoxicity in the eastern Uttar Pradesh population. Cureus 2019;11:e4425.
DOI: https://doi.org/10.7759/cureus.4425
Rana SV, Ola RP, Sharma SK, et al. Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients. Hepatol Int 2012;6:397-402.
DOI: https://doi.org/10.1007/s12072-011-9309-4
Jain M, Kumar S, Lal P, et al. Association of genetic polymorphisms of N-acetyltransferase 2 and susceptibility to esophageal cancer in north Indian population. Cancer Invest 2007;25:340-6.
DOI: https://doi.org/10.1080/07357900701358074
Morton LM, Schenk M, Hein DW, et al. Genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2) and risk of non-Hodgkin lymphoma. Pharmacogenet Genomics 2006;16:537-45.
DOI: https://doi.org/10.1097/01.fpc.0000215071.59836.29
Loktionov A, Moore W, Spencer SP, et al. Differences in N-acetylation genotypes between Caucasians and Black South Africans: implications for cancer prevention. Cancer Detect Prev 2002;26:15-22.
DOI: https://doi.org/10.1016/S0361-090X(02)00010-7
Singh N, Dubey S, Chinnaraj S, Golani A, Maitra A. Study of NAT2 gene polymorphisms in an Indian population: association with plasma isoniazid concentration in a cohort of tuberculosis patients. Mol Diagn Ther 2009;13:49-58.
DOI: https://doi.org/10.1007/BF03256314
Chen B, Li JH, Xu YM, Wang J, Cao XM. The influence of NAT2 genotypes on the plasma concentration of isoniazid and acetyl isoniazid in Chinese pulmonary tuberculosis patients. Clin Chim Acta 2006;365:104-8.
DOI: https://doi.org/10.1016/j.cca.2005.08.012
Ellard GA. Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis. Clin Pharmacol Ther 1976; 19 (5 Pt 2): 610-25.
DOI: https://doi.org/10.1002/cpt1976195part2610
Ungcharoen U, Sriplung H, Mahasirimongkol S, et al. The influence of NAT2 genotypes on isoniazid plasma concentration of pulmonary tuberculosis patients in southern Thailand. Tuberc Respir Dis 2020;83:S55-62.
DOI: https://doi.org/10.4046/trd.2020.0068
Parthasarathy R, Sarma GR, Janardhanam B, et al. Hepatic toxicity in south Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 1986;67:99-108.
DOI: https://doi.org/10.1016/0041-3879(86)90003-6
Purohit SD, Gupta PR, Sharma TN, et al. Rifampicin and hepatic toxicity. Indian J Tuberc 1983;30:107-9.
How to Cite
Munshi, Renuka, Falguni Panchal, Unnati Desai, Ketaki Utpat, and Kirti Rajoria. 2024. “A Study of N-Acetyltransferase 2 Gene Polymorphisms in the Indian Population and Its Relationship With Serum Isoniazid Concentrations in a Cohort of Tuberculosis Patients”. Monaldi Archives for Chest Disease, December. https://doi.org/10.4081/monaldi.2024.3181.
Copyright (c) 2024 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Fatemeh Khelghati, Fatemeh Nasirpour Seilakhori, Mehdi Goudarzi, Shima Malekloo, Amir Hashem Shahidi Bonjar, Hossein Goudarzi, Mohammad Javad Nasiri, Multidrug-resistant tuberculosis in Iran: a multicenter study , Monaldi Archives for Chest Disease: Early Access
- Maryam Hassan, Akbar Shoukat Ali, Ali Bin Sarwar Zubairi, Zahra Ali Padhani, Salman Kirmani, Huzaifa Ahmad, Zafar Fatmi, Jai K Das, Gene polymorphisms and risk of idiopathic pulmonary fibrosis: a systematic review and meta-analysis , Monaldi Archives for Chest Disease: Early Access
- Jayabharathi Palanivel, Madhusmita Mohanty Mohapatra, Manju Rajaram, Debasis Gochhait, Sunitha Vellathussery Chakkalakkoombil, Rakesh Singh, Exploring the role of Aspergillus galactomannan antigen in assessing the risk factor of acute exacerbations in chronic obstructive pulmonary disease patients: a cross-sectional study , Monaldi Archives for Chest Disease: Early Access
- Vivek Sharma, Pruthu Thekkur, Poonam R. Naik, Brojo Kishore Saha, Niraj Agrawal, Milan K. Dinda, S. Parthiban, Abhijit Dey, Basavaraj Poojar, Amrita N. Shamanewadi, Srinath Satyanarayana, Treatment success rates among tuberculosis patients notified from the private sector in West Bengal, India , Monaldi Archives for Chest Disease: Vol. 91 No. 1 (2021)
- Taymmia Ejaz, Mahmood Iqbal Malik, Jamal Ahmed, Rizwan Azam, Yousaf Jamal, Sheema Saadia, Clinico-radiological and bronchoscopic predictors of microbiological yield in sputum negative tuberculosis in Pakistan , Monaldi Archives for Chest Disease: Vol. 92 No. 3 (2022)
- Vinnie Sarah Ch Sangma, Surabhi Jaggi, Varinder Saini, Deepak Aggarwal, Pankaj Kumar, Jagdish Chander, Prevalence of latent tuberculosis infection in household contacts of pulmonary tuberculosis, time to treat , Monaldi Archives for Chest Disease: Vol. 94 No. 1 (2024)
- Barbara Bordoni, Stefano Urbinati, Alicia Tosoni, Graziana Labanti, Alba Brandes, Cardiologic evaluation of patients undergoing chemoterapy , Monaldi Archives for Chest Disease: Vol. 82 No. 2 (2014): Cardiac series
- Mamta Singh, Kunal Deokar, Bibhuti Prassan Sinha, Jinish Doshi, CDS Katoch, Infective pulmonary diseases and the eye: a narrative review , Monaldi Archives for Chest Disease: Early Access
- Stefania Paolillo, Giuseppe Luca Della Ratta, Alice Vitagliano, Annapaola Cirillo, Elisabetta Lardino, Tiziana Formisano, Irma Fabiani, Angela Maria Pellegrino, Pietro Riello, Pasquale Perrone Filardi, New perspectives in cardiovascular risk reduction: focus on HDL , Monaldi Archives for Chest Disease: Vol. 80 No. 1 (2013): Cardiac series
- Saulius Diktanas, Oleksandr Korotych, Yuliia Sereda, Ogtay Gozalov, Olga Rubcova, Jay Achar, Factors associated with time to sputum culture conversion of rifampicin-resistant tuberculosis patients in Klaipeda, Lithuania in 2016-2019: a cohort study , Monaldi Archives for Chest Disease: Vol. 91 No. 1 (2021)
<< < 2 3 4 5 6 7 8 9 10 11 > >>
You may also start an advanced similarity search for this article.
