PHARMACOGENOMIC VARIATIONS INFLUENCING DRUG RESPONSE IN TUBERCULOSIS TREATMENT
Abstract
Tuberculosis remains a major global health concern, and variability in response to anti-tuberculosis drugs often complicates treatment outcomes. Genetic differences among individuals can influence drug metabolism, pharmacokinetics, and susceptibility to adverse drug reactions. Pharmacogenomics has therefore emerged as an important approach for understanding variability in drug response and improving personalised treatment strategies. Pharmacogenomic clinical information and genomic probe information from the GPL570 microarray platform were integrated to identify gene–drug relationships associated with anti-tuberculosis treatment. Data preprocessing included the removal of incomplete entries and the normalisation of gene identifiers. Pharmacogenomic variants were mapped to corresponding genes, followed by functional classification, bioinformatics analysis, and descriptive statistical evaluation of gene and drug association frequencies. Analysis identified 10 pharmacogenomic genes associated with antituberculosis drug response. N-Acetyltransferase 2 (NAT2) showed the highest frequency (n = 13), followed by Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) (n = 5) and ATP/GTP Binding Protein Like 4 (AGBL4) (n = 3). Other genes, including Cytochrome P450 Family 2 Subfamily E Member 1 (CYP2E1), ATP Binding Cassette Subfamily B Member 1 (ABCB1), Cytochrome P450 Family 2 Subfamily B Member 6 (CYP2B6), and Exportin
1 (XPO1), were observed with moderate frequencies. Drug association analysis revealed that rifampin had the highest frequency (n = 11), followed by tuberculosis drug combinations and isoniazid-related therapies. Pharmacogenomic variability in metabolic enzymes and transporter genes plays a significant role in determining anti-tuberculosis drug response. Integrating pharmacogenomic information into clinical practice may improve personalised treatment strategies and optimise therapeutic outcomes.
Downloads
References
Aminkeng, F., Ross, C. J. D., Rassekh, S. R., Brunham, L. R., Sistonen, J., Dube, M. P., ... & Hayden, M. R. (2014).
Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer,
AIDS and tuberculosis in persons of African descent. The pharmacogenomics journal, 14(2), 160-170.
Bao, Y., Ma, X., Rasmussen, T. P., & Zhong, X. B. (2018). Genetic variations associated with anti-tuberculosis druginduced liver injury. Current pharmacology reports, 4(3), 171-181.
Cacabelos, R., Naidoo, V., Corzo, L., Cacabelos, N., & Carril, J. C. (2021). Genophenotypic factors and
pharmacogenomics in adverse drug reactions. International journal of molecular sciences, 22(24), 13302.
Calcagno, A., Cusato, J., Sekaggya‐Wiltshire, C., Von Braun, A., Motta, I., Turyasingura, G., ... & Lamorde, M. (2019).
The influence of pharmacogenetic variants in HIV/tuberculosis coinfected patients in Uganda in the SOUTH
study. Clinical Pharmacology & Therapeutics, 106(2), 450-457.
Chamorro, J. G., Castagnino, J. P., Aidar, O., Musella, R. M., Frías, A., Visca, M., ... & de Larrañaga, G. F. (2017).
Effect of gene–gene and gene–environment interactions associated with antituberculosis drug-induced
hepatotoxicity. Pharmacogenetics and genomics, 27(10), 363-371.
Devaleenal Daniel, B., Ramachandran, G., & Swaminathan, S. (2017). The challenges of pharmacokinetic variability
of first-line anti-TB drugs. Expert Review of Clinical Pharmacology, 10(1), 47-58.
Khan, A., Abbas, M., Verma, S., Verma, S., Rizvi, A. A., Haider, F., ... & Mahdi, F. (2022). Genetic variants and drug
efficacy in tuberculosis: a step toward personalized therapy. Global medical genetics, 9(02), 090-096.
Kumar Sahu, R., Singh, K., & Subodh, S. (2015). Adverse drug reactions to anti-TB drugs: pharmacogenomics
perspective for identification of host genetic markers. Current drug metabolism, 16(7), 538-552.
McIlleron, H., Abdel-Rahman, S., Dave, J. A., Blockman, M., & Owen, A. (2015). Special populations and
pharmacogenetic issues in tuberculosis drug development and clinical research. The Journal of Infectious
Diseases, 211(suppl_3), S115-S125.
Mizzi, C., Dalabira, E., Kumuthini, J., Dzimiri, N., Balogh, I., Başak, N., ... & Patrinos, G. P. (2016). A European
spectrum of pharmacogenomic biomarkers: implications for clinical pharmacogenomics. PloS one, 11(9), e0162866.
Motta, I., Calcagno, A., & Bonora, S. (2018). Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: a tool
for treatment optimization?. Expert opinion on drug metabolism & toxicology, 14(1), 59-82.
Mugusi, S., Habtewold, A., Ngaimisi, E., Amogne, W., Yimer, G., Minzi, O., ... & Aklillu, E. (2020). Impact of
population and pharmacogenetics variations on efavirenz pharmacokinetics and immunologic outcomes during antituberculosis co-therapy: a parallel prospective cohort study in two Sub-Sahara African populations. Frontiers in
Pharmacology, 11, 26.
Mukonzo, J. K., Kengo, A., Kutesa, B., Nanzigu, S., Pohanka, A., McHugh, T. D., ... & Aklillu, E. (2020). Role of
pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB–rifampicin sensitivity among
Ugandan patients. Transactions of the Royal Society of Tropical Medicine and Hygiene, 114(2), 107-114.
Naidoo, A., Chirehwa, M., Ramsuran, V., McIlleron, H., Naidoo, K., Yende-Zuma, N., ... & Padayatchi, N. (2019).
Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent
tuberculosis. Pharmacogenomics, 20(4), 225-240.
Naidoo, A., Ramsuran, V., Chirehwa, M., Denti, P., McIlleron, H., Naidoo, K., ... & Padayatchi, N. (2018). Effect of
genetic variation in UGT1A and ABCB1 on moxifloxacin pharmacokinetics in South African patients with
tuberculosis. Pharmacogenomics, 19(1), 17-29.
Oliver, J., & Mason, W. (2020). Gene Variation: The Key to Understanding Pharmacogenomics and Drug Response
Variability. Fusion of Multidisciplinary Research, An International Journal, 1(2), 97-109.
Pallerla, S. R., Assiana, D. O. E., Cho, F. N., Meyer, C. G., Fagbemi, K. A., Adegnika, A. A., ... & Velavan, T. P.
(2021). Pharmacogenetic considerations in the treatment of co-infections with HIV/AIDS, tuberculosis and malaria in
Congolese populations of Central Africa. International Journal of Infectious Diseases, 104, 207-213.
Pirmohamed, M. (2014). Personalized pharmacogenomics: predicting efficacy and adverse drug reactions. Annual
review of genomics and human genetics, 15(1), 349-370.
Richardson, M., Kirkham, J., Dwan, K., Sloan, D. J., Davies, G., & Jorgensen, A. L. (2018). CYP genetic variants and
toxicity related to anti-tubercular agents: a systematic review and meta-analysis. Systematic reviews, 7(1), 204.
Sloan, D. J., McCallum, A. D., Schipani, A., Egan, D., Mwandumba, H. C., Ward, S. A., ... & Davies, G. R. (2017).
Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis.
Antimicrobial Agents and Chemotherapy, 61(7), 10-1128.
Stocco, G., Lucafò, M., & Decorti, G. (2020). Pharmacogenomics of antibiotics. International Journal of Molecular
Sciences, 21(17), 5975.
Sun, Q., Liu, H. P., Zheng, R. J., Wang, P., Liu, Z. B., Sha, W., & Xiao, H. P. (2017). Genetic polymorphisms of
SLCO1B1, CYP2E1 and UGT1A1 and susceptibility to anti-tuberculosis drug-induced hepatotoxicity: a Chinese
population-based prospective case–control study. Clinical Drug Investigation, 37(12), 1125-1136.
Thomas, L., Sekhar Miraj, S., Surulivelrajan, M., Varma, M., Sanju, C. S., & Rao, M. (2020). Influence of single
nucleotide polymorphisms on rifampin pharmacokinetics in tuberculosis patients. Antibiotics, 9(6), 307.
Verma, R., Patil, S., Zhang, N., Moreira, F. M., Vitorio, M. T., Santos, A. D. S., ... & Andrews, J. R. (2021). A rapid
pharmacogenomic assay to detect NAT2 polymorphisms and guide isoniazid dosing for tuberculosis treatment.
American Journal of Respiratory and Critical Care Medicine, 204(11), 1317-1326.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 International Journal For Research In Biology & Pharmacy
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
In consideration of the journal, Green Publication taking action in reviewing and editing our manuscript, the authors undersigned hereby transfer, assign, or otherwise convey all copyright ownership to the Editorial Office of the Green Publication in the event that such work is published in the journal. Such conveyance covers any product that may derive from the published journal, whether print or electronic. Green Publication shall have the right to register copyright to the Article in its name as claimant, whether separately
or as part of the journal issue or other medium in which the Article is included.
By signing this Agreement, the author(s), and in the case of a Work Made For Hire, the employer, jointly and severally represent and warrant that the Article is original with the author(s) and does not infringe any copyright or violate any other right of any third parties, and that the Article has not been published elsewhere, and is not being considered for publication elsewhere in any form, except as provided herein. Each author’s signature should appear below. The signing author(s) (and, in
