Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor

Antituberculosis drug induced hepatotoxicity (ATDIH) is a serious adverse drug reaction. Factors that affect drug responses or increase the risks of adverse drug reactions include both endogenous and exogenous variables. Genetic variants of N acetyltransferase-2 (NAT2) have been associated with incr...

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Main Author:	Mohamed Noor, Nur Farhana
Format:	Thesis
Language:	English
Published:	2022
Subjects:	Tuberculosis Antibacterial agents
Online Access:	https://ir.uitm.edu.my/id/eprint/76622/1/76622.pdf
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id	my-uitm-ir.76622
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spelling	my-uitm-ir.766222023-05-29T03:56:07Z Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor 2022 Mohamed Noor, Nur Farhana Tuberculosis Antibacterial agents Antituberculosis drug induced hepatotoxicity (ATDIH) is a serious adverse drug reaction. Factors that affect drug responses or increase the risks of adverse drug reactions include both endogenous and exogenous variables. Genetic variants of N acetyltransferase-2 (NAT2) have been associated with increased susceptibility to ATDIH. However, the findings of previous studies are inconclusive. Moreover, data about NAT2 polymorphism among patients in Malaysia is limited. This study aimed to determine the association of NAT2 polymorphism with ATDIH. A systematic literature search and meta-analysis using RevMan5.3 were conducted to compute the pooled effect of the studies. The random-effect model was applied to estimate the pooled odd ratio (OR) and 95% confidence interval (CI). The Cochrane Q-statistic and I 2 statistics were used to assess and quantify heterogeneity. Then, a case-control study was conducted. Thirty-three (33) TB patients with ATDIH and 100 TB patients without ATDIH were recruited from tertiary hospitals in Klang Valley, Malaysia. Seven single nucleotide polymorphisms (SNPs) of the NAT2 gene were determined through polymerase chain reaction and sequencing. The distribution of the genotypes and alleles frequencies between the two groups were compared and analysed using chi-square test. The odds ratio (OR) with 95% CI was used to evaluate the strength of the association between NAT2 gene polymorphism and ATDIH. Risk factors associated with ATDIH were analysed using multiple regression analysis. A total of 12 studies, involving 580 cases and 3129 controls, were included in the meta-analysis. NAT2 polymorphism was significantly associated with the risk of ATDIH with an odd ratio (OR) of 2.76 (1.86 – 4.10, 95% CI). Among the slow acetylator genotypes, NAT25/7 carries the highest risk associated with ATDIH. As for our case control study, the T allele of NAT213A (rs1041983), A allele of NAT26B (rs1799930) and NAT2 slow acetylators (SA) were significantly associated with ATDIH with odd ratios (OR (95% CI) = 2.28 (1.25-4.16), 2.20 (1.25-3.86) and 3.39 (1.43-8.04), respectively. NAT26A/6A is significantly associated with ATDIH among the NAT2 diplotypes, with an OR of 2.67 (1.05-6.79, 95% CI). Underlying diabetes mellitus, high pre-treatment bilirubin, and being a NAT2 slow acetylator are independent risk factors for ATDIH with p-value of 0.041, 0.013 and 0.005, respectively. In conclusion, the meta-analysis show that NAT2 polymorphism is associated with ATDIH. The significant role of NAT2 polymorphism is further confirmed by present case-control study. Pre-genotyping of NAT2 polymorphism in patients with high risk of ATDIH before prescribing antituberculosis treatment may reduce the incidence of ATDIH in Malaysia. 2022 Thesis https://ir.uitm.edu.my/id/eprint/76622/ https://ir.uitm.edu.my/id/eprint/76622/1/76622.pdf text en public masters Universiti Teknologi MARA (UiTM) Faculty of Pharmacy Teh, Lay Kek
institution	Universiti Teknologi MARA
collection	UiTM Institutional Repository
language	English
advisor	Teh, Lay Kek
topic	Tuberculosis Antibacterial agents
spellingShingle	Tuberculosis Antibacterial agents Mohamed Noor, Nur Farhana Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor
description	Antituberculosis drug induced hepatotoxicity (ATDIH) is a serious adverse drug reaction. Factors that affect drug responses or increase the risks of adverse drug reactions include both endogenous and exogenous variables. Genetic variants of N acetyltransferase-2 (NAT2) have been associated with increased susceptibility to ATDIH. However, the findings of previous studies are inconclusive. Moreover, data about NAT2 polymorphism among patients in Malaysia is limited. This study aimed to determine the association of NAT2 polymorphism with ATDIH. A systematic literature search and meta-analysis using RevMan5.3 were conducted to compute the pooled effect of the studies. The random-effect model was applied to estimate the pooled odd ratio (OR) and 95% confidence interval (CI). The Cochrane Q-statistic and I 2 statistics were used to assess and quantify heterogeneity. Then, a case-control study was conducted. Thirty-three (33) TB patients with ATDIH and 100 TB patients without ATDIH were recruited from tertiary hospitals in Klang Valley, Malaysia. Seven single nucleotide polymorphisms (SNPs) of the NAT2 gene were determined through polymerase chain reaction and sequencing. The distribution of the genotypes and alleles frequencies between the two groups were compared and analysed using chi-square test. The odds ratio (OR) with 95% CI was used to evaluate the strength of the association between NAT2 gene polymorphism and ATDIH. Risk factors associated with ATDIH were analysed using multiple regression analysis. A total of 12 studies, involving 580 cases and 3129 controls, were included in the meta-analysis. NAT2 polymorphism was significantly associated with the risk of ATDIH with an odd ratio (OR) of 2.76 (1.86 – 4.10, 95% CI). Among the slow acetylator genotypes, NAT25/7 carries the highest risk associated with ATDIH. As for our case control study, the T allele of NAT213A (rs1041983), A allele of NAT26B (rs1799930) and NAT2 slow acetylators (SA) were significantly associated with ATDIH with odd ratios (OR (95% CI) = 2.28 (1.25-4.16), 2.20 (1.25-3.86) and 3.39 (1.43-8.04), respectively. NAT26A/6A is significantly associated with ATDIH among the NAT2 diplotypes, with an OR of 2.67 (1.05-6.79, 95% CI). Underlying diabetes mellitus, high pre-treatment bilirubin, and being a NAT2 slow acetylator are independent risk factors for ATDIH with p-value of 0.041, 0.013 and 0.005, respectively. In conclusion, the meta-analysis show that NAT2 polymorphism is associated with ATDIH. The significant role of NAT2 polymorphism is further confirmed by present case-control study. Pre-genotyping of NAT2 polymorphism in patients with high risk of ATDIH before prescribing antituberculosis treatment may reduce the incidence of ATDIH in Malaysia.
format	Thesis
qualification_level	Master's degree
author	Mohamed Noor, Nur Farhana
author_facet	Mohamed Noor, Nur Farhana
author_sort	Mohamed Noor, Nur Farhana
title	Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor
title_short	Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor
title_full	Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor
title_fullStr	Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor
title_full_unstemmed	Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor
title_sort	association of n-acetyltransferase 2 (nat2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in malaysia / nur farhana mohamed noor
granting_institution	Universiti Teknologi MARA (UiTM)
granting_department	Faculty of Pharmacy
publishDate	2022
url	https://ir.uitm.edu.my/id/eprint/76622/1/76622.pdf
_version_	1783736115107201024

Association of N-acetyltransferase 2 (NAT2) polymorphism with antituberculosis drug induced hepatotoxicity among patients in Malaysia / Nur Farhana Mohamed Noor

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