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 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, NAT2*5/*7 carries the highest risk associated with ATDIH. As for our case control study, the T allele of NAT2*13A (rs1041983), A allele of NAT2*6B (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. NAT2*6A/*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.