Predominance of N-acetyl transferase 2 slow acetylator alleles in children less than ten years experiencing adverse treatment events following artemisinin-based combination therapy in North and South West Regions of Cameroon

Abstract

The human N-acetyltransferase II (NAT2) gene may vary between individuals resulting in variability in the incidence of adverse drug reactions. We set out in this adhoc analysis to determine the distribution of allele frequencies of NAT2 gene variants among children less than ten years treated with artemisinin-based combinations in Cameroon. Children with uncomplicated malaria were deparasitized with artemisinin based combination therapy (artesunate amodiaquine, dihydroartemisinin-piperaquine and artemether-lumefantrine) and followed up for 42 days and adverse events recorded. Blood was spotted on filter paper prior to drug administration for DNA extraction by chelex method. Standard nested PCR followed by restriction enzyme analysis with KpnI, TaqI, and BamHI for detection of polymorphisms in the NAT2 was performed. Allelic frequencies and acetylator phenotypes were compared between participants with or without adverse drug events. The prevalence of slow, intermediate and fast acetylators was 54, 34 and 12% respectively. Significant clustering of mutant alleles (NAT2*5, NAT2*6 and NAT2*7) occurred among those who experienced skin rash and tiredness (OR = 5.765, P = 0.046) (OR = 13.280, P = 0.020). No significant difference was observed between fast and slow acetylators with respect to the development of other recorded adverse events. Overall, producers of the slow acetylator alleles were more likely to develop any adverse events (OR = 8.286, P = 0.017) during the study period. Mutant alleles of the wild type NAT2*4 associated with the slow acetylator phenotype were the most predominant NAT2 allelic type and individuals with the phenotype were more likely to develop adverse events to ACTs.

Keywords: N-Acetyltransferase 2, Artemisinin based combination therapy, adverse events, slow acetylators, allele