(265) Effect of CYP and NAT2 Gene Polymorphisms on Human Response to Artemisinin-Based Combination Therapies in Yaounde, Cameroon

Publication Number: 925

Background: The human cytochrome p450 (CYP) and arylamine N-acetyltransferase 2 (NAT2) are important liver enzymes involved in the breakdown of anti-malarial drugs into active metabolites. Gene variations are responsible for the change in enzyme activity and these differences lead to the classification of the population into slow, intermediate and rapid metabolisers.

Objectives: This study aimed to determine the effect of CYP and NAT2 gene polymorphisms on the effectiveness and safety of artemisinin-based combination therapies (ACTs) among children infected with Plasmodium falciparum malaria in Yaounde, Cameroon.

Methods: A total of 241 samples were obtained from a pharmacovigilance study on artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) conducted in Yaounde, Cameroon from 2019-2020. The genetic polymorphisms of CYP and NAT2 genes were analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Sanger sequencing. Moreover, eight variants of the CYP genes were investigated namely: CYP2B6*5 (1459C>T), CYP2B6*6 (15631G>T), CYP2C8*2 (805A>T), CYP2C8*3 (416G>A), CYP3A4*1B (-290A>G), CYP3A4*1B (-392A>G), CYP3A5*5 (6986A>G) and CYP3A5*6 (14690G>A). In addition, the seven common genetic variants of the NAT2 gene including 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G and 857G>A were also studied.

Results: The most prevalent mutation of 100% was registered for CYP3A4*1B (-392A>G). The most common NAT2 genetic variant was 803A>G with the frequency of 51.0%. The highest genotype frequency was NAT2*5B/NAT2*6A (8.9%, 17/192), followed by NAT2*4/NAT2*5A genotype with 7.3% (14/192). The acetylation statuses of the NAT2 gene were classified as follows: fast acetylators (9.4%, 18/192), intermediate acetylators (30.7%, 59/192) and slow acetylators (47.9%, 92/192). Out of the 60 genotypes of the NAT2 gene, 32 alleles (haplotypes) were derived. NAT2*5B was the most dominant with 13.0% (50/384), followed by NAT2*6A with 12.8% (49/384). There was no significant association between pharmacogenomics markers and anti-malarial treatment outcomes (P>0.05). An assessment of the safety of AS-AQ and AL showed that slow metabolisers for CYP2B6*5 1459C>T, CYP2B6*6 15631G>T, CYP2C8*2 805A>T, CYP3A4*1B -290A>G and CYP3A5*3 6986A>G significantly clustered with mild to moderate adverse events (P < 0.05).

Conclusions: The genetic studies carried out registered a high prevalence of genotype and allele frequencies of CYP (CYP3A4*1B -392A>G and CYP2B6*6 15631G>T) and NAT2 (803A>G and 282C>T) among the study participants. The fast and slow metabolisers predominated for CYP and NAT2, respectively. There was contrasting evidence on the association between CYP/NAT2 gene variations and the effectiveness/safety of ACTs.