Abstract
Plasmodium vivax is one of the five human malaria parasite species, which has a wide geographical distribution and can cause severe disease and fatal outcomes. It has the ability to relapse from dormant liver stages (hypnozoites), weeks to months after clearance of the acute blood-stage infection. An 8-aminoquinoline drug primaquine (PQ) can clear the hypnozoites, and thus can be used as an anti-relapse therapeutic agent. Recently, a number of studies have found that its efficacy is compromised by polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene; decreased or absence of CYP2D6 activity contributes to PQ therapeutic failure. The present study sought to characterize CYP2D6 genetic variation in Madagascar, where populations originated from admixture between Asian and African populations, vivax malaria is endemic, and PQ can be deployed soon to achieve national malaria elimination. In a total of 211 samples collected from two health districts, CYP2D6 decreased function alleles CYP2D6*10, *17, *29, *36+*10, and *41 were observed at frequencies of 3.55–17.06%. In addition, nonfunctional alleles were observed, the most common of which were CYP2D6*4 (2.13%), *5 (1.66%), and the *4x2 gene duplication (1.42%). Given these frequencies, 34.6% of the individuals were predicted to be intermediate metabolizers (IM) with an enzyme activity score (AS) ≤ 1.0; both the IM phenotype and AS ≤ 1.0 have been found to be associated with PQ therapeutic failure. Furthermore, the allele and genotype frequency distributions add to the archaeological and genomic evidence of Malagasy populations constituting a unique, Asian-African admixed origin. The results from this exploratory study provide fresh insights about genomic characteristics that could affect the metabolism of PQ into its active state, and may enable optimization of PQ treatment across human genetic diversity, which is critical for achieving P. vivax elimination.
Highlights
Five Plasmodium species are known to cause malaria in humans; these are, Plasmodium falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi
The challenges in controlling and eliminating vivax malaria are likely to be related to a number of unique aspects of P. vivax biology (Adams and Mueller, 2017; Bourgard et al, 2018), mainly its ability to relapse from long-lasting, dormant liver stages (Imwong et al, 2007; White, 2011; White and Imwong, 2012; Battle et al, 2014)
These two 8-aminoquinoline drugs are the only likely near-term anti-relapse therapies currently available, their safety and efficacy is severely limited by host genetic variation: patients with a deficiency in glucose-6phosphate dehydrogenase (G6PD) enzyme activity levels can have acute hemolytic anemia (Baird et al, 2018; Baird, 2019; White, 2019)
Summary
Five Plasmodium species are known to cause malaria in humans; these are, Plasmodium falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi. P. vivax has often been regarded as causing a benign self-limiting infection, there is clear evidence that it can cause severe disease and fatality (Baird, 2009; Battle et al, 2012; Baird, 2013). In 2018, the United States Food and Drug Administration approved the use of a new hypnozoitocidal 8-aminoquinoline called tafenoquine (Baird, 2018; White, 2019) These two 8-aminoquinoline drugs are the only likely near-term anti-relapse therapies currently available, their safety and efficacy is severely limited by host genetic variation: patients with a deficiency in glucose-6phosphate dehydrogenase (G6PD) enzyme activity levels can have acute hemolytic anemia (Baird et al, 2018; Baird, 2019; White, 2019). Clinical and laboratory evidence suggested that the efficacy of PQ may depend on genetic variation in cytochrome P450 2D6 (CYP2D6) drugmetabolizing enzyme activity (Baird, 2018; Baird et al, 2018; Baird, 2019)
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