CYP2D6 Genetic Variation and Its Implication for Vivax Malaria Treatment in Madagascar

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.

Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax

“…(A) Predicted incidence of P. vivax in 2017 [incidence in cases per 1,000 people per year are shown on a spectrum of white (zero incidence) to dark grey (1 case per 1,000) and then blue to red (>1 case per 1,000 to >600 cases per 1,000)] (Battle et al, 2019). (B) Map of the median predicted allele frequency of G6PDd (Howes et al, 2012), and CYP2D6 metabolizer status by country and/or ethnicity (selected sample represented) (Dodgen et al, 2016;Leitão et al, 2020;Spring et al, 2020;Koopmans et al, 2021;Mehlotra et al, 2021). Maps used with permission from the Malaria Atlas Project (https://malariaatlas.org).…”

CYP2D6 Gene Resequencing in the Malagasy, a Population at the Crossroads between Asia and Africa: A Pilot Study

“…Recently, for the first time, the authors investigated CYP2D6 genetic variation in Madagascar [ 29 ], an island nation in the Indian Ocean, approximately 400 km (250 miles) off the East African coast. There, vivax malaria is endemic [ 32 ], and PQ could be deployed to support efforts toward national malaria elimination [ 33 ].…”

“…In addition, the Malagasy populations offer a unique, rich admixture history between Southeast Asian and East African ancestral populations and the potential of harboring novel variants and/or combinations of known variants [ 34–38 ]. In a recent study by the authors [ 29 ], using commercially available TaqMan™ genotyping assays on a custom-designed OpenArray (Thermo Fisher Scientific, MA, USA), 211 samples were genotyped for 29 single-nucleotide polymorphisms (SNPs) and interrogated for the presence of CNVs including the CYP2D6*5 gene deletion, duplications, hybrid genes and tandem arrangements [ 39–42 ]. Nine star alleles were detected ( CYP2D6*2 , *4 , *10 , *17 , *29 , *40 , *41 , *45 and *100 ).…”

“…Nine star alleles were detected ( CYP2D6*2 , *4 , *10 , *17 , *29 , *40 , *41 , *45 and *100 ). In addition, the CYP2D6*5 gene deletion, gene duplications ( CYP2D6*1 x2, *2 x2, *4 x2 and *35 x2) and alleles with tandem arrangements ( CYP2D6*36 + *10 and *36 x2 + *10 ) were found in the studied Malagasy [ 29 ].…”

“…In the present study, the authors applied a locus-specific gene sequencing approach to further characterize the CYP2D6 variation in Madagascar and compare it with the OpenArray genotype data. In the authors’ initial study [ 29 ], a discrete set of CYP2D6 alleles was tested, covering many commonly observed variants across populations; the allele selection was, however, limited, as there are no predesigned TaqMan genotyping assays for numerous variants of potential interest. Being a unique population, it is likely that some of the individuals may have undetected rare or novel alleles, which may or may not be functionally relevant.…”