DOI: 10.1097/im9.0000000000000224 ISSN: 2641-5917

Genetic Diversity of the PfATPase6 Gene in African Plasmodium falciparum Isolates from Available Studies: A Systematic Review and Meta-analysis of the E431K Mutation

Austine Atokolo, Yemisi D. Obafemi, Emmanuel O. Mameh, Elizabeth Q. Sule, Mayowa Agbi, Samuel A. Oyegbade, Solomon U. Oranusi
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Background and aim:

Long-term effectiveness of artemisinin-combination therapies (ACTs) in Africa relies on molecular monitoring of resistance. PfATPase6, a sarco/endoplasmic reticulum calcium-ATPase implicated in artemisinin pharmacology, exhibits several recurrent nonsynonymous polymorphisms, of which E431K is the most widespread in African Plasmodium falciparum isolates. Systematic reviews and meta-analyses of pooled prevalence of E431K or synthesized genetic diversity of PfATPase6 across Africa are lacking.

Methods:

This PRISMA 2020-compliant systematic review and meta-analysis was prospectively registered with PROSPERO (CRD420261413281). Five databases were searched for studies reporting PfATPase6 polymorphisms in P. falciparum isolates of African origin, including null results. The pooled prevalence of E431K was calculated using a random effects model with Freeman-Tukey double arcsine transformation, with predefined subregional subgroup analyses.

Results:

Fourteen studies met the inclusion criteria for systematic review; seven, comprising 706 genotyped isolates, were eligible for meta-analysis. The pooled E431K prevalence was 15.2% (95% CI: 12.7%–18.0%), with minimal between-study heterogeneity (I² = 0.0%). Subgroup estimates were comparable across East Africa (16.8%), West Africa (16.0%), and Central Africa (13.3%), with no significant inter-regional differences ( P = 0.713). Qualitative synthesis revealed a heterogeneous PfATPase6 mutational landscape; S769N was nearly absent.

Conclusions:

Among the seven eligible study populations, this study provides a pooled prevalence estimate for PfATPase6 E431K; given its limited, geographically uneven coverage, this finding should not be generalized to P. falciparum populations across Africa. While E431K is not yet an established marker of artemisinin resistance, its prevalence and broad distribution support continued genotype-phenotype investigation rather than immediate inclusion in ACT resistance surveillance systems.

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