Evolutionary diversity of the pfmdr1 hinge region and association with antimalarial drug resistance mutations post ACT introduction

Abstract

The Plasmodium falciparum multidrug resistance-1 (pfmdr1) gene, which encodes the ABC P-glycoprotein homolog PgH1, accumulates mutations that result in amino acid changes, namely single-nucleotide polymorphisms at codons N86Y, Y184F, and D1246Y, associated with altered parasite susceptibility to multiple antimalarial drugs. Among these antimalarials are compounds used in artemisinin-based combination (ACT) therapies, which combine a fast-acting but rapidly clearing artemisinin with a longer-lasting partner drug. The in vitro susceptibility of each of these drugs varies with the pfmdr1 genotype of the treated parasites.

This study characterized sequence diversity within the pfmdr1 hinge domain and the association with pfmdr1 point mutations at codons 86, 184 and 1246 in population samples from Cameroon, the Democratic Republic of Congo, and Benin, two decades after the introduction of ACTs. The data were evaluated and compared with similar data reported before or during the early implementation of ACT-based treatment strategies.

Among 780 successfully sequenced isolates, a high diversity of Arginine-rich repeats in the hinge domain was observed. A significant correlation between the (Asn-Asp-Asn) 7-2-9 variant and both the 86Y and the 1246Y mutation was observed (p < 0.005, OR = 12.6, respectively). We also uncovered, when examining haplotypes across the N86Y, Y184F, and D1246Y codons, that an accumulation of mutations was inversely correlated with diversity in the hinge region. The data suggest patterns consistent with selective pressure and/or linkage with reduced diversity as a potential result of ACT implementation.