Genetics of chloroquine-resistant malaria: a haplotypic view

Abstract

The development and rapid spread of chloroquine resistance (CQR) in Plasmodium falciparum have triggered the identification of several genetic target(s) in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76), are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria.

Surveillance of Antimalarial Resistance Molecular Markers in Imported Plasmodium falciparum Malaria Cases in Anhui, China, 2012–2016

“…The pfcrt K76T mutation is the primary determinant of resistance 21,22 and can be enhanced by the pfmdr1 N86Y mutation. 23 These two mutations that present strong linkage disequilibrium, 24 have been reported to be associated also with in vitro responses to chloroquine, mefloquine, lumefantrine, quinine, monodesethylamodiaquine, and DHA. 25 This study reports a modest prevalence of pfcrt K76T and pfmdr1 N86Y mutations.…”

New insights into the evolutionary history of Plasmodium falciparum from mitochondrial genome sequence analyses of Indian isolates

“…; Mallick et al . ) that are often correlated with the drug‐usage patterns and distribution of drug‐resistant P. falciparum parasites (for details see Awasthi & Das ). However, no effort has ever been made to understand genetic properties of Indian P. falciparum populations utilizing genetic markers that have widely being used to infer evolutionary history of species populations (e.g.…”

Prevalence of Mutant Alleles Responsible for Chloroquine Resistance among Plasmodium falciparum Isolates in North Central, Nigeria

“…Resistance to CQ is primarily mediated by the genetic replacement at codon 76 (K76T) of lysine with threonine in the P. falciparum chloroquine resistance transporter gene (pfcrt) which increases efflux of CQ from the digestive vacuole of the parasite thereby rendering the drug ineffective [7]. Polymorphisms in the Plasmodium falciparum multidrug resistance gene-1 (pfmdr1) which encodes the P-glycoprotein homolog, modulates chloroquine resistance in mutant pfcrtharbouring parasites in vitro and impact on the sensitivity multiple antimalarial drugs.…”