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.

Fig. 1. schematic representation of the three genes, Pfnhe 1, Pfmdr 1 and Pfcrt , respectively, associated with chloroquine resistance in Plasmodium falciparum . The red boxes depict exons.

Fig. 2. : location of the ~100 Kb segment present in the seventh chromosome of Plasmodium falciparum harbouring the transporter genes, Pfcrt and var gene. Further ~36 Kb segment is highlighted encompassing the eight transporter genes including the Pfcrt gene and a more schematic view of the Pfcrt gene with its 13 exons and the K76T mutation is highlighted. The five amino acids present from 72-76 position in exon 2 characterise the resistant (CVIET and SVMNT) and sensitive (CVMNK) chloroquine resistance Pfcrt haplotypes.