Point mutations in the Plasmodium falciparum cg2 gene, polymorphism of thekappa repeat region, and their relationship with chloroquine resistance

Based on the available DNA sequence data of the Plasmodium falciparum cg2 g ene, we have hypothesized that 3 amino-acid substitutions, His275Gln, Gly28 1Ala, and His299Gln, may represent the key mutations that confer resistance to chloroquine. The presence of 14 tandemly repeated hexamer units in the kappa region has also been suggested to be indicative of chloroquine resist ance. These 2 hypotheses were tested by determining the sequence of DNA fra gments containing all 3 codons and kappa repetitive region (approximately 4 50-basepairs) for 53 randomly selected clinical isolates (obtained in Camer oon in 1994-97) with known response in vivo and/or in vitro to chloroquine. The cg2 genotypes based on the 3 codons and the response in vitro to chlor oquine, as well as the number of kappa repeat units and responses in vivo a nd in vitro to chloroquine, were associated (P < 0.05). cg2 gene mutations were more common in parasites from patients with failure in vivo. However, this difference did not achieve statistical significance (P = 0.055). The s ensitivity and specificity of the 3 codons and kappa repeat region to predi ct the response in vitro to chloroquine ranged between 75% and 85%. The sen sitivity and specificity of these genetic markers to predict the response i n vivo to chloroquine were of lower values. The kappa repeat region of the clinical isolates is polymorphic but characterized by several conserved fea tures.