Linkage disequilibrium between two chromosomally distinct loci associated with increased resistance to chloroquine in Plasmodium falciparum

<jats:p>Chloroquine-resistance in <jats:italic>Plasmodium falciparum</jats:italic> is associated with polymorphisms in a locus on or near the <jats:italic>cg2</jats:italic> gene on chromosome 7, and in the <jats:italic>pfmdr1</jats:italic> gene on chromosome 5. In this study we typed <jats:italic>P. falciparum</jats:italic> DNA from uncomplicated malaria cases in The Gambia in 1990, 1995 and 1996 for size polymorphism in the omega repeat of <jats:italic>cg2</jats:italic>, for sequence polymorphisms in <jats:italic>pfmdr1</jats:italic> at codons 86 and 184, in <jats:italic>dhfr</jats:italic> at codon 108 and in the <jats:italic>msp2</jats:italic> gene. Chloroquine sensitivity tests were conducted <jats:italic>in vitro</jats:italic>. A significant but incomplete association was found between the presence of the <jats:italic>cg2</jats:italic> Dd2-like omega repeat size polymorphism and <jats:italic>in vitro</jats:italic> resistance, and between the tyr-86 allele of <jats:italic>pfmdr1</jats:italic> and <jats:italic>in vitro</jats:italic> resistance. Furthermore there was strong linkage disequilibrium between the <jats:italic>pfmdr1</jats:italic> asn-86 allele and the <jats:italic>cg2</jats:italic> not Dd2-like omega repeat allele located on different chromosomes. In contrast, no linkage disequilibrium was found between these alleles and either the <jats:italic>dhfr</jats:italic> ser-108 allele or the <jats:italic>msp2</jats:italic> IC sequence polymorphism. No significant linkage was measured between <jats:italic>pfmdr1</jats:italic> asn-86 and phe-184 although these loci are separated only by 296 base pairs. Our results suggest that genetic elements linked to the <jats:italic>cg2</jats:italic> and the <jats:italic>pfmdr1</jats:italic> genes are important determinants of chloroquine resistance. It can be concluded that the observed linkage disequilibrium is maintained epistatically through selection by chloroquine.</jats:p>