Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia
Takala-Harrison S., Clark TG., Jacob CG., Cummings MP., Miotto O., Dondorp AM., Fukuda MM., Nosten F., Noedl H., Imwong M., Bethell D., Se Y., Lon C., Tyner SD., Saunders DL., Socheat D., Ariey F., Phyo AP., Starzengruber P., Fuehrer H-P., Swoboda P., Stepniewska K., Flegg J., Arze C., Cerqueira GC., Silva JC., Ricklefs SM., Porcella SF., Stephens RM., Adams M., Kenefic LJ., Campino S., Auburn S., MacInnis B., Kwiatkowski DP., Su X-Z., White NJ., Ringwald P., Plowe CV.
The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum -specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.