Genetic architecture of artemisinin-resistant Plasmodium falciparum.
Miotto O., Amato R., Ashley EA., MacInnis B., Almagro-Garcia J., Amaratunga C., Lim P., Mead D., Oyola SO., Dhorda M., Imwong M., Woodrow C., Manske M., Stalker J., Drury E., Campino S., Amenga-Etego L., Thanh T-NN., Tran HT., Ringwald P., Bethell D., Nosten F., Phyo AP., Pukrittayakamee S., Chotivanich K., Chuor CM., Nguon C., Suon S., Sreng S., Newton PN., Mayxay M., Khanthavong M., Hongvanthong B., Htut Y., Han KT., Kyaw MP., Faiz MA., Fanello CI., Onyamboko M., Mokuolu OA., Jacob CG., Takala-Harrison S., Plowe CV., Day NP., Dondorp AM., Spencer CCA., McVean G., Fairhurst RM., White NJ., Kwiatkowski DP.
We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.