Genetic architecture of artemisinin-resistant Plasmodium falciparum.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • March 2015

Published In

Volume / Issue

  • 47 / 3

Start / End Page

  • 226 - 234

PubMed ID

  • 25599401

Pubmed Central ID

  • 25599401

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.3189

Language

  • eng

Conference Location

  • United States