Genetic architecture of artemisinin-resistant Plasmodium falciparum

Olivo Miotto, Roberto Amato, Elizabeth A. Ashley, Bronwyn Macinnis, Jacob Almagro-Garcia, Chanaki Amaratunga, Pharath Lim, Daniel Mead, Samuel O. Oyola, Mehul Dhorda, Mallika Imwong, Charles Woodrow, Magnus Manske, Jim Stalker, Eleanor Drury, Susana Campino, Lucas Amenga-Etego, Thuy Nhien Nguyen Thanh, Hien Tinh Tran, Pascal RingwaldDelia Bethell, Francois Nosten, Aung Pyae Phyo, Sasithon Pukrittayakamee, Kesinee Chotivanich, Char Meng Chuor, Chea Nguon, Seila Suon, Sokunthea Sreng, Paul N. Newton, Mayfong Mayxay, Maniphone Khanthavong, Bouasy Hongvanthong, Ye Htut, Kay Thwe Han, Myat Phone Kyaw, Md Abul Faiz, Caterina I. Fanello, Marie Onyamboko, Olugbenga A. Mokuolu, Christopher G. Jacob, Shannon Takala-Harrison, Christopher V. Plowe, Nicholas P. Day, Arjen M. Dondorp, Chris C.A. Spencer, Gilean Mcvean, Rick M. Fairhurst, Nicholas J. White, Dominic P. Kwiatkowski

Research output: Contribution to journalArticlepeer-review

441 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)226-234
Number of pages9
JournalNature Genetics
Volume47
Issue number3
DOIs
Publication statusPublished - 25 Feb 2015
Externally publishedYes

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