Genetic architecture of artemisinin-resistant Plasmodium falciparum View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-03

AUTHORS

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 Ringwald, Delia 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, 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

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. More... »

PAGES

226-234

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ng.3189

DOI

http://dx.doi.org/10.1038/ng.3189

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1045385714

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25599401


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