학술논문
Genetic architecture of artemisinin-resistant Plasmodium falciparum
Document Type
Report
Author
Miotto, Olivo; Amato, Roberto; Ashley, Elizabeth A.; Maclnnis, Bronwyn; Almagro-Garcia, Jacob; Amaralunga, Chanaki; Lim, Pharath; Mead, Daniel; Oyola, Samuel O.; Dhorda, Mehul; Imwong, Mallika; Woodrow, Charles; Manske, Magnus; Stalker, Jim; Drury, Eleanor; Campino, Susana; Amenga-Etego, Lucas; Thanh, Thuy-Nhien Nguyen; Tran, Hien Tinh; Ringwald, Pascal; Bethell, Delia; Nosten, Francois; Phyo, Aung Pyae; Pukrittayakamee, Sasithon; Chotivanich, Kesinee; Chuor, Char Meng; Nguon, Chea; Suon, Seila; Sreng, Sokunthea; Newton, Paul N.; Mayxay, Mayfong; Khanthavong, Maniphone; Hongvanthong, Bouasy; Htut, Ye; Flan, Kay Thwe; Kyaw, Myat Phone; Faiz, Md Abul; Fanello, Caterina I.; Onyamboko, Marie; Mokuolu, Olugbenga A.; Jacob, Christopher G.; Takala-Harrison, Shannon; Plowe, Christopher V.; Day, Nicholas P.; Dondorp, Arjen M.; Spencer, Chris C.A.; McVcan, Gilean; Fairhurst, Rick M.; White, Nicholas J.; Kwiatkowski, Dominic P.
Source
Nature Genetics. March 2015, Vol. 47 Issue 3, p226, 12 p.
Subject
Language
English
ISSN
1061-4036
Abstract
Preventing the spread of P. falciparum resistance to artemisinin derivatives, the frontline drugs for severe and uncomplicated malaria, is an urgent priority for global health (1). Although artemisinin derivatives remain [...]
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 kelch!3 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.
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 kelch!3 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.