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Genetic architecture of artemisinin-resistant Plasmodium falciparum.

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.

SUBMITTER: Miotto O

PROVIDER: S-EPMC4545236 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Genetic architecture of artemisinin-resistant Plasmodium falciparum.

Miotto Olivo O Amato Roberto R Ashley Elizabeth A EA MacInnis Bronwyn B Almagro-Garcia Jacob J Amaratunga Chanaki C Lim Pharath P Mead Daniel D Oyola Samuel O SO Dhorda Mehul M Imwong Mallika M Woodrow Charles C Manske Magnus M Stalker Jim J Drury Eleanor E Campino Susana S Amenga-Etego Lucas L Thanh Thuy-Nhien Nguyen TN Tran Hien Tinh HT Ringwald Pascal P Bethell Delia D Nosten Francois F Phyo Aung Pyae AP Pukrittayakamee Sasithon S Chotivanich Kesinee K Chuor Char Meng CM Nguon Chea C Suon Seila S Sreng Sokunthea S Newton Paul N PN Mayxay Mayfong M Khanthavong Maniphone M Hongvanthong Bouasy B Htut Ye Y Han Kay Thwe KT Kyaw Myat Phone MP Faiz Md Abul MA Fanello Caterina I CI Onyamboko Marie M Mokuolu Olugbenga A OA Jacob Christopher G CG Takala-Harrison Shannon S Plowe Christopher V CV Day Nicholas P NP Dondorp Arjen M AM Spencer Chris C A CC McVean Gilean G Fairhurst Rick M RM White Nicholas J NJ Kwiatkowski Dominic P DP

Nature genetics 20150119 3

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 ...[more]

PMID: 25599401

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Project description:BackgroundArtemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.MethodsIn two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.ResultsWe studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.ConclusionsP. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)

Dataset Information

Genetic architecture of artemisinin-resistant Plasmodium falciparum.

Publications

Genetic architecture of artemisinin-resistant Plasmodium falciparum.

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