A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms

Area of Science:

• Medical Research
• Parasitology
• Genetics

Background:

• Global malaria control efforts are jeopardized by increasing Plasmodium falciparum resistance to artemisinins.
• Mutations in the kelch (K13)-propeller gene domains are identified as key drivers of artemisinin resistance.
• This discovery enables global monitoring of antimalarial drug resistance.

Purpose of the Study:

• To analyze K13-propeller gene sequence polymorphism across a large international sample set.
• To evaluate the geographic distribution, emergence, and spread of K13 mutations associated with artemisinin resistance.
• To assess the clinical and in vitro significance of identified K13 mutations, particularly in Africa.

Main Methods:

• Sequencing of the K13-propeller domain in 14,037 Plasmodium falciparum samples from 59 malaria-endemic countries.
• Analysis of samples primarily from sentinel surveillance sites for antimalarial resistance.
• Haplotyping of neighboring loci to track mutation emergence and dissemination.

Main Results:

• 108 distinct nonsynonymous K13 mutations were identified, exhibiting significant geographic variation.
• Resistance-associated K13 mutations were predominantly found in Southeast Asia (Cambodia, Vietnam, Laos, Thailand, Myanmar, China).
• African K13 mutations, including the common A578S allele, were not linked to artemisinin resistance in vitro or clinically.

Conclusions:

• Artemisinin resistance in Plasmodium falciparum is geographically restricted to Southeast Asia and China.
• The frequently observed African K13 allele A578S does not confer artemisinin resistance.
• Most K13 mutations identified in Africa appear to be evolutionarily neutral regarding artemisinin resistance.