Genetics behind resistance to an antimalarial drug are revealed

The largest genome-wide association study of the malaria parasite Plasmodium falciparum unveils a complex genetic architecture that enables the parasite to develop resistance to the antimalarial drug, artemisinin. The results were recently published in the journal Nature Genetics.

The global research collaboration analyzed 1612 samples from 15 locations in Southeast Asia and Africa, finding 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in four other genes to support artemisinin resistance. The variety of kelch13 mutations associated with artemisinin resistance, with new variants continually emerging, makes it difficult to use this gene alone as a marker for genetic surveillance.

Researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from the nations of Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, scientists found that the distributions of different kelch13 mutations are localized within relatively well-defined geographical areas. While artemisinin-resistant parasites do appear to have migrated across national borders, this only happened on a limited scale and, in fact, the most widespread kelch13 mutation, C580Y, appeared to have emerged independently on several occasions. Notably, parasites along the Thailand-Myanmar border appear to have acquired this mutation separately from those in Cambodia and Vietnam. Crucially, parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

Mutations in the kelch13 gene were present, yet rare, in Africa but weren't associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa where most malaria deaths occur.