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Mutations in key gene drive malaria drug resistance

26 January 2015
Appeared in BioNews 787

The resistance of the malaria parasite, Plasmodium falciparum, to artemisinin, one of the most effective antimalarial drugs, has been partially unravelled in a Nature Genetics study.

The rapid rise of artemisinin resistance, especially in South East Asia, is of growing concern and these new findings have the potential to help health authorities predict the progress of future outbreaks.

An international team of scientists, led by Professor Dominic Kwiatkowski, of the University of Oxford and the Wellcome Trust Sanger Institute, analysed 1,612 samples from 15 locations across South East Asia and Africa in a genome-wide association study.

In particular, they identified  20 mutations in the kelch13 gene which were associated with resistance to artemisinin treatment. While kelch13 is thought to be the most important gene driving drug resistance, the scientists discovered that mutations in kelch13 are more likely to emerge when mutations in four other genes are present.

Dr Roberto Amato, first author on the paper, explained: 'Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance - until mutations occurred in the kelch13 gene.'

'It's similar to what we see with pre-cancerous cells that accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.'

The scientists say that the identification of background mutations is an important development. As the number of kelch13 variants associated with resistance continues to rise, it becomes increasingly difficult to use this gene alone as a marker for genetic surveillance.

Now, researchers might be able to monitor the genetic background in the hope of identifying parasite populations most likely to become resistant.

Co-author Professor Nick Day, Director of the Mahidol-Oxford Tropical Medicine Research Unit in Thailand, said: 'We are at a pivotal point for malaria control. While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.'

Chloroquine, the first effective anti-malarial drug, was introduced in the late 1940s. But chloroquine and several subsequent treatments have been rendered useless in some parts of the world by the capacity of the malaria parasite to develop resistance. Each time this has happened, the resistant strains emerged in South East Asia.

Genetic architecture of artemisinin-resistant Plasmodium falciparum
Nature Genetics |  19 January 2015
Genetics of malaria drug resistance revealed
BBC News |  19 January 2015
GWAS Results Further Illuminate Genetics of Malaria Drug Resistance
Genomeweb |  19 January 2015
New light on genetics of antimalarial drug resistance
Wellcome Trust Centre for Human Genetics (press release) |  19 January 2015
Understanding Antimalarial Drug Resistance
The Scientist |  21 January 2015
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