Mutations in key gene drive malaria drug resistance

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.