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GWAS Results Further Illuminate Genetics of Malaria Drug Resistance

NEW YORK (GenomeWeb) – Results of the largest-to-date genome-wide association study of the malaria parasite Plasmodium falciparum have revealed new elements of the genetics underpinning the development of resistance to artemisinin, one of the most effective antimalarial drugs.

According to the authors of the study, published today in Nature Genetics, this better picture of a relatively complex genomic contribution to drug resistance could help improve early detection of its development.

Although artemisinin remains an effective treatment, the study authors wrote, the rate at which these drugs clear malaria parasites from the blood has progressively declined in Southeast Asia for at least five years.

Because resistance to previous frontline drugs spread from this region to Africa, where the majority of malaria deaths occur, the potential for the same to happen with artemisinin is of serious concern.

While previous studies had identified several SNPs in a gene called kelch13 linked to artemisinin resistance, many questions about the genomic causes of emerging resistance have remained, the group wrote. Moreover, because new variants in kelch13 are continually emerging, it is difficult to use this gene alone as a marker for genetic surveillance.

In the study, researchers from several international groups set out to try to capture additional players in the genetic contribution to resistance to artemisinin, analyzing a total of 1,612 samples from 15 different locations — in Cambodia, Vietnam, Laos, Thailand, Myanmar, Bangladesh, Democratic Republic of the Congo, and Nigeria — using an Illumina whole-genome sequencing approach.

The GWAS identified strong signals of association at nine independent loci and further analysis identified 20 resistance alleles resulting from mutations in the kelch13 gene, as well as several novel background mutations that appear to work in concert with kelch13 variants to support artemisinin resistance.

According to the authors, their results suggest that the newly-identified background mutations — nonsynonymous polymorphisms in the fd, arps10, mdr2, and crt genes — may not on their own confer much resistance to artemisinin, but rather indicate an atmosphere of sensitivity to the development of further resistance mutations in kelch13.

"Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance until mutations occurred in the kelch13 gene," Roberto Amato, a first author of the study and a research associate at Oxford University's Wellcome Trust Centre for Human Genetics, said in a statement.

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

This suggests that monitoring parasite populations for the presence of these mutations in fd, arps10, mdr2, and crt could serve as a kind of early warning system for the risk of developing resistance. The presence of a background mutation would indicate whether a particular strain in a particular location is predisposed toward developing new resistance-causing mutations in kelch13. This could allow researchers to target high-risk regions even before resistant parasites take hold, the authors reported.

In the study, the researchers also analyzed the GWAS results to compare populations from different areas, and found the kelch13 mutations they identified appeared to localize to well-defined geographic areas.

The data also revealed that the migration of particular parasite populations across national borders was fairly rare, and that some of the same kelch13 mutations appear to have developed independently in different locations in the presence of similar predisposing background mutations. This suggests that spread of resistance is due less to the geographic spread of resistant parasites, and more to independent emergence of new resistance mutations.

According to the study authors, many important questions remain, including the precise biological role of the identified background mutations — whether they directly affect drug resistance, or only provide an environment in which later resistance mutations can develop.

"Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect, Olivo Miotto, another first author of the study and an informatics fellow at the Mahidol-Oxford Tropical Medicine Research Unit in Bangkok, said in a statement.

Interestingly, the research also found that kelch13 mutations were rare in the samples from the two African locations, and were not associated with artemisinin resistance in those parasite populations. The African samples also lacked the genetic background mutations present in the artemisinin-resistant parasites from Southeast Asia.

If the hypothesis that these background alterations are necessary for drug-resistance kelch13 mutations to flourish is true, these data may be encouraging for public health workers concerned about the spread of artemisinin resistance to Africa.

However, the authors wrote, the situation might change, underscoring the importance of better understanding the genetic mechanisms that underlie the development of drug resistance in malaria parasites.