Genome-wide studies to identify markers of artemisinin-resistant malaria

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DESCRIPTION (provided by applicant): Highly effective artemisinin-based antimalarial drugs are used worldwide and have contributed to reductions in the malaria burden in many areas. Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia and its potential spread threatens to reverse recent gains against malaria and to abort plans for a renewed global eradication campaign. Ongoing efforts to contain artemisinin-resistant malaria are hampered by the lack of tools to gauge the extent and direction of its spread. Presently, only laborious clinical trials can reliably measure resistance. A molecular assay to detect markers of artemisinin resistance would be a highly valuable surveillance tool, but the genetic basis of resistance is unknown. We propose genome-wide association studies (GWAS) that aim to identify molecular markers that can be used to track and contain artemisinin-resistant parasites before they spread globally. The work will be accomplished in two aims. First, we will use a dense panel of single nucleotide polymorphisms (SNPs) to map regions of the P. falciparum genome that are associated with artemisinin resistance. To accomplish this, we will use an established SNP- calling pipeline to determine genotypes at ~421,000 SNPs from short-read sequencing data in parasites collected during completed trials of artemisinin efficacy, and we will estimate the association between parasite genotypes and the amount of time it takes to reduce parasitemia by half following artemisinin treatment (i.e. parasite clearance half-life). Associations will be estimated in two independent sample sets, and meta-analysis will be performed to validate genomic regions associated with artemisinin resistance. In the second aim, we will identify and prioritize candidate genes within genomic regions identified in Aim 1 and use next-generation sequencing data to identify polymorphisms within high-priority genes and their association with parasite clearance half-life. If successful, this project will result in the development of a rapid assay to detect candidate markers of artemisinin resistance in subsequent candidate gene association studies, as well as data to begin the functional characterization of candidate genes to better understand the mechanisms underlying resistance.