Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border

Zenglei Wang, Mynthia Cabrera, Jingyun Yang, Lili Yuan, Bhavna Gupta, Xiaoying Liang, Karen Kemirembe, Sony Shrestha, Awtum Brashear, Xiaolian Li, Stephen F. Porcella, Jun Miao, Zhaoqing Yang, Xin Zhuan Su, Liwang Cui

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Abstract

Drug resistance has emerged as one of the greatest challenges facing malaria control. The recent emergence of resistance to artemisinin (ART) and its partner drugs in ART-based combination therapies (ACT) is threatening the efficacy of this front-line regimen for treating Plasmodium falciparum parasites. Thus, an understanding of the molecular mechanisms that underlie the resistance to ART and the partner drugs has become a high priority for resistance containment and malaria management. Using genome-wide association studies, we investigated the associations of genome-wide single nucleotide polymorphisms with in vitro sensitivities to 10 commonly used antimalarial drugs in 94 P. falciparum isolates from the China-Myanmar border area, a region with the longest history of ART usage. We identified several loci associated with various drugs, including those containing pfcrt and pfdhfr. Of particular interest is a locus on chromosome 10 containing the autophagy-related protein 18 (ATG18) associated with decreased sensitivities to dihydroartemisinin, artemether and piperaquine-an ACT partner drug in this area. ATG18 is a phosphatidylinositol-3-phosphate binding protein essential for autophagy and recently identified as a potential ART target. Further investigations on the ATG18 and genes at the chromosome 10 locus may provide an important lead for a connection between ART resistance and autophagy.

Original languageEnglish (US)
Article number33891
JournalScientific reports
Volume6
DOIs
StatePublished - Oct 3 2016

All Science Journal Classification (ASJC) codes

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    Wang, Z., Cabrera, M., Yang, J., Yuan, L., Gupta, B., Liang, X., Kemirembe, K., Shrestha, S., Brashear, A., Li, X., Porcella, S. F., Miao, J., Yang, Z., Su, X. Z., & Cui, L. (2016). Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border. Scientific reports, 6, [33891]. https://doi.org/10.1038/srep33891