Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border.
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.
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Zenglei
Z
Wang
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Mynthia
M
Cabrera
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, USA.|Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA.
Jingyun
J
Yang
Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, Yunnan Province 650500, China.
Lili
L
Yuan
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Bhavna
B
Gupta
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Xiaoying
X
Liang
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Karen
K
Kemirembe
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Sony
S
Shrestha
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Awtum
A
Brashear
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Xiaolian
X
Li
Genomics Unit, Research Technologies Section (RTS), Rocky Mountain Laboratories (RML), NIAID, National Institutes of Health, 904 South 4th Street, Hamilton, MT 59840, USA.
Stephen F
SF
Porcella
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Jun
J
Miao
Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, Yunnan Province 650500, China.
Zhaoqing
Z
Yang
Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
Xin-Zhuan
XZ
Su
Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA.
Liwang
L
Cui
D000962:Antimalarials / Q000494:pharmacology*; D002681:China; D004351:Drug Resistance / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D002052:Myanmar; D010963:Plasmodium falciparum / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics*
D000962:Antimalarials; D015800:Protozoan Proteins
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