Genome-wide Association Analysis Identifies Genetic Loci Associated With Resistance to Multiple Antimalarials in Plasmodium Falciparum From China-Myanmar Border

Sci Rep. 2016 Oct 3;6:33891. doi: 10.1038/srep33891.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / pharmacology*
  • China
  • Drug Resistance / genetics*
  • Genetic Loci*
  • Genome-Wide Association Study
  • Myanmar
  • Plasmodium falciparum / genetics*
  • Polymorphism, Single Nucleotide*
  • Protozoan Proteins / genetics*

Substances

  • Antimalarials
  • Protozoan Proteins