TY - JOUR
T1 - Genetic loci associated with delayed clearance of plasmodium falciparum following artemisinin
AU - Takala-Harrison, Shannon
AU - Clark, Taane G.
AU - Jacob, Christopher G.
AU - Cummings, Michael P.
AU - Miotto, Olivo
AU - Dondorpe, Arjen M.
AU - Fukuda, Mark M.
AU - Nosten, Francois
AU - Noedl, Harald
AU - Imwong, Mallika
AU - Bethell, Delia
AU - Se, Youry
AU - Lon, Chanthap
AU - Tyner, Stuart D.
AU - Saunders, David L.
AU - Socheat, Duong
AU - Ariey, Frederic
AU - Phyo, Aung Pyae
AU - Starzengruber, Peter
AU - Fuehrer, Hans Peter
AU - Swoboda, Paul
AU - Stepniewska, Kasia
AU - Flegg, Jennifer
AU - Arze, Cesar
AU - Cerqueira, Gustavo C.
AU - Silva, Joana C.
AU - Ricklefs, Stacy M.
AU - Porcella, Stephen F.
AU - Stephens, Robert M.
AU - Adams, Matthew
AU - Kenefic, Leo J.
AU - Campino, Susana
AU - Auburn, Sarah
AU - MacInnis, Bronwyn
AU - Kwiatkowskid, Dominic P.
AU - Su, Xin Zhuan
AU - White, Nicholas J.
AU - Ringwald, Pascal
AU - Plowe, Christopher V.
PY - 2013/1/2
Y1 - 2013/1/2
N2 - The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.
AB - The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.
KW - Drug resistance
KW - Genome-wide association
KW - Molecular markers
UR - http://www.scopus.com/inward/record.url?scp=84871944250&partnerID=8YFLogxK
U2 - 10.1073/pnas.1211205110
DO - 10.1073/pnas.1211205110
M3 - Article
C2 - 23248304
AN - SCOPUS:84871944250
SN - 0027-8424
VL - 110
SP - 240
EP - 245
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -