TY - JOUR
T1 - Differences in selective pressure on dhps and dhfr drug resistant mutations in western Kenya
AU - McCollum, Andrea M.
AU - Schneider, Kristan A.
AU - Griffing, Sean M.
AU - Zhou, Zhiyong
AU - Kariuki, Simon
AU - Ter-Kuile, Feiko
AU - Shi, Ya Ping
AU - Slutsker, Laurence
AU - Lal, Altaf A.
AU - Udhayakumar, Venkatachalam
AU - Escalante, Ananias A.
N1 - Funding Information:
Financial support from the CDC Antimicrobial Resistance Working Group and support from the Atlanta Research and Education Foundation (Atlanta, GA) are appreciated. AE and KS are supported by the grant R01GM084320 from the US National Institute of Health. SMG was supported by a National Science Foundation Graduate Research Fellowship. We thank the CDC Biotechnology Core Facility for the use the PSQ MA96 system for pyrosequencing. This paper is published with the permission of KEMRI Director. The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
PY - 2012
Y1 - 2012
N2 - Background: Understanding the origin and spread of mutations associated with drug resistance, especially in the context of combination therapy, will help guide strategies to halt and prevent the emergence of resistance. Unfortunately, studies have assessed these complex processes when resistance is already highly prevalent. Even further, information on the evolutionary dynamics leading to multidrug-resistant parasites is scattered and limited to areas with low or seasonal malaria transmission. This study describes the dynamics of strong selection for mutations conferring resistance against sulphadoxine-pyrimethamine (SP), a combination therapy, in western Kenya between 1992 and 1999, just before SP became first-line therapy (1999). Importantly, the study is based on longitudinal data, which allows for a comprehensive analysis that contrasts with previous cross-sectional studies carried out in other endemic regions. Methods. This study used 236 blood samples collected between 1992 and 1999 in the Asembo Bay area of Kenya. Pyrosequencing was used to determine the alleles of dihydrofolate reductase (dhfr) and dihydropterote synthase (dhps) genes. Microsatellite alleles spanning 138 kb around dhfr and dhps, as well as, neutral markers spanning approximately 100 kb on chromosomes 2 and 3 were characterized. Results: By 1992, the South-Asian dhfr triple mutant was already spreading, albeit in low frequency, in this holoendemic Kenyan population, prior to the use of SP as a first-line therapy. Additionally, dhfr triple mutant alleles that originated independently from the predominant Southeast Asian lineage were present in the sample set. Likewise, dhps double mutants were already present as early as 1992. There is evidence for soft selective sweeps of two dhfr mutant alleles and the possible emergence of a selective sweep of double mutant dhps alleles between 1992 and 1997. The longitudinal structure of the dataset allowed estimation of selection pressures on various dhfr and dhps mutants relative to each other based on a theoretical model tailored to P. falciparum. The data indicate that drug selection acted differently on the resistant alleles of dhfr and dhps, as evidenced by fitness differences. Thus a combination drug therapy such as SP, by itself, does not appear to select for "multidrug"-resistant parasites in areas with high recombination rate. Conclusions: The complexity of these observations emphasizes the importance of population-based studies to evaluate the effects of strong drug selection on Plasmodium falciparum populations.
AB - Background: Understanding the origin and spread of mutations associated with drug resistance, especially in the context of combination therapy, will help guide strategies to halt and prevent the emergence of resistance. Unfortunately, studies have assessed these complex processes when resistance is already highly prevalent. Even further, information on the evolutionary dynamics leading to multidrug-resistant parasites is scattered and limited to areas with low or seasonal malaria transmission. This study describes the dynamics of strong selection for mutations conferring resistance against sulphadoxine-pyrimethamine (SP), a combination therapy, in western Kenya between 1992 and 1999, just before SP became first-line therapy (1999). Importantly, the study is based on longitudinal data, which allows for a comprehensive analysis that contrasts with previous cross-sectional studies carried out in other endemic regions. Methods. This study used 236 blood samples collected between 1992 and 1999 in the Asembo Bay area of Kenya. Pyrosequencing was used to determine the alleles of dihydrofolate reductase (dhfr) and dihydropterote synthase (dhps) genes. Microsatellite alleles spanning 138 kb around dhfr and dhps, as well as, neutral markers spanning approximately 100 kb on chromosomes 2 and 3 were characterized. Results: By 1992, the South-Asian dhfr triple mutant was already spreading, albeit in low frequency, in this holoendemic Kenyan population, prior to the use of SP as a first-line therapy. Additionally, dhfr triple mutant alleles that originated independently from the predominant Southeast Asian lineage were present in the sample set. Likewise, dhps double mutants were already present as early as 1992. There is evidence for soft selective sweeps of two dhfr mutant alleles and the possible emergence of a selective sweep of double mutant dhps alleles between 1992 and 1997. The longitudinal structure of the dataset allowed estimation of selection pressures on various dhfr and dhps mutants relative to each other based on a theoretical model tailored to P. falciparum. The data indicate that drug selection acted differently on the resistant alleles of dhfr and dhps, as evidenced by fitness differences. Thus a combination drug therapy such as SP, by itself, does not appear to select for "multidrug"-resistant parasites in areas with high recombination rate. Conclusions: The complexity of these observations emphasizes the importance of population-based studies to evaluate the effects of strong drug selection on Plasmodium falciparum populations.
KW - Dihydrofolate Reductase
KW - Dihydropterote synthase
KW - Drug resistance
KW - Malaria
KW - Natural selection
KW - Plasmodium
KW - Selective sweep
KW - Sulphadoxine-pyrimethamine
UR - http://www.scopus.com/inward/record.url?scp=84862819556&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862819556&partnerID=8YFLogxK
U2 - 10.1186/1475-2875-11-77
DO - 10.1186/1475-2875-11-77
M3 - Article
C2 - 22439637
AN - SCOPUS:84862819556
SN - 1475-2875
VL - 11
JO - Malaria journal
JF - Malaria journal
M1 - 77
ER -