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London School of Hygiene & Tropical Medicine Malaria Centre

Malaria research in parasite biology

Estimating selection on Plasmodium falciparum drug resistance alleles in an endemic population over a 25 year period.

LSHTM investigators:
David Conway, Paul Milligan, Colin Sutherland & Brian Greenwood.
External collaborators:
Davis Nwakanma, Eniyou Ereiro, Alfred Amambua-Ngwa & Margaret Pinder (Medical Research Council, The Gambia).
Funding body:
Medical Research Council, UK.

Using archived blood samples, we surveyed drug resistance polymorphisms in The Gambia over a 25 year period from 1984 when resistance was unknown locally through periods of gradual failure of chloroquine therapy and increasing use of sulphadoxine-pyrimethamine until eventual introduction of artemisinin combination therapy.

At the first survey there were no drug resistance alleles detected at two of the loci (crt and dhps) and very few isolates contained resistance alleles at the other two loci (mdr1 and dhfr). Proportions of isolates with resistance alleles increased progressively over subsequent surveys, reaching peaks for the chloroquine resistance alleles crt 76T (76%) and mdr1 86N (78%) in the year 2000, and for antifolate resistance dhfr alleles (94%, mostly as a triple combination of 51I, 59C and 108N) and dhps 437G (86%) in 2007 and 2008 respectively. To analyse allele frequencies, we counted one allele at each locus per isolate, and estimated 95% confidence intervals. Changes in allele frequencies occurred at different times and rates over the period, and the data fit closely a very simple model for each locus with assumed fitness costs and a change in selection coefficients reflecting historical change in therapeutic use. We are exploring the fit between these historical selection data and signatures of selection at these loci derived from genome wide polymorphism data in a population sample taken at the end of the period.