Questions over high frequency of mutant PfATP6 haplotypes in traveller isolates
© Woodrow et al.; license Biomed Central Ltd. 2012
Received: 17 May 2012
Accepted: 1 June 2012
Published: 8 June 2012
A recent paper in Malaria Journal suggests that a high proportion of Plasmodium falciparum isolates found in travellers returning from a range of African countries carry the PfATP6 A623E S769N haplotype, and that this genotype is associated with artemether resistance. Such a finding would represent a substantial departure from the extensive literature reporting these individual mutations to be very rare, with the double mutation never documented. The number of isolates screened to obtain these double mutants is unstated, but highly relevant, not least because selection of isolates could have introduced significant confounders, such as timing of in vitro testing. An additional concern relates to the location of sequencing primers used to assess these positions. In the absence of clear information on these fundamental questions it would be appropriate to treat the findings with caution.
Previous publications on prevalence of the A623E and S769N polymorphisms in the countries described by Pillai et al.
The finding of A623E S769N double mutants in 11 of 28 patients in one centre is, therefore, highly unexpected. The authors propose that natural selection for these polymorphisms may be taking place in the countries of origin for these parasites, because of the rapid scale up of anti-malarial treatment programmes being implemented in recent years. However, before natural selection is invoked, a much more basic concern needs to be addressed, namely selection of isolates in the laboratory. It is notable that the median date of receipt for the mutant isolates was around 500 days before that of the wild-type samples (according to the supplementary data). This is of profound methodological importance since use of wild-type controls with different properties to the mutant population (such as date of assay) would introduce a significant confounder. How many isolates were screened to obtain the final 11 double mutants? And how were the wild-type controls selected?
In the absence of clear information on these fundamental questions it would be appropriate to treat the findings and conclusions of the article with caution.
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