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Spatial distribution of G6PD deficiency variants across malaria-endemic regions

Rosalind E Howes1*, Mewahyu Dewi2, Frédéric B Piel3, Wuelton M Monteiro45, Katherine E Battle1, Jane P Messina1, Anavaj Sakuntabhai6, Ari W Satyagraha7, Thomas N Williams89, J Kevin Baird102 and Simon I Hay1

Author Affiliations

1 Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, South Parks Road, Oxford, UK

2 Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, Indonesia

3 Evolutionary Ecology of Infectious Disease Group, Department of Zoology, University of Oxford, South Parks Road, Oxford, UK

4 Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil

5 University of the State of Amazonas, Manaus, Amazonas, Brazil

6 Institut Pasteur, Unité de Génétique Fonctionnelle des Maladies Infectieuses, Paris, France

7 Eijkman Institute for Molecular Biology, Jakarta, Indonesia

8 Kenya Medical Research Institute/Wellcome Trust Programme, Centre for Geographic Medicine Research-Coast, Kilifi District Hospital, Kilifi, Kenya

9 Department of Medicine, Imperial College, St Mary’s Hospital, London, UK

10 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

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Malaria Journal 2013, 12:418  doi:10.1186/1475-2875-12-418

Published: 15 November 2013

Abstract

Background

Primaquine is essential for malaria control and elimination since it is the only available drug preventing multiple clinical attacks by relapses of Plasmodium vivax. It is also the only therapy against the sexual stages of Plasmodium falciparum infectious to mosquitoes, and is thus useful in preventing malaria transmission. However, the difficulties of diagnosing glucose-6-phosphate dehydrogenase deficiency (G6PDd) greatly hinder primaquine’s widespread use, as this common genetic disorder makes patients susceptible to potentially severe and fatal primaquine-induced haemolysis. The risk of such an outcome varies widely among G6PD gene variants.

Methods

A literature review was conducted to identify surveys of G6PD variant frequencies among representative population groups. Informative surveys were assembled into two map series: (1) those showing the relative proportions of the different variants among G6PDd individuals; and (2) those showing allele frequencies of G6PD variants based on population surveys without prior G6PDd screening.

Results

Variants showed conspicuous geographic patterns. A limited repertoire of variants was tested for across sub-Saharan Africa, which nevertheless indicated low genetic heterogeneity predominated by the G6PD A-202A mutation, though other mutations were common in western Africa. The severe G6PD Mediterranean variant was widespread across western Asia. Further east, a sharp shift in variants was identified, with high variant heterogeneity in the populations of China and the Asia-Pacific where no single variant dominated.

Conclusions

G6PD variants exhibited distinctive region-specific distributions with important primaquine policy implications. Relative homogeneity in the Americas, Africa, and western Asia contrasted sharply with the heterogeneity of variants in China, Southeast Asia and Oceania. These findings will inform rational risk assessments for primaquine in developing public health strategies for malaria control and elimination, and support the future development of regionally targeted policies. The major knowledge gaps highlighted here strongly advocate for further investigation of G6PD variant diversity and their primaquine-sensitivity phenotypes.

Keywords:
Glucose-6-phosphate dehydrogenase deficiency; G6PD; Genetic variants; Spatial distribution; Primaquine; Plasmodium vivax; Malaria elimination; Haemolysis