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Several lines of evidence link glucose-6-phosphate dehydrogenase (G6PD) deficiency to protection from severe malaria. Early reports suggested most G6PD deficiency in sub-Saharan Africa was because of the 202A/376G G6PD A- allele, and recent association studies of G6PD deficiency have employed genotyping as a convenient way to determine enzyme status. However, further work has suggested that other G6PD deficiency alleles are relatively common in some regions of West Africa. To investigate the consequences of unrecognized allelic heterogeneity on association studies, in particular studies of G6PD deficiency and malaria, we carried out a case-control analysis of 2488 Gambian children with severe malaria and 3875 controls. No significant association was found between severe malaria and the 202A/376G G6PD A- allele when analyzed alone, but pooling 202A/376G with other deficiency alleles revealed the signal of protection (male odds ratio (OR) 0.77, 95% CI 0.62-0.95, P=0.016; female OR 0.71, 95% CI 0.56-0.89, P=0.004). We have identified the 968C mutation as the most common G6PD A- allele in The Gambia. Our results highlight some of the consequences of allelic heterogeneity, particularly the increased type I error. They also suggest that G6PD-deficient male hemizygotes and female heterozygotes are protected from severe malaria.

Original publication

DOI

10.1038/ejhg.2009.8

Type

Journal article

Journal

European journal of human genetics : ejhg

Publication Date

08/2009

Volume

17

Pages

1080 - 1085

Addresses

Wellcome Trust Centre for Human Genetics, University of Oxford, UK. tgc@well.ox.ac.uk

Keywords

Animals, Humans, Plasmodium falciparum, Malaria, Falciparum, Glycogen Storage Disease Type I, Genetic Predisposition to Disease, Glucosephosphate Dehydrogenase, Severity of Illness Index, Case-Control Studies, Gene Frequency, Genetic Heterogeneity, Polymorphism, Single Nucleotide, Africa, Western, Female, Male, Genetic Linkage