Allelic heterogeneity of G6PD deficiency in West Africa and severe malaria susceptibility.
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.
Clark
Taane G
TG
Wellcome Trust Centre for Human Genetics, University of Oxford, UK. tgc@well.ox.ac.uk
Fry
Andrew E
AE
Auburn
Sarah
S
Campino
Susana
S
Diakite
Mahamadou
M
Green
Angela
A
Richardson
Anna
A
Teo
Yik Y
YY
Small
Kerrin
K
Wilson
Jonathan
J
Jallow
Muminatou
M
Sisay-Joof
Fatou
F
Pinder
Margaret
M
Sabeti
Pardis
P
Kwiatkowski
Dominic P
DP
Rockett
Kirk A
KA
D000354:Africa, Western; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D005953:Glycogen Storage Disease Type I / Q000150:complications / Q000235:genetics*; D006801:Humans; D016778:Malaria, Falciparum / Q000150:complications / Q000235:genetics*; D008297:Male; D010963:Plasmodium falciparum; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
D005954:Glucosephosphate Dehydrogenase; C482910:glucose-6-phosphate dehydrogenase A-