Abstract
X-linked Glucose-6-phosphate dehydrogenase (G6PD) A- deficiency is prevalent in sub-Saharan Africa populations, and has been associated with protection from severe malaria. Whether females and/or males are protected by G6PD deficiency is uncertain, due in part to G6PD and malaria phenotypic complexity and misclassification. Almost all large association studies have genotyped a limited number of G6PD SNPs (e.g. G6PD202 / G6PD376), and this approach has been too blunt to capture the complete epidemiological picture. Here we have identified 68 G6PD polymorphisms and analysed 29 of these (i.e. those with a minor allele frequency greater than 1%) in 983 severe malaria cases and controls in Tanzania. We establish, across a number of SNPs including G6PD376, that only female heterozygotes are protected from severe malaria. Haplotype analysis reveals the G6PD locus to be under balancing selection, suggesting a mechanism of protection relying on alleles at modest frequency and avoiding fixation, where protection provided by G6PD deficiency against severe malaria is offset by increased risk of life-threatening complications. Our study also demonstrates that the much-needed large-scale studies of severe malaria and G6PD enzymatic function across African populations require the identification and analysis of the full repertoire of G6PD genetic markers.
Highlights
Amongst the approximately 190 genetic variants causing clinical deficiency of Glucose-6-phosphate dehydrogenase (G6PD) that have been characterised [1], the A- deficiency is the most common in sub-Saharan Africa populations, and is associated with protection from severe malaria [2,3]
Numerous genetic variants of G6PD, residing in the X chromosome, are found among African populations: mutations causing A- deficiency can lead to serious clinical outcomes and confer protection against severe malaria
In this study we analysed more than 30 G6PD genetic markers in 506 Tanzanian children with severe malaria and 477 without malaria
Summary
Amongst the approximately 190 genetic variants causing clinical deficiency of Glucose-6-phosphate dehydrogenase (G6PD) that have been characterised [1], the A- deficiency is the most common in sub-Saharan Africa populations, and is associated with protection from severe malaria [2,3]. Establishing whether malaria patients are G6PD deficient is important because of the potential use of 8-aminoquinoline drugs (e g, primaquine and its derivatives) for malaria elimination in sub-Saharan Africa [4]. Whilst genotyping approaches have been advocated, there is evidence of extensive diversity at the G6PD locus (X chromosome, 16.2kb), with more than 150 single nucleotide polymorphisms (SNPs) reported [1]. Many of these known genetic variants result in amino acid changes and have been detected through sequencing the G6PD gene locus in enzyme deficient individuals. The genetic variability in G6PD and IKBKG is complex [7], and new alleles are still being discovered, making a simple G6PD genetic approach unreliable [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
