Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.
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ABSTRACT:
SUBMITTER: Clarke GM
PROVIDER: S-EPMC5222559 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.
Clarke Geraldine M GM Rockett Kirk K Kivinen Katja K Hubbart Christina C Jeffreys Anna E AE Rowlands Kate K Jallow Muminatou M Conway David J DJ Bojang Kalifa A KA Pinder Margaret M Usen Stanley S Sisay-Joof Fatoumatta F Sirugo Giorgio G Toure Ousmane O Thera Mahamadou A MA Konate Salimata S Sissoko Sibiry S Niangaly Amadou A Poudiougou Belco B Mangano Valentina D VD Bougouma Edith C EC Sirima Sodiomon B SB Modiano David D Amenga-Etego Lucas N LN Ghansah Anita A Koram Kwadwo A KA Wilson Michael D MD Enimil Anthony A Evans Jennifer J Amodu Olukemi K OK Olaniyan Subulade S Apinjoh Tobias T Mugri Regina R Ndi Andre A Ndila Carolyne M CM Uyoga Sophie S Macharia Alexander A Peshu Norbert N Williams Thomas N TN Manjurano Alphaxard A Sepúlveda Nuno N Clark Taane G TG Riley Eleanor E Drakeley Chris C Reyburn Hugh H Nyirongo Vysaul V Kachala David D Molyneux Malcolm M Dunstan Sarah J SJ Phu Nguyen Hoan NH Quyen Nguyen Ngoc NN Thai Cao Quang CQ Hien Tran Tinh TT Manning Laurens L Laman Moses M Siba Peter P Karunajeewa Harin H Allen Steve S Allen Angela A Davis Timothy Me TM Michon Pascal P Mueller Ivo I Molloy Síle F SF Campino Susana S Kerasidou Angeliki A Cornelius Victoria J VJ Hart Lee L Shah Shivang S SS Band Gavin G Spencer Chris Ca CC Agbenyega Tsiri T Achidi Eric E Doumbo Ogobara K OK Farrar Jeremy J Marsh Kevin K Taylor Terrie T Kwiatkowski Dominic P DP
eLife 20170109
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against <i>Plasmodium falciparum</i> malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of <i>P. falciparum</i> infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-cont ...[more]
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Project description:BackgroundGlucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A- form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection.Methods and findingsWe conducted large case-control studies of the A- form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies.ConclusionsThe A- form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these conclusions are consistent with data from at least one previous study, they have not heretofore been realized to our knowledge, and they therefore give fresh perspectives on malaria protection by G6PD deficiency as an X-linked trait.
| S-EPMC1820604 | biostudies-literature
Project description:BackgroundGlucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits considerable allelic heterogeneity which manifests with variable biochemical and clinical penetrance. It has long been thought that G6PD deficiency confers partial protection against severe malaria, however prior genetic association studies have disagreed with regard to the strength and specificity of a protective effect, which might reflect differences in the host genetic background, environmental influences, or in the specific clinical phenotypes considered.MethodsA case-control association study of severe malaria was conducted in The Gambia, a region in West Africa where there is considerable allelic heterogeneity underlying expression of G6PD deficiency trait, evaluating the three major nonsynonymous polymorphisms known to be associated with enzyme deficiency (A968G, T542A, and C202T) in a cohort of 3836 controls and 2379 severe malaria cases.ResultsEach deficiency allele exhibited a similar trend toward protection against severe malaria overall (15-26% reduced risk); however, in stratifying severe malaria to two of its constituent clinical subphenotypes, severe malarial anaemia (SMA) and cerebral malaria (CM), the three deficiency alleles exhibited trends of opposing effect, with risk conferred to SMA and protection with respect to CM. To assess the overall effect of G6PD deficiency trait, deficiency alleles found across all three loci were pooled. G6PD deficiency trait was found to be significantly associated with protection from severe malaria overall (OR 0.83 [0.75-0.92], P = 0.0006), but this was limited to CM (OR 0.73 [0.61-0.87], P = 0.0005), with a trend toward increased risk for SMA, especially in fully-deficient individuals (OR 1.43 [0.99-2.08], P = 0.056). Sex-stratified testing largely comported with these results, with evidence suggesting that protection by G6PD deficiency trait is conferred to both males and females, though susceptibility to SMA may be restricted to fully-deficient male hemizygotes.ConclusionsIn a part of Africa where multiple alleles contribute to expression of G6PD deficiency trait, these findings clarify and extend previous work done in populations where a single variant predominates, and taken together suggest a causal role for G6PD deficiency trait itself with respect to severe malaria, with opposing effects seen on two major clinical subphenotypes.
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Project description:BackgroundControl of malaria increasingly involves administration of 8-aminoquinolines, with accompanying risk of haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Few data on the prevalence and genotypic basis of G6PD deficiency are available from Bangladesh, where malaria remains a major problem in the South (Chittagong Division). The aim of this study was to determine the prevalence of G6PD deficiency, and associated G6PD genotypes, in adults with falciparum malaria in southern Bangladesh.MethodsG6PD status was assessed via a combination of fluorescent spot testing (FST) and genotyping in 141 Bengali patients admitted with falciparum malaria to two centres in Chittagong Division from 2012 to 2014. In addition, an analysis of genomic data from 1000 Genomes Project was carried out among five healthy Indian subcontinent populations.ResultsOne male patient with uncomplicated malaria was found to have G6PD deficiency on FST and a genotype associated with deficiency (hemizygous Orissa variant). In addition, there were two female patients heterozygous for deficiency variants (Orissa and Kerala-Kalyan). These three patients had a relatively long duration of symptoms prior to admission compared to G6PD normal cases, possibly suggesting an interaction with parasite multiplication rate. In addition, one of 27 healthy local controls was deficient on FST and hemizygous for the Mahidol variant of G6PD deficiency. Examination of 1000 Genomes Project sequencing data across the Indian subcontinent showed that 19/723 chromosomes (2.63%) carried a variant associated with deficiency. In the Bengali from Bangladesh 1000 Genomes population, three of 130 chromosomes (2.31%) carried deficient alleles; this included single chromosomes carrying the Kerala-Kalyan and Orissa variants.ConclusionsIn line with other recent work, G6PD deficiency is uncommon in Bengalis in Bangladesh. Further studies of particular ethnic groups are needed to evaluate the potential risk of wide deployment of primaquine in malaria control efforts in Bangladesh.
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