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 pict… Show more
“…We also examined the HbC variant, and the ABO, ATP2B4, and FREM3/GYPE loci, which have well-validated protective effects against severe malaria (Malaria Genomic Epidemiology Network, 2014, 2015) and found no evidence that they affected the association of G6PD variants with severe malaria (Figure 1—figure supplement 3). The available data did not allow us to analyse α thalassemia across all study sites, but recent analyses at individual study sites have shown no evidence of interaction between the malaria-protective effects of G6PD deficiency and α thalassemia (Manjurano et al, 2015; Uyoga et al, 2015). 10.7554/eLife.15085.005Figure 1.Summary of single SNP tests of association at all sites combined.( A ) Schematic of genes across the genotyped region plotted relative to evenly spaced positions of SNPs in (B).…”
Section: Resultsmentioning
confidence: 99%
“…This is partly due to the genetic complexity of the locus, being X-linked with multiple deficiency alleles with the result that it has extensive allelic and phenotypic heterogeneity, and also to the fact that clinical and epidemiological studies have appeared to give conflicting results. An early study concluded that G6PD deficiency protects against P. falciparum malaria in heterozygous females (Bienzle et al, 1972) and this is supported by a number of more recent studies (Manjurano et al, 2012; Sirugo et al, 2014; Luzzatto, 2015; Manjurano et al, 2015; Uyoga et al, 2015). However other studies have indicated that the protective effect is present in both heterozygous females and hemizygous males (Ruwende et al, 1995; Clark et al, 2009; Shah et al, 2016) or that it is confined to hemizygous G6PD-deficient males (Guindo et al, 2007), or that there are no protective effects at all (Johnson et al, 2009; Toure et al, 2012).…”
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has 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 P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual’s level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.DOI:
http://dx.doi.org/10.7554/eLife.15085.001
“…We also examined the HbC variant, and the ABO, ATP2B4, and FREM3/GYPE loci, which have well-validated protective effects against severe malaria (Malaria Genomic Epidemiology Network, 2014, 2015) and found no evidence that they affected the association of G6PD variants with severe malaria (Figure 1—figure supplement 3). The available data did not allow us to analyse α thalassemia across all study sites, but recent analyses at individual study sites have shown no evidence of interaction between the malaria-protective effects of G6PD deficiency and α thalassemia (Manjurano et al, 2015; Uyoga et al, 2015). 10.7554/eLife.15085.005Figure 1.Summary of single SNP tests of association at all sites combined.( A ) Schematic of genes across the genotyped region plotted relative to evenly spaced positions of SNPs in (B).…”
Section: Resultsmentioning
confidence: 99%
“…This is partly due to the genetic complexity of the locus, being X-linked with multiple deficiency alleles with the result that it has extensive allelic and phenotypic heterogeneity, and also to the fact that clinical and epidemiological studies have appeared to give conflicting results. An early study concluded that G6PD deficiency protects against P. falciparum malaria in heterozygous females (Bienzle et al, 1972) and this is supported by a number of more recent studies (Manjurano et al, 2012; Sirugo et al, 2014; Luzzatto, 2015; Manjurano et al, 2015; Uyoga et al, 2015). However other studies have indicated that the protective effect is present in both heterozygous females and hemizygous males (Ruwende et al, 1995; Clark et al, 2009; Shah et al, 2016) or that it is confined to hemizygous G6PD-deficient males (Guindo et al, 2007), or that there are no protective effects at all (Johnson et al, 2009; Toure et al, 2012).…”
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has 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 P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual’s level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.DOI:
http://dx.doi.org/10.7554/eLife.15085.001
“…Three G6PD deficiency alleles are particularly common and relatively well studied: the A – allele found in much of sub-Saharan Africa; the Med allele found in the Mediterranean and Middle East; and the Mahidol allele found Myanmar and Thailand. The protective effects of these G6PD alleles are complicated, and are likely heterogeneous across study populations and the form of malaria considered (see Manjurano et al, 2015; Malaria Genomic Epidemiology Network, 2014, for recent discussion). The A – and Mahidol alleles are thought to offer some protective effects against Plasmodium falciparum and P. vivax in both heterozygote females and/or hemizygote males (Ruwende et al, 1995; Louicharoen et al, 2009; Manjurano et al, 2015).…”
Section: Introductionmentioning
confidence: 99%
“…The protective effects of these G6PD alleles are complicated, and are likely heterogeneous across study populations and the form of malaria considered (see Manjurano et al, 2015; Malaria Genomic Epidemiology Network, 2014, for recent discussion). The A – and Mahidol alleles are thought to offer some protective effects against Plasmodium falciparum and P. vivax in both heterozygote females and/or hemizygote males (Ruwende et al, 1995; Louicharoen et al, 2009; Manjurano et al, 2015). Haplotype-based analysis of genetic diversity surrounding A –, Med, and Mahidol suggest that they have spread over the past few thousand years (Tishkoff et al, 2001; Slatkin, 2008; Saunders et al, 2005; Louicharoen et al, 2009), consistent with the age of other known malaria resistance alleles.…”
Section: Introductionmentioning
confidence: 99%
“…Indeed, hemizygous males and homozygous females suffer from G6PD deficiency, and homozygote females may also not be protected against malaria (Manjurano et al, 2015; Malaria Genomic Epidemiology Network, 2014). The theory we use regarding the “wave of advance” (Fisher, 1937) applies as well in the case of heterozygote advantage (Aronson & Weinberger, 1975), with the selected allele spreading locally to the equilibrium frequency (rather than fixation).…”
The extent to which populations experiencing shared selective pressures adapt through a shared genetic response is relevant to many questions in evolutionary biology. In a number of well studied traits and species, it appears that convergent evolution within species is common. In this paper, we explore how standing, genetic variation contributes to convergent genetic responses in a geographically spread population, extending our previous work on the topic. Geographically limited dispersal slows the spread of each selected allele, hence allowing other alleles – newly arisen mutants or present as standing variation – to spread before any one comes to dominate the population. When such alleles meet, their progress is substantially slowed – if the alleles are selectively equivalent, they mix slowly, dividing the species range into a random tessellation, which can be well understood by analogy to a Poisson process model of crystallization. In this framework, we derive the geographic scale over which a typical allele is expected to dominate, the time it takes the species to adapt as a whole, and the proportion of adaptive alleles that arise from standing variation. Finally, we explore how negative pleiotropic effects of alleles before an environment change can bias the subset of alleles that contribute to the species’ adaptive response. We apply the results to the many geographically localized G6PD deficiency alleles thought to confer resistance to malaria, where the large mutational target size makes it a likely candidate for adaptation from standing variation, despite the selective cost of G6PD deficiency alleles in the absence of malaria. We find the numbers and geographic spread of these alleles matches our predictions reasonably well, consistent with the view that they arose from a combination of standing variation and new mutations since the advent of malaria. Our results suggest that much of adaptation may be geographically local even when selection pressures are homogeneous. Therefore, we argue that caution must be exercised when arguing that strongly geographically restricted alleles are necessarily the outcome of local adaptation. We close by discussing the implications of these results for ideas of species coherence and the nature of divergence between species.
African populations harbor more genetic variation than any other biogeographical group. There is also a strong infectious-and growing noninfectious-disease burden across the continent that has seen the use of an ever-expanding array of therapeutics. The coexistence of these factors makes understanding pharmacogenomic variation in African populations an imperative for health across the continent and globally. Using G6PD and cytochrome P450 genes, we illustrate this imperative and discuss the future challenges and opportunities for African pharmacogenomics.
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