scholarly journals Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Geraldine M Clarke ◽  
Kirk Rockett ◽  
Katja Kivinen ◽  
Christina Hubbart ◽  
Anna E Jeffreys ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
G6pd Deficiency ◽  
Balancing Selection ◽  
Plasmodium Falciparum Malaria ◽  
Falciparum Infection ◽  
Human Populations ◽  
Severe Malarial Anaemia ◽  
Heterogeneous Effects ◽  
Increased Risk ◽  
Opposing Effects

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.

scholarly journals Author response: Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

2016 ◽  
Author(s):  
Geraldine M Clarke ◽  
Kirk Rockett ◽  
Katja Kivinen ◽  
Christina Hubbart ◽  
Anna E Jeffreys ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
G6pd Deficiency ◽  
Author Response ◽  
Severe Malarial Anaemia ◽  
Opposing Effects

scholarly journals Collider bias and the apparent protective effect of glucose-6-phosphate dehydrogenase deficiency on cerebral malaria

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
James A Watson ◽  
Stije J Leopold ◽  
Julie A Simpson ◽  
Nicholas PJ Day ◽  
Arjen M Dondorp ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Severe Malaria ◽  
Causal Reasoning ◽  
Large Scale ◽  
Dehydrogenase Deficiency ◽  
Balancing Selection ◽  
Case Fatality ◽  
Severe Malarial Anaemia ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Collider Bias

Case fatality rates in severe falciparum malaria depend on the pattern and degree of vital organ dysfunction. Recent large-scale case-control analyses of pooled severe malaria data reported that glucose-6-phosphate dehydrogenase deficiency (G6PDd) was protective against cerebral malaria but increased the risk of severe malarial anaemia. A novel formulation of the balancing selection hypothesis was proposed as an explanation for these findings, whereby the selective advantage is driven by the competing risks of death from cerebral malaria and death from severe malarial anaemia. We re-analysed these claims using causal diagrams and showed that they are subject to collider bias. A simulation based sensitivity analysis, varying the strength of the known effect of G6PDd on anaemia, showed that this bias is sufficient to explain all of the observed association. Future genetic epidemiology studies in severe malaria would benefit from the use of causal reasoning.

scholarly journals Cannabis, a complex plant: different compounds and different effects on individuals

2012 ◽  
Vol 2 (6) ◽  
pp. 241-254 ◽  
Author(s):  
Zerrin Atakan
Keyword(s):  
Endocannabinoid System ◽  
The Body ◽  
Vulnerability Factors ◽  
Negative Effects ◽  
Biochemical Basis ◽  
Neurotransmitter System ◽  
Increased Risk ◽  
Opposing Effects ◽  
Available Information ◽  
The Brain

Cannabis is a complex plant, with major compounds such as delta-9-tetrahydrocannabinol and cannabidiol, which have opposing effects. The discovery of its compounds has led to the further discovery of an important neurotransmitter system called the endocannabinoid system. This system is widely distributed in the brain and in the body, and is considered to be responsible for numerous significant functions. There has been a recent and consistent worldwide increase in cannabis potency, with increasing associated health concerns. A number of epidemiological research projects have shown links between dose-related cannabis use and an increased risk of development of an enduring psychotic illness. However, it is also known that not everyone who uses cannabis is affected adversely in the same way. What makes someone more susceptible to its negative effects is not yet known, however there are some emerging vulnerability factors, ranging from certain genes to personality characteristics. In this article we first provide an overview of the biochemical basis of cannabis research by examining the different effects of the two main compounds of the plant and the endocannabinoid system, and then go on to review available information on the possible factors explaining variation of its effects upon different individuals.

scholarly journals New Biology to New Treatment of Helicobacter pylori-Induced Gastric Cancer

2016 ◽  
Vol 34 (5) ◽  
pp. 510-516 ◽  
Author(s):  
Richard M. Peek Jr.
Keyword(s):  
Gastric Cancer ◽  
Salt Intake ◽  
Disease Risk ◽  
Host Cells ◽  
Human Populations ◽  
High Salt Intake ◽  
Increased Risk ◽  
New Biology ◽  
New Treatment ◽  
H Pylori

Background:Helicobacter pylori is a bacterial carcinogen that is supposed to have the highest known level of risk for the development of gastric cancer, a disease that claims hundreds of thousands of lives per year. Approximately 89% of the global gastric cancer burden and 5.5% of malignancies worldwide are attributed to H. pylori-induced inflammation and injury. However, only a fraction of colonized persons ever develop neoplasia, and disease risk involves well-choreographed interactions between pathogen and host, which are dependent upon strain-specific bacterial factors, host genotypic traits, and/or environmental conditions. Key Messages: One H. pylori strain-specific virulence determinant that augments the risk for gastric cancer is the cag pathogenicity island, a secretion system that injects the bacterial oncoprotein CagA into host cells. Host polymorphisms within genes that regulate immunity and oncogenesis also heighten the risk for gastric cancer, in conjunction with H. pylori strain-specific constituents. Further, conditions such as iron deficiency and high salt intake can influence H. pylori phenotypes that lower the threshold for disease. Conclusions: Delineation of bacterial, host, and environmental mediators that augment gastric cancer risk has profound ramifications for both physicians and biomedical researchers as such findings will not only focus prevention approaches that target H. pylori-infected human populations at increased risk for stomach cancer, but will also provide mechanistic insights into inflammatory carcinomas that develop beyond the gastric niche.

The ABO blood group system and Plasmodium falciparum malaria

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2250-2258 ◽  
Author(s):  
Christine M. Cserti ◽  
Walter H. Dzik
Keyword(s):  
Plasmodium Falciparum ◽  
Relative Proportion ◽  
Plasmodium Falciparum Malaria ◽  
Blood Groups ◽  
Falciparum Infection ◽  
Human Migration ◽  
Published Data ◽  
Sequence Information ◽  
Blood Group System ◽  
Abo Blood Groups

In the century since the discovery of the ABO blood groups, numerous associations between ABO groups and disease have been noted. However, the selection pressures defining the ABO distributions remain uncertain. We review published information on Plasmodium falciparum infection and ABO blood groups. DNA sequence information dates the emergence and development of the group O allele to a period of evolution before human migration out of Africa, concomitant with P falciparum's activity. The current geographic distribution of group O is also consistent with a selection pressure by P falciparum in favor of group O individuals in malaria-endemic regions. We critically review clinical reports of ABO and P falciparum infection, documenting a correlation between disease severity and ABO group. Finally, we review published data on the pathogenesis of P falciparum infection, and propose a biologic model to summarize the role of ABO blood groups in cytoadherence biology. Such ABO-related mechanisms also point to a new hypothesis to account for selection of the Le(a−b−) phenotype. Taken together, a broad range of available evidence suggests that the origin, distribution, and relative proportion of ABO blood groups in humans may have been directly influenced by selective genetic pressure from P falciparum infection.

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