The indirect health effects of malaria estimated from health advantages of the sickle cell trait

Uyoga, Sophie; Macharia, Alex; Ndila, Carolyne; Nyutu, Gideon; Mohammed, Shebe; Awuondo, Kennedy O.; Mturi, Neema; Peshu, Norbert; Tsofa, Benjamin; Scott, J. Anthony G.; Maitland, Kathryn; Williams, Thomas N.

doi:10.1038/s41467-019-08775-0

Cited by 30 publications

(32 citation statements)

References 38 publications

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“…1B), an effect approximately twice as strong as that of PIEZO1 E756del in our study population. This result is consistent with published literature on the protective effect of the sickle cell trait for severe malaria (28,29).…”

Section: Resultssupporting

confidence: 93%

A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans

Nguetse

Purington

Ebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Malaria caused by the apicomplexan parasite Plasmodium falciparum has served as a strong evolutionary force throughout human history, selecting for red blood cell polymorphisms that confer innate protection against severe disease. Recently, gain-of-function mutations in the mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, blood–brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-of-function allele PIEZO1 E756del is highly prevalent and enriched in Africans, raising the possibility that it is under positive selection due to malaria. Here we used a case-control study design to test for an association between PIEZO1 E756del and malaria severity among children in Gabon. We found that the E756del variant is strongly associated with protection against severe malaria in heterozygotes. In subjects with sickle cell trait, heterozygosity for PIEZO1 E756del did not confer additive protection and homozygosity was associated with an elevated risk of severe disease, suggesting an epistatic relationship between hemoglobin S and PIEZO1 E756del. Using donor blood samples, we show that red cells heterozygous for PIEZO1 E756del are not dehydrated and can support the intracellular growth of P. falciparum similar to wild-type cells. However, surface expression of the P. falciparum virulence protein PfEMP-1 was significantly reduced in infected cells heterozygous for PIEZO1 756del, a phenomenon that has been observed with other protective polymorphisms, such as hemoglobin C. Our findings demonstrate that PIEZO1 is an important innate determinant of malaria susceptibility in humans and suggest that the mechanism of protection may be related to impaired export of P. falciparum virulence proteins.

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Section: Resultssupporting

confidence: 93%

A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans

Nguetse

Purington

Ebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…33 All three of these mechanisms could potentially have resulted in the birth of stronger, healthier babies with a reduced susceptibility to a range of both infectious and non-infectious diseases. 31 As the study was done in a resource poor region where children commonly die outside health facilities and post-mortem examinations are not routinely available, we were not able to identify the cause of death in most children. Therefore, we could not investigate the association between specific causes of death and individual exposures, such as compliance with particular interventions.…”

Section: Discussionmentioning

confidence: 99%

“…Second, based on previous studies, it appears that HbSS red cells are more resistant to malaria than HbAS red cells and might therefore have provided a malaria-protective advantage during pregnancy. 31 Finally, the rate of decline of HbF is significantly slower in children with sickle cell disease than in those without the disease, 32 which could have led to further protection against P falciparum malaria. 33 All three of these mechanisms could potentially have resulted in the birth of stronger, healthier babies with a reduced susceptibility to a range of both infectious and non-infectious diseases.…”

Section: Discussionmentioning

confidence: 99%

The epidemiology of sickle cell disease in children recruited in infancy in Kilifi, Kenya: a prospective cohort study

Uyoga

Macharia

Mochamah

et al. 2019

The Lancet Global Health

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Background Sickle cell disease is the most common severe monogenic disorder in humans. In Africa, 50-90% of children born with sickle cell disease die before they reach their fifth birthday. In this study, we aimed to describe the comparative incidence of specific clinical outcomes among children aged between birth and 5 years with and without sickle cell disease, who were resident within the Kilifi area of Kenya. Methods This prospective cohort study was done on members of the Kilifi Genetic Birth Cohort Study (KGBCS) on the Indian Ocean coast of Kenya. Recruitment to the study was facilitated through the Kilifi Health and Demographic Surveillance System (KHDSS), which covers a resident population of 260 000 people, and was undertaken between Jan 1, 2006, and April 30, 2011. All children who were born within the KHDSS area and who were aged 3-12 months during the recruitment period were eligible for inclusion. Participants were tested for sickle cell disease and followed up for survival status and disease-specific admission to Kilifi County Hospital by passive surveillance until their fifth birthday. Children with sickle cell disease were offered confirmatory testing and care at a dedicated outpatient clinic. Findings 15 737 infants were recruited successfully to the KGBCS, and 128 (0•8%) of these infants had sickle cell disease, of whom 70 (54•7%) enrolled at the outpatient clinic within 12 months of recruitment. Mortality was higher in children with sickle cell disease (58 per 1000 person-years of observation, 95% CI 40-86) than in those without sickle cell disease (2•4 per 1000 person-years of observation, 2•0-2•8; adjusted incidence rate ratio [IRR] 23•1, 95% CI 15•1-35•3). Among children with sickle cell disease, mortality was lower in those who enrolled at the clinic (adjusted IRR 0•26, 95% CI 0•11-0•62) and in those with higher levels of haemoglobin F (HbF; adjusted IRR 0•40, 0•17-0•94). The incidence of admission to hospital was also higher in children with sickle cell disease than in children without sickle cell disease (210 per 1000 person-years of observation, 95% CI 174-253, vs 43 per 1000 person-years of observation, 42-45; adjusted IRR 4•80, 95% CI 3•84-6•15). The most common reason for admission to hospital among those with sickle cell disease was severe anaemia (incidence 48 per 1000 person-years of observation, 95% CI 32-71). Admission to hospital was lower in those with a recruitment HbF level above the median (IRR 0•43, 95% CI 0•24-0•78; p=0•005) and those who were homozygous for α-thalassaemia (0•07, 0•01-0•83; p=0•035). Interpretation Although morbidity and mortality were high in young children with sickle cell disease in this Kenyan cohort, both were reduced by early diagnosis and supportive care. The emphasis must now move towards early detection and prevention of long-term complications of sickle cell disease. Funding Wellcome Trust.

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“…Genetic variation at G6PD modifies risk of SMA. SMA is a major risk factor for community-acquired bacteremia in African children [12,13], and the malaria-protective effects of HbAS carriage reduce the risk of some of the clinical syndromes that are associated with invasive pneumococcal diseases such as severe pneumonia and meningitis [14]. Moreover, severe anemia in African children, irrespective of its etiology, is associated with increased risk of community-acquired bacteremia [15].…”

Section: Introductionmentioning

confidence: 99%

Risk of pneumococcal bacteremia in Kenyan children with glucose-6-phosphate dehydrogenase deficiency

Gilchrist

Uyoga

Pirinen

et al. 2020

BMC Med

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Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency state in humans. The clinical phenotype is variable and includes asymptomatic individuals, episodic hemolysis induced by oxidative stress, and chronic hemolysis. G6PD deficiency is common in malaria-endemic regions, an observation hypothesized to be due to balancing selection at the G6PD locus driven by malaria. G6PD deficiency increases risk of severe malarial anemia, a key determinant of invasive bacterial disease in malaria-endemic settings. The pneumococcus is a leading cause of invasive bacterial infection and death in African children. The effect of G6PD deficiency on risk of pneumococcal disease is undefined. We hypothesized that G6PD deficiency increases pneumococcal disease risk and that this effect is dependent upon malaria. Methods: We performed a genetic case-control study of pneumococcal bacteremia in Kenyan children stratified across a period of falling malaria transmission between 1998 and 2010. Results: Four hundred twenty-nine Kenyan children with pneumococcal bacteremia and 2677 control children were included in the study. Among control children, G6PD deficiency, secondary to the rs1050828 G>A mutation, was common, with 11.2% (n = 301 of 2677) being hemi-or homozygotes and 33.3% (n = 442 of 1329) of girls being heterozygotes. We found that G6PD deficiency increased the risk of pneumococcal bacteremia, but only during a period of high malaria transmission (P = 0.014; OR 2.33, 95% CI 1.19-4.57). We estimate that the population attributable fraction of G6PD deficiency on risk of pneumococcal bacteremia in areas under high malaria transmission is 0.129.

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The indirect health effects of malaria estimated from health advantages of the sickle cell trait

Cited by 30 publications

References 38 publications

A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans

A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans

The epidemiology of sickle cell disease in children recruited in infancy in Kilifi, Kenya: a prospective cohort study

Risk of pneumococcal bacteremia in Kenyan children with glucose-6-phosphate dehydrogenase deficiency

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