Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia
- Kenya Medical Research Institute-Wellcome Trust Research Programme, Kenya
- University of Edinburgh, United Kingdom
- University of Oxford, United Kingdom
- University of Bamako, Mali
- University of Maryland, United States
- Lifeshare Blood Centers, United States
Abstract
Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.
Data availability
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MalariaGEN Consortial Project 1Application for access to data: https://www.malariagen.net/data/terms-use/human-gwas-data.
Article and author information
Author details
Funding
Wellcome Trust (Senior Research Fellowship 091758)
- Thomas Williams
Wellcome Trust (Senior Research Fellowship202800)
- Thomas Williams
Wellcome Trust (Senior Research Fellowship084226)
- J Alexandra Rowe
Wellcome Trust (203077)
- D Herbert Opi
Wellcome Trust (84538)
- D Herbert Opi
Wellcome Trust (101910/Z/13/Z)
- Olivia Swann
Medical Research Council (G19/9)
- Dominic P Kwiatkowski
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: This work involved analysing blood samples from patients with malaria and from healthy controls. Written informed consent was obtained from the parents or legal guardians of all participants. The Kenyan studies received ethical approval from the Kenya Medical Research Institute National Ethical Review Committee (approval number SCC1192 for the case-control study and SCC3149 for the longitudinal cohort study), and the Malian studies received ethical approval from the University of Bamako and the University of Maryland (approval number #0899139), and were conducted in accordance with the Declaration of Helsinki.
Copyright
© 2018, Opi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia
eLife 7:e31579.
https://doi.org/10.7554/eLife.31579
Further reading
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background:
In many settings, a large fraction of the population has both been vaccinated against and infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, quantifying the protection provided by post-infection vaccination has become critical for policy. We aimed to estimate the protective effect against SARS-CoV-2 reinfection of an additional vaccine dose after an initial Omicron variant infection.
Methods:
We report a retrospective, population-based cohort study performed in Shanghai, China, using electronic databases with information on SARS-CoV-2 infections and vaccination history. We compared reinfection incidence by post-infection vaccination status in individuals initially infected during the April–May 2022 Omicron variant surge in Shanghai and who had been vaccinated before that period. Cox models were fit to estimate adjusted hazard ratios (aHRs).
Results:
275,896 individuals were diagnosed with real-time polymerase chain reaction-confirmed SARS-CoV-2 infection in April–May 2022; 199,312/275,896 were included in analyses on the effect of a post-infection vaccine dose. Post-infection vaccination provided protection against reinfection (aHR 0.82; 95% confidence interval 0.79–0.85). For patients who had received one, two, or three vaccine doses before their first infection, hazard ratios for the post-infection vaccination effect were 0.84 (0.76–0.93), 0.87 (0.83–0.90), and 0.96 (0.74–1.23), respectively. Post-infection vaccination within 30 and 90 days before the second Omicron wave provided different degrees of protection (in aHR): 0.51 (0.44–0.58) and 0.67 (0.61–0.74), respectively. Moreover, for all vaccine types, but to different extents, a post-infection dose given to individuals who were fully vaccinated before first infection was protective.
Conclusions:
In previously vaccinated and infected individuals, an additional vaccine dose provided protection against Omicron variant reinfection. These observations will inform future policy decisions on COVID-19 vaccination in China and other countries.
Funding:
This study was funded the Key Discipline Program of Pudong New Area Health System (PWZxk2022-25), the Development and Application of Intelligent Epidemic Surveillance and AI Analysis System (21002411400), the Shanghai Public Health System Construction (GWVI-11.2-XD08), the Shanghai Health Commission Key Disciplines (GWVI-11.1-02), the Shanghai Health Commission Clinical Research Program (20214Y0020), the Shanghai Natural Science Foundation (22ZR1414600), and the Shanghai Young Health Talents Program (2022YQ076).
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- Epidemiology and Global Health
Background:
The role of circulating metabolites on child development is understudied. We investigated associations between children’s serum metabolome and early childhood development (ECD).
Methods:
Untargeted metabolomics was performed on serum samples of 5004 children aged 6–59 months, a subset of participants from the Brazilian National Survey on Child Nutrition (ENANI-2019). ECD was assessed using the Survey of Well-being of Young Children’s milestones questionnaire. The graded response model was used to estimate developmental age. Developmental quotient (DQ) was calculated as the developmental age divided by chronological age. Partial least square regression selected metabolites with a variable importance projection ≥1. The interaction between significant metabolites and the child’s age was tested.
Results:
Twenty-eight top-ranked metabolites were included in linear regression models adjusted for the child’s nutritional status, diet quality, and infant age. Cresol sulfate (β=–0.07; adjusted-p <0.001), hippuric acid (β=–0.06; adjusted-p <0.001), phenylacetylglutamine (β=–0.06; adjusted-p <0.001), and trimethylamine-N-oxide (β=–0.05; adjusted-p=0.002) showed inverse associations with DQ. We observed opposite directions in the association of DQ for creatinine (for children aged –1 SD: β=–0.05; pP=0.01;+1 SD: β=0.05; p=0.02) and methylhistidine (–1 SD: β = - 0.04; p=0.04;+1 SD: β=0.04; p=0.03).
Conclusions:
Serum biomarkers, including dietary and microbial-derived metabolites involved in the gut-brain axis, may potentially be used to track children at risk for developmental delays.
Funding:
Supported by the Brazilian Ministry of Health and the Brazilian National Research Council.
