APOL1 renal risk variants have contrasting resistance and susceptibility associations with African trypanosomiasis
- University of Glasgow, United Kingdom
- Centre International de Recherche-Développement sur l'Elevage en zone Subhumide, Burkina Faso
- Makerere University, Uganda
- Institut de Recherche pour le Développement, France
- Programme National de Lutte contre la Trypanosomiase Humaine Africaine, Guinea
Abstract
Reduced susceptibility to infectious disease can increase the frequency of otherwise deleterious alleles. In populations of African ancestry, two apolipoprotein-L1 (APOL1) variants with a recessive kidney disease risk, named G1 and G2, occur at high frequency. APOL1 is a trypanolytic protein that confers innate resistance to most African trypanosomes, but not Trypanosoma brucei rhodesiense or T.b. gambiense, which cause human African trypanosomiasis. In this case-control study we test the prevailing hypothesis that these APOL1 variants reduce trypanosomiasis susceptibility, resulting in their positive selection in sub-Saharan Africa. We demonstrate a five-fold dominant protective association for G2 against T.b. rhodesiense infection. Furthermore, we report unpredicted strong opposing associations with T.b. gambiense disease outcome. G2 associates with faster progression of T.b. gambiense trypanosomiasis, while G1 associates with asymptomatic carriage and undetectable parasitemia. These results implicate both forms of human African trypanosomiasis in the selection and persistence of otherwise detrimental APOL1 kidney disease variants.
Article and author information
Author details
Funding
Wellcome (095201/Z/10/Z)
- Anneli Cooper
- William Weir
- Paul Capewell
- Annette MacLeod
Ministère des Affaires Étrangères
- Hamidou Ilboudo
World Health Organization
- Mamadou Camara
- Oumou Camara
Ministère des Affaires Étrangères
- Sophie Ravel
Wellcome (99310)
- Hamidou Ilboudo
- V Pius Alibu
- John Enyaru
- Harry Noyes
- Mamadou Camara
- Vincent Jamonneau
- Enock matovu
- Bruno Bucheton
- Annette MacLeod
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Sarah Tishkoff, University of Pennsylvania, United States
Ethics
Human subjects: Participants were identified through healthcare providers, community engagement and active field surveillance in association with the national control programmes. Written informed consent for sample collection, analysis and publication of anonymised data was obtained from all participants by trained local healthcare workers. Subjects or their legal guardian gave consent as a signature or a thumbprint after receiving standardised information in English, French or their local language, as preferred, and were free to withdraw from the study at any time. Efforts were made to ensure the engagement of all local stake holders and approval was obtained from local leaders in each study area where appropriate. Ethical approvals for the study were obtained from within the TrypanoGEN Project following H3Africa Consortium guidelines for informed consent, from Comité Consultatif de Déontologie et d'Ethique (CCDE) at the Institut de recherche pour le développement (IRD; 10/06/2013) for the Guinea study, and from the Uganda National Council for Science and Technology (UNCST; 21/03/2013) for the Uganda study. Research procedures were also approved by the University of Glasgow MVLS Ethics Committee for Non-Clinical Research Involving Human Subjects (Reference no. 200120043).
Version history
- Received: January 25, 2017
- Accepted: May 22, 2017
- Accepted Manuscript published: May 24, 2017 (version 1)
- Accepted Manuscript updated: June 1, 2017 (version 2)
- Version of Record published: July 3, 2017 (version 3)
Copyright
© 2017, Cooper 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.
Metrics
-
- 3,014
- views
-
- 468
- downloads
-
- 83
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
APOL1 renal risk variants have contrasting resistance and susceptibility associations with African trypanosomiasis
eLife 6:e25461.
https://doi.org/10.7554/eLife.25461
Further reading
-
- Medicine
- Microbiology and Infectious Disease
- Epidemiology and Global Health
- Immunology and Inflammation
eLife has published articles on a wide range of infectious diseases, including COVID-19, influenza, tuberculosis, HIV/AIDS, malaria and typhoid fever.
-
- Computational and Systems Biology
- Genetics and Genomics
We propose a new framework for human genetic association studies: at each locus, a deep learning model (in this study, Sei) is used to calculate the functional genomic activity score for two haplotypes per individual. This score, defined as the Haplotype Function Score (HFS), replaces the original genotype in association studies. Applying the HFS framework to 14 complex traits in the UK Biobank, we identified 3619 independent HFS–trait associations with a significance of p < 5 × 10−8. Fine-mapping revealed 2699 causal associations, corresponding to a median increase of 63 causal findings per trait compared with single-nucleotide polymorphism (SNP)-based analysis. HFS-based enrichment analysis uncovered 727 pathway–trait associations and 153 tissue–trait associations with strong biological interpretability, including ‘circadian pathway-chronotype’ and ‘arachidonic acid-intelligence’. Lastly, we applied least absolute shrinkage and selection operator (LASSO) regression to integrate HFS prediction score with SNP-based polygenic risk scores, which showed an improvement of 16.1–39.8% in cross-ancestry polygenic prediction. We concluded that HFS is a promising strategy for understanding the genetic basis of human complex traits.
