APOL1 renal risk variants have contrasting resistance and susceptibility associations with African trypanosomiasis 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.
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).
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
-
- 3,180
- views
-
- 489
- downloads
-
- 93
- 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 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.
-
- Genetics and Genomics
Mitochondrial biogenesis requires the expression of genes encoded by both the nuclear and mitochondrial genomes. However, aside from a handful transcription factors regulating specific subsets of mitochondrial genes, the overall architecture of the transcriptional control of mitochondrial biogenesis remains to be elucidated. The mechanisms coordinating these two genomes are largely unknown. We performed a targeted RNAi screen in developing eyes with reduced mitochondrial DNA content, anticipating a synergistic disruption of tissue development due to impaired mitochondrial biogenesis and mitochondrial DNA (mtDNA) deficiency. Among 638 transcription factors annotated in the Drosophila genome, 77 were identified as potential regulators of mitochondrial biogenesis. Utilizing published ChIP-seq data of positive hits, we constructed a regulatory network revealing the logic of the transcription regulation of mitochondrial biogenesis. Multiple transcription factors in core layers had extensive connections, collectively governing the expression of nearly all mitochondrial genes, whereas factors sitting on the top layer may respond to cellular cues to modulate mitochondrial biogenesis through the underlying network. CG1603, a core component of the network, was found to be indispensable for the expression of most nuclear mitochondrial genes, including those required for mtDNA maintenance and gene expression, thus coordinating nuclear genome and mtDNA activities in mitochondrial biogenesis. Additional genetic analyses validated YL-1, a transcription factor upstream of CG1603 in the network, as a regulator controlling CG1603 expression and mitochondrial biogenesis.
