APOL1 renal risk variants have contrasting resistance and susceptibility associations with African trypanosomiasis

  1. Anneli Cooper
  2. Hamidou Ilboudo
  3. V Pius Alibu
  4. Sophie Ravel
  5. John Enyaru
  6. William Weir
  7. Harry Noyes
  8. Paul Capewell
  9. Mamadou Camara
  10. Jacqueline Milet
  11. Vincent Jamonneau
  12. Oumou Camara
  13. Enock matovu
  14. Bruno Bucheton
  15. Annette MacLeod  Is a corresponding author
  1. University of Glasgow, United Kingdom
  2. Centre International de Recherche-Développement sur l'Elevage en zone Subhumide, Burkina Faso
  3. Makerere University, Uganda
  4. Institut de Recherche pour le Développement, France
  5. 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

  1. Anneli Cooper

    Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1159-142X
  2. Hamidou Ilboudo

    Centre International de Recherche-Développement sur l'Elevage en zone Subhumide, Bobo-Dioulasso, Burkina Faso
    Competing interests
    The authors declare that no competing interests exist.
  3. V Pius Alibu

    College of Natural Sciences, Makerere University, Kampala, Uganda
    Competing interests
    The authors declare that no competing interests exist.
  4. Sophie Ravel

    Unité Mixte de Recherche IRD-CIRAD 177, Institut de Recherche pour le Développement, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  5. John Enyaru

    College of Natural Sciences, Makerere University, Kampala, Uganda
    Competing interests
    The authors declare that no competing interests exist.
  6. William Weir

    Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Harry Noyes

    Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Paul Capewell

    Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Mamadou Camara

    Programme National de Lutte contre la Trypanosomiase Humaine Africaine, Conakry, Guinea
    Competing interests
    The authors declare that no competing interests exist.
  10. Jacqueline Milet

    Unité Mixte de Recherche IRD-CIRAD 177, Institut de Recherche pour le Développement, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Vincent Jamonneau

    Centre International de Recherche-Développement sur l'Elevage en zone Subhumide, Bobo-Dioulasso, Burkina Faso
    Competing interests
    The authors declare that no competing interests exist.
  12. Oumou Camara

    Programme National de Lutte contre la Trypanosomiase Humaine Africaine, Conakry, Guinea
    Competing interests
    The authors declare that no competing interests exist.
  13. Enock matovu

    College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, Kampala, Uganda
    Competing interests
    The authors declare that no competing interests exist.
  14. Bruno Bucheton

    Unité Mixte de Recherche IRD-CIRAD 177, Institut de Recherche pour le Développement, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Annette MacLeod

    Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom
    For correspondence
    annette.macleod@glasgow.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0150-5049

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).

Reviewing Editor

  1. Sarah Tishkoff, University of Pennsylvania, United States

Publication history

  1. Received: January 25, 2017
  2. Accepted: May 22, 2017
  3. Accepted Manuscript published: May 24, 2017 (version 1)
  4. Accepted Manuscript updated: June 1, 2017 (version 2)
  5. 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.

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  1. Anneli Cooper
  2. Hamidou Ilboudo
  3. V Pius Alibu
  4. Sophie Ravel
  5. John Enyaru
  6. William Weir
  7. Harry Noyes
  8. Paul Capewell
  9. Mamadou Camara
  10. Jacqueline Milet
  11. Vincent Jamonneau
  12. Oumou Camara
  13. Enock matovu
  14. Bruno Bucheton
  15. Annette MacLeod
(2017)
APOL1 renal risk variants have contrasting resistance and susceptibility associations with African trypanosomiasis
eLife 6:e25461.
https://doi.org/10.7554/eLife.25461
  1. Further reading

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    Research Article

    Background: Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases.

    Methods: Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption.

    Results: Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 21 associations persisted after adjusting for genetically-predicted alcohol consumption. Genetically-predicted higher alcohol consumption was associated with increased risk of duodenal cancer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain after adjustment for genetic predisposition to smoking initiation.

    Conclusion: This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases.

    Funding: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.