A genome-wide functional genomics approach uncovers genetic determinants of immune phenotypes in type 1 diabetes
- University Medical Center Groningen, Netherlands
- Radboud University Nijmegen Medical Centre, Netherlands
- Helmholtz Centre for Infection Research, Germany
- University of Groningen, Netherlands
Abstract
Background: The large inter-individual variability in immune-cell cell composition and function determines immune responses in general and susceptibility to immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes (T1D), the pathophysiological mechanisms through which these variations exert their effects remain unknown.
Methods: Blood samples were collected from 243 patients with T1D of Dutch descent. We applied genetic association analysis on > 200 immune cell traits and >100 cytokine production profiles in response to stimuli measured to identify genetic determinants of immune function, and compared the results obtained in T1D to healthy controls.
Results: Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTL) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D, including 12 that have never been reported in healthy population studies, implying a disease-specific genetic regulation.
Conclusion: This study provides new insights into the genetic factors that affect immunological responses in T1D.
Funding: This work was supported by an ERC starting grant (no. 948207) and a Radboud University Medical Centre Hypatia grant (2018) to Y.L. and an ERC advanced grant (no. 833247) and a Spinoza grant of the Netherlands Association for Scientific Research to M.G.N. C.T received funding from the Perspectief Biomarker Development Center Research Programme, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). AJ was funded by a grant from the European Foundation for the Study of Diabetes (EFSD/AZ Macrovascular Programme 2015). X.C was supported by the China Scholarship Council (201706040081).
Data availability
All the raw data on immune phenotypes and summary statistics generated directly from genetic data needed to precisely reproduce published results are deposited in Dryad (https://doi.org/10.5061/dryad.4f4qrfjd0). Custom scripts for generating summary statistics and all results are deposited in GitHub (https://github.com/Chuxj/Gf_of_ip_in_T1D). Individual genetic data and other privacy-sensitive individual information are not publicly available because they contain information that could compromise research participant privacy. For data access, please contact Prof. Cees Tack (Cees.Tack@radboudumc.nl). This original data is available for qualified researchers, i.e. senior investigators employed or legitimately affiliated with an academic, non-profit or government institution who have a track record in the field. We would ask the researcher to sign a data access agreement that needs to be signed by applicants and legal representatives of their universities. In addition, we would require a research proposal, to ensure that 'Applications for access to Data must be Specific, Measurable, Attainable, Resourced and Timely.' The applicant must implement the proposed research within the designed time frame and the data must be deleted after finishing the proposal.
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Datasets for Genetic and environmental effects on the immune phenotypes in type 1 diabetesDryad Digital Repository, doi:10.5061/dryad.4f4qrfjd0.
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Custom scripts for Genetic and environmental effects on the immune phenotypes in type 1 diabetesGitHub Repository, https://github.com/Chuxj/Gf_of_ip_in_T1D.git.
Article and author information
Author details
Funding
ERC Starting grant (948207)
- Yang Li
Radboud Universitair Medisch Centrum (Hypatia Grant 2018)
- Yang Li
ERC advanced grant (833247)
- Mihai G Netea
the Netherlands Association of Scientific Reasearch (Spinoza grant)
- Mihai G Netea
the Netherlands Organisation for Scientific Research (Perspectief Biomarker Development Center Research Programme)
- Cees J Tack
European Foundation for the Study of Diabetes (AZ Macrovascular Programme 2015)
- Anna WM Janssen
China Scholarship Council (201706040081)
- Anna WM Janssen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Christoph Buettner, Rutgers Robert Wood Johnson Medical School, United States
Ethics
Human subjects: The 500FG-DM study was approved by the ethical committee of Radboud University Nijmegen (NL-number: 54214.091.15). Experiments were conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from all participants.
Version history
- Received: September 8, 2021
- Preprint posted: December 7, 2021 (view preprint)
- Accepted: May 16, 2022
- Accepted Manuscript published: May 31, 2022 (version 1)
- Version of Record published: June 17, 2022 (version 2)
Copyright
© 2022, Chu 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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A genome-wide functional genomics approach uncovers genetic determinants of immune phenotypes in type 1 diabetes
eLife 11:e73709.
https://doi.org/10.7554/eLife.73709
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