A genome-wide functional genomics approach uncovers genetic determinants of immune phenotypes in type 1 diabetes

Xiaojing Chu; Anna WM Janssen; Hans Koenen; Linzhung Chang; Xuehui He; Irma Joosten; Rinke Stienstra; Yunus Kuijpers; Cisca Wijmenga; Cheng-Jian Xu; Mihai G Netea; Cees J Tack; Yang Li

doi:10.7554/eLife.73709

eLife (May 2022)

A genome-wide functional genomics approach uncovers genetic determinants of immune phenotypes in type 1 diabetes

Xiaojing Chu,
Anna WM Janssen,
Hans Koenen,
Linzhung Chang,
Xuehui He,
Irma Joosten,
Rinke Stienstra,
Yunus Kuijpers,
Cisca Wijmenga,
Cheng-Jian Xu,
Mihai G Netea,
Cees J Tack,
Yang Li

Affiliations

Xiaojing Chu: ORCiD; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Centre for Individualised Infection Medicine, CiiM, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
Anna WM Janssen: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
Hans Koenen: Department of Laboratory Medicine, Laboratory Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands
Linzhung Chang: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Xuehui He: Department of Laboratory Medicine, Laboratory Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands
Irma Joosten: Department of Laboratory Medicine, Laboratory Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands
Rinke Stienstra: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands; Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands
Yunus Kuijpers: ORCiD; Centre for Individualised Infection Medicine, CiiM, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
Cisca Wijmenga: ORCiD; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Cheng-Jian Xu: ORCiD; Centre for Individualised Infection Medicine, CiiM, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
Mihai G Netea: ORCiD; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
Cees J Tack: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
Yang Li: ORCiD; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Centre for Individualised Infection Medicine, CiiM, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands

DOI: https://doi.org/10.7554/eLife.73709
Journal volume & issue: Vol. 11

Abstract

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Background: The large inter-individual variability in immune-cell composition and function determines immune responses in general and susceptibility o 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 (QTLs) 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. Conclusions: 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 YL and an ERC advanced grant (no. 833247) and a Spinoza grant of the Netherlands Association for Scientific Research to MGN CT 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). XC was supported by the China Scholarship Council (201706040081).

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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