A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans
Open accessAbstract
As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases. PAPERCLIP.
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Stimulus-induced cytokine production in response to bacterial, fungal, viral, or nonmicrobial challenge can be highly influenced by genetic variation.
“Like basal cytokine levels, the stimulus-induced cytokine production in response to bacterial, fungal, viral, or a nonmicrobial challenge can also be highly influenced by genetic variation.”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [119]
The degree to which genetics contributes to cytokine responses varies considerably according to the inflammatory stimulus, suggesting a genetic influence on trigger-specific responses.
“However, the degree to which genetics contributes to cytokine responses varies considerably according to the inflammatory stimulus, suggesting a genetic influence on trigger-specific responses (119–121).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [119]
The proportion of variance in TNF-α levels explained by genome-wide SNP data was more than 70% after ex vivo stimulation with fungi and more than 50% after ex vivo stimulation with LPS.
“For example, the proportion of variance in TNF-α levels explained by genome-wide SNP data was more than 70% after ex vivo stimulation with fungi and more than 50% after ex vivo stimulation with LPS.”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [119]
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Self-citation
- Authors
- Li, Y., Oosting, M., Smeekens, S. P., Jaeger, M., Aguirre-Gamboa, R., Le, K. T. T., Deelen, P., Ricaño-Ponce, I., Schoffelen, T., Jansen, A. F. M., Swertz, M. A., Withoff, S., van de Vosse, E., van Deuren, M., van de Veerdonk, F., Zhernakova, A., van der Meer, J. W. M., Xavier, R. J., Franke, L., Joosten, L. A. B., Wijmenga, C., Kumar, V., & Netea, M. G.
- Affiliations
- University Medical Center Groningen (NL)
- Radboud University Nijmegen (NL)
- Broad Institute (US)
- Oslo University Hospital (NO)
- Corresponding author
- Li, Yang
- Joosten, Leo A.B.
- Wijmenga, Cisca
- Kumar, Vinod
- Netea, Mihai G.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 167
- Issue
- 4
- Pages
- 1099-1110.e14
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2547161721
- Cited by
- 324
- References
- 47
- Citations by year
- 2026: 22 · 2025: 19 · 2024: 33 · 2023: 27 · 2022: 51 · 2021: 49 · 2020: 34 · 2019: 35 · 2018: 28 · 2017: 20 · 2016: 6
- FWCI
- 23.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- Seventh Framework Programme (HEALTH-F3-2012-305279)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (863.13.011, FP/2007-2013/ERC, SPI 92-266, 2012-322698, SPI 94-212)
- Maag Lever Darm Stichting (WO11-30)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- cytokine production, genetic variants, immune response variability, heritability, whole blood, blood mononuclear cells, macrophages, pattern recognition receptors, complement inhibitors, positive selection, immune-mediated diseases, infection, ex vivo stimulation
- MeSH terms
- Adolescent, Adult, Aged, Blood, Female, Humans, Infections, Leukocytes, Mononuclear, Macrophages, Male, Middle Aged, Human Genome Project, Cytokines, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study
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