The IL1RN Promoter rs4251961 Correlates with IL-1 Receptor Antagonist Concentrations in Human Infection and Is Differentially Regulated by GATA-1
Open accessAbstract
IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucleotide polymorphisms. Human embryonic kidney HEK293(T) cells were transfected with the promoter reporter plasmid pGL3p containing either allelic variant C (pGL3pCC) or T (pGL3pTT) with or without cotransfection with an expression construct overexpressing the globin transcription factor GATA-1. Plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors (p < 0.0005), and the C allele of rs4251961 was associated with a significant increase in plasma IL-1Ra concentrations (p = 0.01) during the acute illness of IPD. These findings were validated in a cohort of 276 treatment-naive HIV-infected adults, with borderline significance (p = 0.058). Functional analyses demonstrated that the activity of the promoter constructs containing the T allele increased ~6-fold as compared with basal activity, and that containing the C allele by ~9-fold (p < 0.001) in the presence of GATA-1. Our findings suggest that the IL-1Ra single-nucleotide polymorphism rs4251961 plays a key role in the pathophysiology of IPD and in other human infections.
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IL1RN variants affect the pathophysiology of human infections and the risk of insulin resistance and knee osteoarthritis.
“These findings have been confirmed in three independent cohorts26, and further research has demonstrated that these factors affect the pathophysiology of human infections27 and the risk of developing insulin resistance28 and knee osteoarthritis29.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [27]
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- Authors
- Carrol, E. D., Payton, A., Payne, D., Miyajima, F., Chaponda, M., Mankhambo, L. A., Banda, D. L., Molyneux, E. M., Cox, H., Jacobson, G., Carr, D. F., Molyneux, M. E., Stewart, J. P., Quinn, J. P., Hart, C. A., & Ollier, W. E.
- Affiliations
- University of Liverpool (GB)
- University of Manchester (GB)
- Department of Pharmacology, University of Liverpool , Liverpool ,
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MW)
- Department of Paediatrics, College of Medicine , Blantyre ,
- School of Biomedical Sciences, University of Liverpool , Liverpool ,
- Corresponding author
- Carrol, Enitan D
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-02
- Volume
- 186
- Issue
- 4
- Pages
- 2329-2335
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2133966664
- Cited by
- 38
- References
- 26
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 1 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 2
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Wellcome Trust (068026, 078857/Z/05/Z)
- 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 › Molecular Biology › Inflammasome and immune disorders
- Keywords
- interleukin-1 receptor antagonist, GATA-1, promoter polymorphism, invasive pneumococcal disease, single nucleotide polymorphisms, haplotype-tagging SNPs, host defense, HIV infection, gene expression regulation
- MeSH terms
- Adult, Alleles, Child, Child, Preschool, Female, Humans, Infant, Male, Meningitis, Pneumococcal, Pneumonia, Pneumococcal, Promoter Regions, Genetic, Cohort Studies, Gene Expression Regulation, Bacterial, Polymorphism, Single Nucleotide, GATA1 Transcription Factor, Interleukin 1 Receptor Antagonist Protein, Young Adult, HEK293 Cells
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