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The IL1RN promoter rs4251961 correlates with IL-1 receptor antagonist concentrations in human infection and is differentially regulated by GATA-1

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, an...

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Published in:The Journal of immunology (1950) 2011-02, Vol.186 (4), p.2329-2335
Main Authors: Carrol, Enitan D, Payton, Antony, Payne, Deborah, Miyajima, Fabio, Chaponda, Mas, Mankhambo, Limangeni A, Banda, Daniel L, Molyneux, Elizabeth M, Cox, Helen, Jacobson, Greg, Carr, Daniel F, Molyneux, Malcolm E, Stewart, James P, Quinn, John P, Hart, C Anthony, Ollier, William E
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cited_by cdi_FETCH-LOGICAL-c372t-1e4a9515fa7946c165087f0e85980a3745bf6a810440cdf837e9c89d867d16fc3
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container_title The Journal of immunology (1950)
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creator Carrol, Enitan D
Payton, Antony
Payne, Deborah
Miyajima, Fabio
Chaponda, Mas
Mankhambo, Limangeni A
Banda, Daniel L
Molyneux, Elizabeth M
Cox, Helen
Jacobson, Greg
Carr, Daniel F
Molyneux, Malcolm E
Stewart, James P
Quinn, John P
Hart, C Anthony
Ollier, William E
description 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.
doi_str_mv 10.4049/jimmunol.1002402
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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 &lt; 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 &lt; 0.001) in the presence of GATA-1. 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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 &lt; 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.</abstract><cop>United States</cop><pmid>21248262</pmid><doi>10.4049/jimmunol.1002402</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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subjects Adult
Alleles
Child
Child, Preschool
Cohort Studies
Female
GATA1 Transcription Factor - blood
GATA1 Transcription Factor - physiology
Gene Expression Regulation, Bacterial - immunology
HEK293 Cells
Human immunodeficiency virus
Humans
Infant
Interleukin 1 Receptor Antagonist Protein - biosynthesis
Interleukin 1 Receptor Antagonist Protein - blood
Interleukin 1 Receptor Antagonist Protein - genetics
Interleukin 1 Receptor Antagonist Protein - metabolism
Male
Meningitis, Pneumococcal - blood
Meningitis, Pneumococcal - genetics
Meningitis, Pneumococcal - immunology
Pneumonia, Pneumococcal - blood
Pneumonia, Pneumococcal - genetics
Pneumonia, Pneumococcal - immunology
Polymorphism, Single Nucleotide - genetics
Promoter Regions, Genetic - immunology
Streptococcus pneumoniae
Young Adult
title The IL1RN promoter rs4251961 correlates with IL-1 receptor antagonist concentrations in human infection and is differentially regulated by GATA-1
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