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, 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.
Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi. edcarrol@liverpool.ac.uk
Enitan D
ED
Carrol
Antony
A
Payton
Deborah
D
Payne
Fabio
F
Miyajima
Mas
M
Chaponda
Limangeni A
LA
Mankhambo
Daniel L
DL
Banda
Elizabeth M
EM
Molyneux
Helen
H
Cox
Greg
G
Jacobson
Daniel F
DF
Carr
Malcolm E
ME
Molyneux
James P
JP
Stewart
John P
JP
Quinn
C Anthony
CA
Hart
William E
WE
Ollier
D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D050982:GATA1 Transcription Factor / Q000097:blood / Q000502:physiology*; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008586:Meningitis, Pneumococcal / Q000097:blood / Q000235:genetics / Q000276:immunology*; D011018:Pneumonia, Pneumococcal / Q000097:blood / Q000235:genetics / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D055815:Young Adult
D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein