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.
↵1 C.A.H. died suddenly in September 2007, but in view of his significant contribution to this study, it was agreed by all authors that he should be included as an author.
This work was supported by Wellcome Trust Career Development Grant 068026 (to E.D.C.), Wellcome Trust Training Fellowship Grant 078857/Z/05/Z (to M.C.), and Alder Hey Children’s National Health Service Foundation Trust Endowment Grant Ref 7565 (to H.C.). F.M. is supported by the National Institute of Health Research Liverpool Biomedical Research Centre for Microbial Diseases.
The online version of this article contains supplemental material.
- Received July 20, 2010.
- Accepted December 14, 2010.
- Copyright © 2011 by The American Association of Immunologists, Inc.