The IL1RN Promoter rs4251961 Correlates with IL-1 Receptor Antagonist Concentrations in Human Infection and Is Differentially Regulated by GATA-1

Abstract

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.

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

“…Examining common variants of the IL1RN gene revealed that the rs4251961 minor allele is associated with a lowered serum level of IL-1RN and that the rs579543 single nucleotide polymorphism (SNP) is also independently associated with IL-1RN levels, whereas the IL1RN 1018 haplotype correlates with higher concentrations of IL-1β and IFNγ 22 . These findings have been confirmed in three independent cohorts 26 , and further research has demonstrated that these factors affect the pathophysiology of human infections 27 and the risk of developing insulin resistance 28 and knee osteoarthritis 29 .…”

Cytokines of the Immune System

“…Namely, plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors, and the major (C) allele of rs4251961 was associated with a significant increase in plasma IL-1Ra. 23 The minor allele has been previously shown to be associated with decreased IL-1Ra production in healthy adults.…”

Interleukin-1 and Stroke: Biomarker, Harbinger of Damage, and Therapeutic Target

“…Elevated circulating IL-1Ra concentrations are also associated with increased levels of infection in patients with respiratory disease [79,84,85] and with post-stroke infection [86]. This may indicate that increased IL-1 activity and reduced host defence against the infectious agents occur.…”