1. ¹Peninsula College of Medicine and Dentistry, Exeter, UK
2. ²School of Mathematics and Statistics, University of Plymouth, Plymouth, UK
3. ³Laboratory of Clinical Epidemiology, Italian National Research Council on Aging, Geriatric Rehabilitation Unit, ASF, Florence, Italy
4. ⁴Tuscany Regional Health Agency, I.O.T, Florence, Italy
5. ⁵Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy
6. ⁶Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD, USA
7. ⁷Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA

Correspondence: Dr TM Frayling, Peninsula Medical School, University of Exeter, Magdalen Road, Exeter, EX1 2LU, UK. E-mail: Tim.Frayling@pms.ac.uk

Received 9 February 2007; Revised 12 March 2007; Accepted 12 March 2007; Published online 19 April 2007.

Abstract

Interleukin-1-receptor antagonist (IL-1RA) modulates the biological activity of the proinflammatory cytokine interleukin-1 (IL-1) and could play an important role in the pathophysiology of inflammatory and metabolic traits. We genotyped seven single nucleotide polymorphisms (SNPs) that capture a large proportion of common genetic variation in the IL-1RN gene in 1256 participants from the Invecchiare in Chianti study. We identified five SNPs associated with circulating IL-1RA levels with varying degrees of significance (P-value range=0.016–4.9 10^-5). We showed that this association is likely to be driven by one haplotype, most strongly tagged by rs4251961. This variant is only in weak linkage disequilibrium (r²=0.25) with a previously reported variable number of tandem repeats polymorphism (VNTR) in intron-2 although a second variant, rs579543, that tags the VNTR (r²=0.91), may also be independently associated with IL-1RA levels (P=0.03). We found suggestive evidence that the C allele at rs4251961 that lowers IL-1RA levels is associated with an increased IL-1 (P=0.03) level and may also be associated with interferon - (P=0.03), -2 macroglobulin (P=0.008) and adiponectin (P=0.007) serum levels. In conclusion, common variation across the IL-1RN gene is strongly associated with IL-1RA levels.