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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1407.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Polymorphisms of the IL1-Receptor Antagonist Gene (IL1RN) Are Associated With Multiple Markers of Systemic Inflammation

Alexander P. Reiner; Mark M. Wurfel; Leslie A. Lange; Christopher S. Carlson; Alex S. Nord; Cara L. Carty; Mark J. Rieder; Cindy Desmarais; Nancy S. Jenny; Carlos Iribarren; Jeremy D. Walston; O. Dale Williams; Deborah A. Nickerson; Gail P. Jarvik

From the Departments of Epidemiology (A.P.R., C.L.C.), Medicine (M.M.W., A.S.N., G.P.J.), and Genome Sciences (M.J.R., C.D., D.A.N.), University of Washington; the Division of Public Health Sciences (C.S.C.), Fred Hutchinson Cancer Research Center, Seattle, Wash; the Department of Genetics (L.A.L.), University of North Carolina; and the Department of Pathology (N.S.J.), University of Vermont College of Medicine; Kaiser Permanente Division of Research (C.I.), Oakland, Calif; the Department of Medicine (J.W.), Johns Hopkins University, Baltimore, Md; and the Department of Medicine (O.D.W.), Division of Preventive Medicine, University of Alabama at Birmingham.

Correspondence to Alex Reiner, Department of Epidemiology, Box 357236, University of Washington, Seattle, Washington 98195. E-mail apreiner{at}u.washington.edu

Abstract

Background— Circulating levels of acute phase reactant proteins such as plasma C-reactive protein (CRP) are likely influenced by multiple genes regulating the innate immune response.

Methods and Results— We screened a set of 16 inflammation-related genes for association with CRP in a large population-based study of healthy young adults (n=1627). Results were validated in 2 independent studies (n=1208 and n=4310), including a pooled analysis of all 3 studies. In the pooled analysis, the minor allele of IL1RN 1018 (rs4251961) within the gene encoding interleukin (IL)-1 receptor antagonist (IL-1RA) was significantly associated with higher mean plasma log(CRP) level (P<1x10^–4). The same IL1RN 1018 allele was associated with higher mean plasma log(IL-6) levels (P=0.004). In the pooled analysis, the minor allele of IL1RN 13888 (rs2232354) was associated with higher fibrinogen, (P=0.001). The IL1RN 1018 and 13888 variant alleles tag a clade of IL1RN haplotypes linked to allele 1 of an 86-bp VNTR polymorphism. We confirmed that the IL1RN 1018 variant (rs4251961) was associated with decreased cellular IL-1RA production ex vivo.

Conclusions— Common functional polymorphisms of the IL1RN gene are associated with several markers of systemic inflammation.

Using data from 3 large studies comprising younger and older adults, we demonstrate that common variants of the IL-1RA gene (IL1RN) are associated with circulating levels of multiple markers of systemic inflammation. The IL1RN polymorphisms were also associated with cellular IL-1RA production ex vivo in response to an inflammatory stimulus.

Key Words: IL-1 receptor antagonist • C-reactive protein • inflammation • fibrinogen