Open AccessInterleukin‐1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the Genetics, Osteoarthritis and Progression Study
Author(s) -
Meulenbelt Ingrid,
Bos Steffan D.,
Kloppenburg Margreet,
Lakenberg Nico,
HouwingDuistermaat Jeanine J.,
Watt Iain,
de Craen Anton J.,
van Duijn Cornelia M.,
Slagboom P. Eline
Publication year - 2010
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.27325
Subject(s) - single nucleotide polymorphism , biology , ex vivo , haplotype , linkage disequilibrium , immunology , genetics , interleukin 1 receptor antagonist , genotype , gene , in vivo , receptor antagonist , receptor , antagonist
Objective To assess whether genetic variation in the interleukin‐1 (IL‐1) gene cluster contributes to familial osteoarthritis (OA) by influencing innate ex vivo production of IL‐1β or IL‐1 receptor antagonist (IL‐1Ra). Methods Innate ex vivo IL‐1β and IL‐1Ra production upon lipopolysaccharide (LPS) stimulation of whole blood cells was measured in subjects from the Genetics, Osteoarthritis and Progression (GARP) Study, which includes sibling pairs in which at least one sibling has symptomatic OA at multiple sites. Radiographic OA (ROA) was assessed by Kellgren/Lawrence score. Subjects from the GARP Study and controls from the Rotterdam Study were genotyped for 7 single‐nucleotide polymorphisms (SNPs) encompassing the IL‐1 gene cluster on chromosome 2q13. Linkage disequilibrium analysis and genotype and haplotype association analysis were performed to assess the relationship between the IL‐1 gene cluster SNPs, innate ex vivo cytokine production, and OA. Results Among subjects in the GARP Study, the haplotype variable‐number tandem repeat in intron 2/T+8006C/T+11100C 2/2/1 of the IL1RN gene was significantly associated with reduced innate ex vivo bioavailability of IL‐1β upon LPS stimulation ( P = 0.026) and with ROA at the highest number of joint locations. Conclusion These results show that genetic variation at the IL‐1 gene cluster is associated with lower IL‐1β bioavailability and with OA at a large number of joint locations. The data further indicate that, among subjects with OA affecting the highest number of joints, the innate immune system may be activated, thereby obscuring possible underlying mechanisms.