Association of the interleukin‐1 gene cluster with radiographic signs of osteoarthritis of the hip

Abstract

Objective. To study the role of the interleukin-1␤ gene (IL1B) and the IL-1 receptor antagonist gene (IL1RN) in relation to the occurrence of radiographic osteoarthritis (ROA) in the hip, knee, and hand and disc degeneration of the spine.Methods. The study population consisted of a random sample of 886 subjects (ages 55-65 years) from a population-based cohort (the Rotterdam study). Two polymorphisms within IL1B (3953C>T and ؊511C>T) and one within IL1RN (the variable-number tandem repeat [VNTR]) were analyzed and used in an association study of the occurrence of ROA. Haplotyping and simultaneous logistic regression analysis were performed to investigate whether the associations observed were independent.Results. Associations with a predisposition for hip ROA were observed for heterozygous and homozygous carriers of the rare IL1B allele ؊511T (crude odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.0-3.4 and OR 2.9, 95% CI 1.4-6.3, respectively) and of the IL1RN VNTR allele 2 (crude OR 2.0, 95% CI 1.1-3.4 and OR 3.3, 95% CI 1.4-7.8, respectively). An additive effect was observed for carriers of risk alleles of both polymorphisms, with a significant linear-by-linear association (P ‫؍‬ 0.00022). Conclusion.Our findings suggest that the IL-1 gene cluster polymorphisms may play a significant role in the pathogenesis of OA of the hip.Osteoarthritis (OA) is a joint disease characterized by degeneration of articular cartilage and remodeling of the subchondral bone with sclerosis. It has been demonstrated that genetic factors also play an important role in late-onset OA. Familial aggregation of OA (especially hand, knee, and hip OA) was observed in population-based studies (1-4). Candidate genes that may exert this genetic influence have been investigated by means of population-based association studies and genetic linkage studies in OA families. A large number of association studies using various definitions of OA have been performed, mainly investigating genes encoding structural proteins of the extracellular matrix of cartilage (e.g., COL2A1, CRTM, and AGN) or genes playing a role in the regulation of bone density and mass (e.g., VDR, IGF1, and ER), and have shown both positive and negative results for each of the genes (for review, see ref. 5). These differences in study results may indicate either false-positive or false-negative results, could be the result of differences in the OA phenotype investigated, or could be attributable to different linkage disequilibrium (LD) between the associated polymorphism and the causal mutation in various populations. Moreover, it is becoming increasingly clear that the genetic risk factors for OA at different joint sites may be distinct (6).Several groups of investigators have performed genome-wide screens of sibling pairs or nuclear families with OA and reported multiple chromosome areas (e.g., 2p24, 3p12, 4q32, 11q12, 4q27, Xp11.3, and 7p22) that show positive linkage to specific OA phenotypes, such as radiographic OA (ROA) in the distal interphalangeal (DIP) joints, s...

Polymorphism of the interleukin‐1 receptor antagonist gene: A factor in susceptibility to rheumatoid arthritis in a Spanish population

“…In RA, the association has not been observed in Caucasian patients with RA who are of northern European origin (24,25), but it has been observed in the Spanish population (as reported here). In a smaller-scale study of the same polymorphism, which was performed in a group of RA patients from southern France (26), who are similar both geographically and perhaps genetically to our population, a tendency toward an association of IL1RN*2 and RA was shown.…”

Correlation of polymorphic variation in the promoter region of the interleukin‐1β gene with secretion of interleukin‐1β protein

“…As a direct result of the functional data presented herein and the biologic rationale surrounding IL-1B as a candidate gene for OA, we subsequently investigated the CϪ511T polymorphism for genetic association with hip OA. As described by Meulenbelt et al (25), the T allele at Ϫ511 of the IL1B gene is significantly associated with OA of the hip. These genetic associations are in concor-IL-1␤ GENE PROMOTER POLYMORPHISM AND LEVELS OF IL-1␤ PROTEINdance with the hypothesis that an increase in the levels of IL-1␤ protein secretion due to the genetic variation in the IL-1␤ gene may contribute to the pathogenesis of OA.…”

“…It is well documented that IL-1␤ plays a role in several inflammatory diseases, such as in the severity of RA and in inflammatory bowel disease (1)(2)(3). In addition, the IL1 gene cluster has been identified as a significant region of linkage to OA of the hand (20), and more recently, Meulenbelt et al (25) demonstrated a significant genetic association between the T allele at Ϫ511 of the IL1B gene and allele 2 in the IL-1RN variable-number tandem repeat and OA of the hip. Polymorphisms within the IL-1 cluster have also been associated with differences in protein levels (18).…”

Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: An analysis of three Canadian populations

“…Several groups have now reported case-control studies in which extended haplotypes in the IL1 gene cluster have been associated with specific features of osteoarthritis (31)(32)(33). Given the low levels of LD seen between IL1A/B and ILRN in our control populations, there is little reason to expect that an extended haplotype spanning this region would be strongly associated with disease.…”