Association of genotypes affecting the expression of interleukin-1β or interleukin-1 receptor antagonist with osteoarthritis
Abstract
Objective
The majority of cytokines and growth factors known to be involved in cartilage metabolism are synthesized by the chondrocytes themselves. They are up-regulated in osteoarthritic (OA) cartilage, resulting in 2 opposite phenotypes, TNFαhigh and TNFαlow, that are characterized by an elevated number of tumor necrosis factor α (TNFα)–positive and interleukin-1β (IL-1β)–positive chondrocytes, respectively. To establish a hierarchy among the cytokines and growth factors expressed in articular chondrocytes, this study investigated cytokine genes for known polymorphisms that may contribute to the deregulated expression in OA cartilage.
Methods
Polymerase chain reaction techniques were performed either in a thermal cycler using standard methods or in a light cycler to analyze the frequencies of the TNFα (−308), IL-1 receptor antagonist (IL-1Ra) (intron 2), IL-1β (exon 5), and IL-6 (−174) polymorphisms in 61 OA patients and 254 randomly chosen controls.
Results
For the TNFαlow phenotype, a statistically significant association was found with the less frequent allele of IL-1β, which carries a single-basepair substitution in exon 5 and may contribute to the characteristic increase in IL-1β–positive chondrocytes. In contrast, the TNFαhigh phenotype was significantly associated with the less frequent allele of IL-1Ra, which carries two 86-bp repeats in the second intron and is assumed to lead to an elevated expression of the antagonist.
Conclusion
These results point to an association between the IL-1β polymorphism and the TNFαhigh phenotype and between the IL-1Ra polymorphism and the TNFαlow phenotype found in OA. Both associations suggest that IL-1β may be more important than TNFα for the regulation of cytokine and growth factor expression in articular chondrocytes.
