Interleukin‐1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the Genetics, Osteoarthritis and Progression Study

Abstract

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-1␤ or IL-1 receptor antagonist (IL-1Ra).Methods. Innate ex vivo IL-1␤ 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-1␤ 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-1␤ 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.Osteoarthritis (OA) is a common joint disease and an important cause of pain and disability in the general population. Genetic factors play an important role in the etiology of various subtypes of OA (1-5). There has been a large amount of interest in the role of cytokines as mediators of joint damage and inflammation in the pathogenesis of OA. Chondrocytes are known to respond to interleukin-1␤ (IL-1␤) by reducing the synthesis of matrix components and increasing the synthesis of matrix metalloproteinases (MMPs) (6). MMPs degrade extracellular matrix components in articular cartilage. IL-1 receptor antagonist (IL-1Ra) is the natural competitive inhibitor of IL-1␤, occupying the cell surface IL-1 receptor without triggering signal transduction, and its levels might be considered critical in determining IL-1␤ bioavailability (6).

Association of interleukin‐1 gene variations with moderate to severe chronic periodontitis in multiple ethnicities

“…The composite genotype of the two was therefore uncommon and uninformative in Asians . In addition, contradicting findings have been reported regarding the association between these IL‐1 markers and periodontitis or between these markers and the production of IL‐1 proteins ; although in some studies, the small sample size might have contributed to negative or inconclusive findings. The IL‐1 functional patterns used in this study were found commonly in all the populations studied, and as expected, the carriage rate differed among the ethnic groups, with for example 72% of African Americans testing positive compared to 27% of Caucasians and 11% of Asians.…”

“Generalized osteoarthritis”: A systematic review

“…Evidence of genetic/familial risk factors was reported (29–36). Some studies reported associations between elevated body mass index and other measures of body mass and multiple joint OA(22, 37, 38), but this finding was not consistent(39, 40).…”

“…These included summed radiographic grades(44, 50) and sums of numbers of affected joints or joint groups(30, 36, 45, 51–53). Cerhan, et al, reported associations between the number of joints with OA, number of joint groups with OA, and a binary definition of GOA (3 or more joints with K–L grade of 2 or higher) and survival time(51).…”

IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort

“…The primary objective of this study was to test whether IL1RN gene variations previously associated cross-sectionally with knee OA severity 15,16,38 or susceptibility 39,40 might be associated with longitudinally monitored radiographic progression of knee OA in a population cohort. We found a significant association between progression and several SNPs and their haplotypes in the gene for IL-1Ra, indicating that variants of this gene may be important predictive markers of severity or progression.…”