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

Abstract

Objective Within the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time. Design 1153 Caucasian adults (age range 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥ 2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective. Results Of 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/ rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression (OR 1.91 (95%CI 1.16-3.15), p = 0.012). Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype. Conclusion A significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development.

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

“…Examining common variants of the IL1RN gene revealed that the rs4251961 minor allele is associated with a lowered serum level of IL-1RN and that the rs579543 single nucleotide polymorphism (SNP) is also independently associated with IL-1RN levels, whereas the IL1RN 1018 haplotype correlates with higher concentrations of IL-1β and IFNγ 22 . These findings have been confirmed in three independent cohorts 26 , and further research has demonstrated that these factors affect the pathophysiology of human infections 27 and the risk of developing insulin resistance 28 and knee osteoarthritis 29 .…”

Cytokines of the Immune System

“…Thus, IL1RN gene markers could be useful in monitoring patients for medical management and possibly drug development. 4 Analysis of SNPs in the IL1R1 gene revealed an association with severe hand OA in family-based and case-control studies, with the strongest candidate for predisposition to disease being the SNP rs2287047. 5 Some IL1 gene cluster polymorphisms seem to affect risk of small joint OA as well.…”

Exogenous expression ofIL-1RaandTGF-β1promotes in vivo repair in experimental rabbit osteoarthritis

“…IL-1 and TNF-α are the two most important pro-inflammatory factors during cartilage matrix degradation and articular cartilage damage in OA pathology, and thus are natural targets for therapy in OA (20,34). IL-1 may elevate matrix metalloproteinase expression in chondrocytes and synoviocytes and promote prostaglandin E production, and it also inhibits the synthesis of hyaline cartilage specific II, IX collagen and protein polysaccharide, acting synergistically with TNF-α (35,36).…”

“…TGF-β1) are significantly decreased, while inflammatory cytokine expression (e.g. IL-1) increases (20,21). As such, blocking the adverse effects of IL-1 signalling in OA could potentially inhibit cartilage matrix degradation and IL-1Ra could play a major protective role in this process (22).…”