Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations

Abstract

Background: A lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs.

Objective: To determine whether inflammatory genetic markers could stratify patients with knee OA into high and low risk for destructive disease.

Methods: Genotype associations with knee OA severity were assessed in two Caucasian populations. Fifteen single nucleotide polymorphisms (SNPs) in six inflammatory genes were evaluated for association with radiographic severity and with synovial fluid mediators in a subset of the patients.

Results: Interleukin 1 receptor antagonist (IL1RN) SNPs (rs419598, rs315952 and rs9005) predicted Kellgren-Lawrence scores independently in each population. One IL1RN haplotype was associated with lower odds of radiographic severity (OR=0.15; 95% CI 0.065 to 0.349; p<0.0001), greater joint space width and lower synovial fluid cytokine levels. Carriage of the IL1RN haplotype influenced the age relationship with severity.

Conclusion: IL1RN polymorphisms reproducibly contribute to disease severity in knee OA and may be useful biomarkers for patient selection in disease-modifying OA drug trials.

Figure 1

Influence of interleukin 1 receptor antagonist (IL1RN) haplotypes on the age relationship to severity of knee osteoarthritis (OA). (A) The figure stratifies patients with knee OA into thirds by age (<59, n=42; 59–68, n=40; >68, n=47). The numbers in each group are not exactly equal owing to the distribution of patients at the intersection of the groups. Patients within each age group were then stratified by carriage (dot-filled bars) or no carriage (grey-filled bars) of the IL1RN haplotype CTA of the single nucleotide polymorphisms (SNPs) rs419598/rs315952/rs9005. For each age strata and haplotype status, the frequency of severe radiographic knee OA (Kellgren–Lawrence (K–L) score >2) is plotted. (B, C) The joint space width (JSW) of each knee in patients with knee OA who do not (B) or do carry (C) the IL1RN CTA haplotype (rs419598/rs315952/rs9005) is plotted relative to age, and the regression line is shown for JSW relative to age. The JSW is significantly associated with age (p=0.0059) in patients with knee OA who do not carry the IL1RN CTA haplotype, but not associated with age (p=0.56) in patients who carried one or two copies of the CTA haplotype.