Extended report 1New York University Hospital for Joint Diseases, New York, USA 2Interleukin Genetics, Waltham, Massachusetts, USA 3Duke University Medical Center, Durham, North Carolina, USA 4Harvard Medical School, Boston, Massachusetts, USA Correspondence to Dr Steven B Abramson, Division of Rheumatology, 301E, 17th Street Suite 1410, NYU Hospital for Joint Diseases, New York, NY 10003, USA; stevenb. abramson@nyumc.org Accepted 1 November 2009 Published Online First 23 November 2009 856 Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations Mukundan Attur,1 Hwa-Ying Wang,2 Virginia Byers Kraus,3 Jack F Bukowski,2,4 Nazneen Aziz,2 Svetlana Krasnokutsky,1 Jonathan Samuels,1 Jeffrey Greenberg,1 Gary McDaniel,3 Steven B Abramson,1 Kenneth S Kornman2 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. INTRODUCTION Osteoarthritis (OA) is characterised by progressive loss of joint articular cartilage and subchondral bone remodelling. Although OA is the greatest cause of disability and much of the population is susceptible, some patients remain relatively stable with minimal change in their symptoms over time. Other patients, however, progress to severe structural deterioration that often leads to disability and joint replacement. One challenge in both clinical management of OA and develop- ment of disease-modifying drugs is the lack of imaging or biomarker tools that predict which patients with OA are more likely to progress to severe disease. Genetics explain substantial OA variance,1 but genetic associations with knee OA severity or progression have not been replicated. Inﬂammatory mediators regulate breakdown of collagen, proteoglycans and bone that constitute the articular joint tissues and appear to be part of the destructive process in OA. We and oth- ers have previously shown that an imbalance in interleukin 1 (IL1) and IL1 antagonists contrib- ute to cartilage loss and increased inﬂammatory mediators in OA.2 Variations in several genes for proteins that regu- late inﬂammation, including interleukin-1α (IL1α), IL1β, IL1 receptor antagonist (IL1Ra), IL10, tumour necrosis factor α (TNFα) and oestrogen receptor-α (ESR1), have been associated with differential expression of inﬂammatory mediators,3–5 and most of these gene variations have been associated with susceptibility to OA in various joints.6–10 In this study, we therefore evaluated whether polymor- phisms in selected inﬂammatory genes and genes that regulate inﬂammation could stratify patients with knee OA into high and low risk for radio- graphic severity in two independent populations. PATIENTS AND METHODS Patient populations Two independent populations were recruited at New York University Hospital for Joint Diseases (NYUHJD) and from the Prediction of Osteoarthritis Progression (POP) study (Duke University Medical Center). Institutional review board approval of protocols and informed consent of patients for this study were obtained. All Caucasian patients in the NYUHJD and POP populations that met clinical symptomatic criteria (American College of Rheumatology) and radiographic criteria for OA (Kellgren–Lawrence (KL) grade >1) of at least one knee and were age ≥38 years were included. Patients with histories of corticosteroid use, bilat- eral knee replacements, other forms of arthritis, cancer or other chronic diseases beyond hyperten- sion or hypercholesterolaemia were excluded. POP included subjects with knee OA of KL grade 1–3 in at least one knee and excluded subjects with bilateral knee KL=4 scores, since the primary goal of the POP study was to evaluate the risk factors for progression and to develop a predictive model. Patient demographics are shown in table 1. Patients underwent standardised ﬁxed-ﬂexion postero- anterior knee radiographs with a positioning frame (SynaFlexer; Synarc, San Francisco, California, USA). Radiographs were scored for KL grade (0–4), medial and lateral joint space width (JSW) at the midportion of the joint space via electronic callipers in the NYUHJD cohort, or minimal JSW with digi- tal callipers (TESA ISO 9001) in the POP cohort. Genotyping Blood samples (5 ml) were collected (pyrogen-free heparinised tubes) for DNA extraction. Fifteen single nucleotidepolymorphisms(SNPs)insixinﬂammatory Ann Rheum Dis 2010;69:856–861. doi:10.1136/ard.2009.113043