title: 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.
  
  
  METHODS
  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 [odds ratio (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Interleukin Genetics, Waltham, MA 02452, USA. xwu@ilgenetics.com
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: V
authors.initials: V
authors.lastname: Kondragunta
authors.forename: K S
authors.initials: KS
authors.lastname: Kornman
authors.forename: H Y
authors.initials: HY
authors.lastname: Wang
authors.forename: G W
authors.initials: GW
authors.lastname: Duff
authors.forename: J B
authors.initials: JB
authors.lastname: Renner
authors.forename: J M
authors.initials: JM
authors.lastname: Jordan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D005260:Female; D005500:Follow-Up Studies; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011859:Radiography; D012307:Risk Factors
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein