title: Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women.
abstract: OBJECTIVE
  Osteoarthritis (OA) is recognized to have a genetic component, and in this study, we aimed to replicate in a case-control study of men and women with clinical knee OA genetic associations in 12 candidate genes previously reported to be associated with OA.
  
  
  METHODS
  Twenty-five single-nucleotide polymorphisms were genotyped in 298 men and 305 women ages 50-86 who were diagnosed as having knee OA, as assessed both clinically and radiographically, and in 297 men and 299 women matched for age and ethnicity (controls). Standardized anteroposterior radiographs of the knee in extension were performed on each of the cases, and all cases met the American College of Rheumatology criteria for OA of the knee. Genotype and haplotype frequencies in cases and controls were compared separately in men and women. The 12 genes tested were AACT, ADAM12, BMP2, CD36, CILP, COX2, ESR1, NCOR2, OPG, TNA, TNFAIP6, and VDR.
  
  
  RESULTS
  Eight of the candidate genes were associated in women and 5 in men, and only 3 genes (TNFAIP6, NCOR2, and CD36) were not significantly associated in either sex. The strongest associations in terms of odds ratios (ORs) were a haplotype in ADAM12 (OR 7.1 [95% confidence interval (95% CI) 3.3-33.8]) and a haplotype in ESR1 (OR 3.6 [95% CI 1.18-10.98]) in women. The same ADAM12 haplotype (OR 2.54 [95% CI 1.2-5.4]) and a haplotype in the CILP gene (OR 0.38 [95% CI 0.23-0.62]) were the strongest associations in men.
  
  
  CONCLUSIONS
  We found that genes previously identified by their association with subclinical features of knee OA or progression were also associated with clinical knee OA. These genetic associations may identify individuals at a particularly high risk of developing knee OA.
authors.affiliation: St. Thomas' Hospital, London, UK.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.forename: Mark
authors.initials: M
authors.lastname: Van Oene
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Hart
authors.forename: Gabriela L
authors.initials: GL
authors.lastname: Surdulescu
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020370:Osteoarthritis, Knee / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D006113:United Kingdom / Q000453:epidemiology