title: Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis.
abstract: OBJECTIVE
  Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor beta signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA)-like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large-joint OA in humans.
  
  
  METHODS
  Ten tag single-nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA.
  
  
  RESULTS
  A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta-analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12-1.34), P < 7.5 x 10(-6). For hip OA, the OR was 1.22 (95% CI 1.09-1.36), P < 4.0 x 10(-4). No evidence for heterogeneity was found (I(2) = 0%).
  
  
  CONCLUSIONS
  Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital Campus, King's College London, London SE1 7EH, UK. ana.valdes@kcl.ac.uk
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Agu
authors.initials: A
authors.lastname: Tamm
authors.forename: Kalle
authors.initials: K
authors.lastname: Kisand
authors.forename: Sally A
authors.initials: SA
authors.lastname: Doherty
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Dennison
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Ann
authors.initials: A
authors.lastname: Tamm
authors.forename: Irina
authors.initials: I
authors.lastname: Kerna
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Hart
authors.forename: Margaret
authors.initials: M
authors.lastname: Wheeler
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Lories
authors.forename: Nigel K
authors.initials: NK
authors.lastname: Arden
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
mesh_terms: D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007438:Introns; D016017:Odds Ratio; D015207:Osteoarthritis, Hip / Q000235:genetics*; D020370:Osteoarthritis, Knee / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051900:Smad3 Protein / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D051900:Smad3 Protein