title: Gene-gene interactions between TGF-β/Smad3 signalling pathway polymorphisms affect susceptibility to knee osteoarthritis.
abstract: OBJECTIVE
  Transforming growth factor/Smad family member 3 (TGF)-β/Smad3 signalling is essential for maintaining articular cartilage. A relationship between the genetic variants of TGF-β itself, TGF-β signalling and binding molecules, and osteoarthritis (OA) has been reported. Although variants of candidate genes have become prime targets for genetic analysis, their detailed interplay has not been documented. Our goal was to establish whether single nucleotide polymorphisms (SNPs) of TGF-β1, TGF-βRI, Smad3 and tissue inhibitor of metalloproteinases 3 (TIMP3), and their interactions, are associated with knee OA.
  
  
  METHODS
  We performed a case-control association study and genotyped 518 knee patients with OA and 468 healthy controls. All participants were genotyped for TGF-β1 (rs1800469C/T), TGF-βRI (rs1590A/G), Smad3 (rs12901499A/G and rs6494629T/C), and TIMP3 (rs715572G/A and rs1962223G/C) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions.
  
  
  RESULTS
  Significant associations were observed for TIMP3 rs715572G/A polymorphisms in knee patients with OA and healthy individuals. The GA heterozygote in TIMP3 (rs715572G/A) was significantly associated with OA (p=0.007). Patient stratification using the Kellgren-Lawrence grading scale showed significant differences in TIMP3 rs715572G/A genotypes between grade 4 knee OA and controls. By MDR analysis, a two-locus model (Smad3 rs6494629T/C and TIMP3 rs715572G/A) of gene-gene interaction was the best for predicting knee OA risk, and its maximum testing accuracy was 57.55% and maximum cross-validation consistency was 10/10.
  
  
  CONCLUSIONS
  TIMP3 rs715572G/A is a candidate protective gene for severe knee OA. Gene-gene interactions between Smad3 rs6494629T/C and TIMP3 rs715572G/A polymorphisms may play more important protective roles in knee OA.
authors.affiliation: School of Public Health, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Sui-Lung
authors.initials: SL
authors.lastname: Su
authors.affiliation: School of Public Health, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Herng-Sheng
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Radiology, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Guo-Shu
authors.initials: GS
authors.lastname: Huang
authors.affiliation: Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University and Hospital, Taipei, Taiwan.
authors.forename: Chian-Her
authors.initials: CH
authors.lastname: Lee
authors.affiliation: School of Public Health, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Wan-Shan
authors.initials: WS
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Peng
authors.affiliation: School of Public Health, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ching-Huang
authors.initials: CH
authors.lastname: Lai
authors.affiliation: Department of Radiology, Tri-Service General Hospital Song-Shan Branch, Taipei, Taiwan.
authors.forename: Ching-Yang
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chin
authors.initials: C
authors.lastname: Lin
authors.affiliation: School of Public Health, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Pan
authors.affiliation: Center for Molecular Medicine, MRC IGMM, University of Edinburgh, Edinburgh, UK.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Salter
authors.affiliation: Division of Rheumatology/Immunology/Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Hsiang-Cheng
authors.initials: HC
authors.lastname: Chen
mesh_terms: D000368:Aged; D002358:Cartilage, Articular / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000503:physiopathology; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: C497790:SMAD3 protein, human; D051900:Smad3 Protein; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D016212:Transforming Growth Factor beta
keywords: GENETICS; ORTHOPAEDIC & TRAUMA SURGERY; RHEUMATOLOGY