ArticleBMJ open2015
Gene-gene interactions between TGF-β/Smad3 signalling pathway polymorphisms affect susceptibility to knee osteoarthritis.
Article in BMJ open, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 4 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 4 syntheses or guidelines pooled it, 21 citations in OpenAlex.
- Pooled it
- The association of transforming growth factor beta 1 gene polymorphisms with arthritis: a systematic review and meta-analysis.Clinical and experimental medicine · 2021Pooled it
- Association between SMAD3 gene polymorphisms and osteoarthritis risk: a systematic review and meta-analysis.Journal of orthopaedic surgery and research · 2018Pooled it
- Pooled it
- SMAD3 Gene Polymorphisms and Protein Expression as Potential Biomarkers of Susceptibility to Knee Osteoarthritis.Cureus · 2026Article
- Genetics in Cartilage Lesions: Basic Science and Therapy Approaches.International journal of molecular sciences · 2020Review
- Multifactor dimensionality reduction reveals a strong gene-gene interaction between STC1 and COL11A1 genes as a possible risk factor of knee osteoarthritis.Molecular biology reports · 2020Article
- Identification of differentially expressed miRNAs and mRNAs in synovial of osteoarthritis via RNA-sequencing.BMC medical genetics · 2020Article
- Epistasis of polymorphisms related to the articular cartilage extracellular matrix in knee osteoarthritis: Analysis-based multifactor dimensionality reduction.Genetics and molecular biology · 2020Article
- Impact of the gene-gene interactions related to the HIF-1α signaling pathway with the knee osteoarthritis development.Clinical rheumatology · 2019Article
- The polymorphism of SMAD3 rs1065080 is associated with increased risk for knee osteoarthritis.Molecular biology reports · 2019Article
- Effects of receptor activator nuclear factor κB gene polymorphisms on the susceptibility to knee osteoarthritis: A case-control study.Medicine · 2019Observational
- Gene-gene interactions of the Wnt/β-catenin signaling pathway in knee osteoarthritis.Molecular biology reports · 2018Article
- Association between SMAD3 gene rs12901499 polymorphism and knee osteoarthritis in a Chinese population.Journal of clinical laboratory analysis · 2018Article
- The association between rs12901499 polymorphism in SMAD3 gene and risk of osteoarthritis: a meta-analysis.Therapeutics and clinical risk management · 2018Article
- Association between Single Nucleotide Polymorphisms ofJournal of clinical and diagnostic research : JCDR · 2017Article
- Strong association of the polymorphisms in PBEF1 and knee OA risk: a two-stage population-based study in China.Scientific reports · 2016Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveTransforming 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.
designWe 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.
resultsSignificant 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.
conclusionsTIMP3 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.
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