Gene-gene interactions between TGF-β/Smad3 signalling pathway polymorphisms affect susceptibility to knee osteoarthritis

Sui Lung Su, Hsin Yi Yang, Herng Sheng Lee, Guo Shu Huang, Chian Her Lee, Wan Shan Liu, Chih Chien Wang, Yi Jen Peng, Ching Huang Lai, Ching Yang Chen, Chin Lin, Yu Ting Pan, Donald M. Salter, Hsiang Cheng Chen

Research output: Contribution to journalArticle

11 Citations (Scopus)

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. Design: 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.

Original languageEnglish
Article numbere007931
JournalBMJ Open
Volume5
Issue number6
DOIs
Publication statusPublished - 2015

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Tissue Inhibitor of Metalloproteinase-3
Knee Osteoarthritis
Osteoarthritis
Genes
Multifactor Dimensionality Reduction
Knee
Articular Cartilage
Transforming Growth Factors
Heterozygote
Restriction Fragment Length Polymorphisms
Single Nucleotide Polymorphism
Case-Control Studies
Genotype
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Medicine(all)

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Gene-gene interactions between TGF-β/Smad3 signalling pathway polymorphisms affect susceptibility to knee osteoarthritis. / Su, Sui Lung; Yang, Hsin Yi; Lee, Herng Sheng; Huang, Guo Shu; Lee, Chian Her; Liu, Wan Shan; Wang, Chih Chien; Peng, Yi Jen; Lai, Ching Huang; Chen, Ching Yang; Lin, Chin; Pan, Yu Ting; Salter, Donald M.; Chen, Hsiang Cheng.

In: BMJ Open, Vol. 5, No. 6, e007931, 2015.

Research output: Contribution to journalArticle

Su, SL, Yang, HY, Lee, HS, Huang, GS, Lee, CH, Liu, WS, Wang, CC, Peng, YJ, Lai, CH, Chen, CY, Lin, C, Pan, YT, Salter, DM & Chen, HC 2015, 'Gene-gene interactions between TGF-β/Smad3 signalling pathway polymorphisms affect susceptibility to knee osteoarthritis', BMJ Open, vol. 5, no. 6, e007931. https://doi.org/10.1136/bmjopen-2015-007931
Su, Sui Lung ; Yang, Hsin Yi ; Lee, Herng Sheng ; Huang, Guo Shu ; Lee, Chian Her ; Liu, Wan Shan ; Wang, Chih Chien ; Peng, Yi Jen ; Lai, Ching Huang ; Chen, Ching Yang ; Lin, Chin ; Pan, Yu Ting ; Salter, Donald M. ; Chen, Hsiang Cheng. / Gene-gene interactions between TGF-β/Smad3 signalling pathway polymorphisms affect susceptibility to knee osteoarthritis. In: BMJ Open. 2015 ; Vol. 5, No. 6.
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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. Design: 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.",
author = "Su, {Sui Lung} and Yang, {Hsin Yi} and Lee, {Herng Sheng} and Huang, {Guo Shu} and Lee, {Chian Her} and Liu, {Wan Shan} and Wang, {Chih Chien} and Peng, {Yi Jen} and Lai, {Ching Huang} and Chen, {Ching Yang} and Chin Lin and Pan, {Yu Ting} and Salter, {Donald M.} and Chen, {Hsiang Cheng}",
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AU - Su, Sui Lung

AU - Yang, Hsin Yi

AU - Lee, Herng Sheng

AU - Huang, Guo Shu

AU - Lee, Chian Her

AU - Liu, Wan Shan

AU - Wang, Chih Chien

AU - Peng, Yi Jen

AU - Lai, Ching Huang

AU - Chen, Ching Yang

AU - Lin, Chin

AU - Pan, Yu Ting

AU - Salter, Donald M.

AU - Chen, Hsiang Cheng

PY - 2015

Y1 - 2015

N2 - 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. Design: 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.

AB - 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. Design: 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.

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