• Wenfei Li First Hospital of Qinhuangdao
  • Fang Han Affiliated Zhongshan Hospital of Dalian University
  • Dandan Song Beijing Northern Hospital of China North Industries Group Corporation
  • Tahir Mehmood Shakir Xi'an Jiaotong University


Background: Osteoarthritis is regarded as one of the most frequent disorders of musculoskeletal, which is characterized by the degeneration of articular cartilage and loss of cartilage of the joints. However, the relationship of OA susceptibility with rs12901499 polymorphism in SMAD3 is controversial. Although multiple studies have investigated the correlation of rs12901499A/G polymorphism in SMAD family member 3 (SMAD3) andosteoarthritis (OA) susceptibility, the results from previous studies remain controversial and unsolved. A meta-analysis utilizing fixed and random effects model was performed to clarify the association. Methods:Eligible studies were systematically searched from PubMed, Web of Science, Cochrane Library and EMBASE on April 17, 2019 for reporting the correlation of rs12901499 polymorphism and osteoarthritis susceptibility. Pooled Odds ratio of 95% confidence interval was performed to estimate the strength of relationship of rs12901499 polymorphism and osteoarthritis susceptibility. Publication bias was detected by Begg’s test and STATA 11.0 software was used to evaluate statistical analysis. Results: Seven casecontrol papers involving eight studies from Caucasian and Asian populations were included. A significant increase in osteoarthritis susceptibility was found in recessive, homozygous and allele models. Stratified analysis on ethnicity suggested that the polymorphism with increased risk of OA only in Asians under allele model. Stratified analysis related to population-based studies indicated the increased risk of OA with polymorphism in recessive, homozygous, allele and dominant models. Conclusion:This meta-analysis demonstrated that there may be a weak association of rs12901499 polymorphism and OA susceptibility. Due to the limited size of sample and given ethnic groups, more studies need to validate the result in future.


Sun BH, Wu CW, Kalunian KC. New developments in osteoarthritis. Rheum Dis Clin North Am 2007;33(1):135–48.

Felson DT, Zhang Y. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum 1998;41(8):1343–55.

Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 2010;18(1):24–33.

Grotle M, Hagen KB, Natvig B, Dahl FA, Kvien TK. Obesity and osteoarthritis in knee, hip and/or hand: an epidemiological study in the general population with 10 years follow-up. BMC Musculoskelet Disord 2008;9:132.

Bijsterbosch J, Kloppenburg M, Reijnierse M, Rosendaal FR, Huizinga TW, Slagboom PE, et al. Association study of candidate genes for the progression of hand osteoarthritis. Osteoarthritis Cartilage 2013;21(4):565–9.

Serra R, Chang C. TGF-beta signaling in human skeletal and patterning disorders. Birth Defects Res C Embryo Today 2003;69(4):333–51.

van der Kraan PM, Blaney Davidson EN, Blom A, van den Berg WB. TGF-beta signaling in chondrocyte terminal differentiation and osteoarthritis: modulation and integration of signaling pathways through receptor-Smads. Osteoarthritis Cartilage 2009;17(12):1539–45.

Li Y, Schang G, Boehm U, Deng CX, Graff J, Bernard DJ. SMAD3 Regulates Follicle-stimulating Hormone Synthesis by Pituitary Gonadotrope Cells in Vivo. J Biol Chem 2017;292(6):2301–14.

Zhong F, Lu J, Wang Y, Song H. Genetic variation of SMAD3 is associated with hip osteoarthritis in a Chinese Han population. J Int Med Res 2018;46(3):1178–86.

Zhang L, Zhang L, Zhang H, Wang W, Zhao Y. Association between SMAD3 gene rs12901499 polymorphism and knee osteoarthritis in a Chinese population. J Clin Lab Anal 2018;32(5):e22383.

Xiao JL, Meng JH, Gan YH, Zhou CY, Ma XC. Association of GDF5, SMAD3 and RUNX2 polymorphisms with temporomandibular joint osteoarthritis in female Han Chinese. J Oral Rehabil 2015;42(7):529–36.

Su SL, Yang HY, Lee HS, Huang GS, Lee CH, Liu WS, et al. Gene-gene interactions between TGF-beta/Smad3 signalling pathway polymorphisms affect susceptibility to knee osteoarthritis. BMJ Open 2015;5(6):e007931.

Sharma AC, Srivastava RN, Srivastava SR, Parmar D, Singh A, Raj S. Association between Single Nucleotide Polymorphisms of SMAD3 and BMP5 with the Risk of Knee Osteoarthritis. J Clin Diagn Res 2017;11(6):GC1–4.

Liying J, Yuchun T, Youcheng W, Yingchen W, Chunyu J, Yanling Y, et al. A SMAD3 gene polymorphism is related with osteoarthritis in a Northeast Chinese population. Rheumatol Int 2013;33(7):1763–8.

Liva E, Panagiotou I, Palikyras S, Parpa E, Tsilika E, Paschou P, et al. Candidate gene investigation of spinal degenerative osteoarthritis in Greek population. Spine J 2017;17(12):1881–8.

Valdes AM, Spector TD, Tamm A, Kisand K, Doherty SA, Dennison EM, et al. Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 2010;62(8):2347–52.

Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25(9):603–5.

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7(3):177–88.