{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T04:08:05Z","timestamp":1768882085032,"version":"3.49.0"},"reference-count":22,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,28]],"date-time":"2021-11-28T00:00:00Z","timestamp":1638057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Osteoarthritis is an important health issue for the elderly. Many studies indicate that genetics is an important risk factor for osteoarthritis, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is one gene that is most frequently implicated. Many recent studies have examined the relationship between a polymorphism in the ADAMTS5 gene (rs226794) and the risk for developing osteoarthritis without definitive results. Objective: In this case-control study, we examined the correlation between the ADAMTS5 gene polymorphism, rs226794, and knee osteoarthritis. We used a meta-analysis and trial sequential analysis to determine whether ADAMTS5 rs226794 expression increases susceptibility to osteoarthritis. Methods: This study consisted of two parts: a case-control study and a meta-analysis. The case-control study included subjects who underwent knee radiography at the Health Examination Center of the Tri Service General Hospital from 2015 to 2019. The Kellgren\u2013Lawrence (KL) grading system was used as diagnostic criteria. Patients with unsuccessful gene sequencing were excluded. There were 606 subjects in the knee osteoarthritis group (KL \u2265 2) and 564 in the control group (KL &lt; 2). Gene sequencing was performed using iPLEX Gold to determine the association between the gene polymorphism of ADAMTS5 rs226794 and knee osteoarthritis. For the meta-analysis, databases such as PubMed, Embase, and Cochrane were queried to identify studies that examined the relationship between ADAMTS5 rs226794 and osteoarthritis. Next, the findings of the meta-analysis were incorporated with the results of the case-control study and samples from the published studies to estimate the association between the genetic polymorphism and osteoarthritis using an odds ratio and a 95% confidence interval. Results: We found a non-significant association between the G allele and knee OA (crude-OR: 0.93 (95% CI: 0.79\u20131.10) and adjusted-OR: 1.02 (95% CI: 0.76\u20131.36) in the allele model) in the present study, and the analysis of other genetic models revealed a similar trend. After including five published studies and our case-control study, the results with 2866 Asians indicated a conclusively null association between ADAMTS5 rs226794 and knee OA) OR: 1.09 (95% CI: 0.93\u20131.26). The results for Caucasians also revealed a null association (OR: 1.21 (95% CI: 0.81\u20131.82)). Conclusions: This study indicates that the gene polymorphism, ADAMTS5 rs226794, is not significantly associated with knee osteoarthritis. Additionally, assuming that the cumulative sample size in the allele model is sufficient, we confirmed that the G allele is not a risk factor for osteoarthritis. This study integrated all available evidence to arrive at this conclusion, and it suggests that no additional studies are necessary.<\/jats:p>","DOI":"10.3390\/genes12121916","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T05:23:02Z","timestamp":1638163382000},"page":"1916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Decisive Case-Control Study Elaborates the Null Association between ADAMTS5 rs226794 and Osteoarthritis in Asians: A Case-Control Study and Meta-Analysis"],"prefix":"10.3390","volume":"12","author":[{"given":"Chung-Cheng","family":"Kao","sequence":"first","affiliation":[{"name":"Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei 105309, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsiang-En","family":"Hsu","sequence":"additional","affiliation":[{"name":"School of Public Health, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Chou","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 325208, Taiwan"},{"name":"Institute of Medical Sciences, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-Yu","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Kaohsiung Armed Forces General Hospital Gangshan Branch, Kaohsiung 820004, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2127-0539","authenticated-orcid":false,"given":"Su-Wen","family":"Chuang","sequence":"additional","affiliation":[{"name":"School of Public Health, National Defense Medical Center, Taipei 114201, Taiwan"},{"name":"Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3122-1116","authenticated-orcid":false,"given":"Sui-Lung","family":"Su","sequence":"additional","affiliation":[{"name":"School of Public Health, National Defense Medical Center, Taipei 114201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13075-018-1785-7","article-title":"Prevalence and development of hip and knee osteoarthritis according to American College of Rheumatology criteria in the CHECK cohort","volume":"21","author":"Damen","year":"2019","journal-title":"Arthritis Res Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1136\/bmj.312.7036.940","article-title":"Genetic influences on osteoarthritis in women: A twin study","volume":"312","author":"Spector","year":"1996","journal-title":"BMJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1186\/ar595","article-title":"The role of structural genes in the pathogenesis of osteoarthritic disorders","volume":"4","author":"Reginato","year":"2002","journal-title":"Arthritis Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"64","DOI":"10.21037\/aoj.2018.07.04","article-title":"Genome-wide association study of knee osteoarthritis: Present and future","volume":"3","author":"Takuwa","year":"2018","journal-title":"Ann. Jt."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nature03369","article-title":"Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis","volume":"434","author":"Glasson","year":"2005","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"22201","DOI":"10.1074\/jbc.M200431200","article-title":"Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage","volume":"277","author":"Malfait","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/art.23201","article-title":"Genetic variation including nonsynonymous polymorphisms of a major aggrecanase, ADAMTS-5, in susceptibility to osteoarthritis","volume":"58","author":"Mustafa","year":"2008","journal-title":"Arthritis Rheum. Off. J. Am. Coll. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15038264","DOI":"10.4238\/gmr.15038264","article-title":"Polymorphisms in ADAMTS4 and ADAMTS5 are not linked to susceptibility to knee osteoarthritis in the Turkish population","volume":"15","author":"Canbek","year":"2016","journal-title":"Genet Mol. Res."},{"key":"ref_9","first-page":"512","article-title":"Correlation study of disintegrin and metalloproteinase with thrombospondin motifs 5 gene single nucleotide polymorphism and osteoarthritis in Beijing","volume":"19","author":"Chen","year":"2015","journal-title":"Chin. J. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1002\/jor.22582","article-title":"The involvement of ADAMTS-5 genetic polymorphisms in predisposition and diffusion tensor imaging alterations of lumbar disc degeneration","volume":"32","author":"Wu","year":"2014","journal-title":"J. Orthop. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1007\/s00296-012-2506-1","article-title":"Association of ADAMTS5 gene polymorphisms with osteoarthritis in Chinese Han population: A community-based case\u2014Control study","volume":"33","author":"Gu","year":"2013","journal-title":"Rheumatol. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.jclinepi.2007.10.007","article-title":"Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses","volume":"61","author":"Brok","year":"2008","journal-title":"J. Clin. Epidemiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1136\/ard.16.4.485","article-title":"Radiological assessment of rheumatoid arthritis","volume":"16","author":"Kellgren","year":"1957","journal-title":"Ann. Rheum. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., and Altman, D.G. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor package","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Schwarzer, G., Carpenter, J., and R\u00fccker, G. (2015). Meta-Analysis with R, Springer International Publishing.","DOI":"10.1007\/978-3-319-21416-0"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Thorlund, K., Engstr\u00f8m, J., Wetterslev, J., Brok, J., Imberger, G., and Gluud, C. (2021, November 25). False-Positive Findings in Cochrane Meta-Analyses with and without Application of Trial Sequential Analysis: An Empirical Review. Available online: https:\/\/bmjopen.bmj.com\/content\/6\/8\/e011890.short.","DOI":"10.1136\/bmjopen-2016-011890"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e8109","DOI":"10.1590\/1414-431x20188109","article-title":"Genetic variation of aggrecanase-2 (ADAMTS5) in susceptibility to osteoarthritis","volume":"52","author":"Zhou","year":"2019","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"BSR20181619","DOI":"10.1042\/BSR20181619","article-title":"Association of ADAMTS4 and ADAMTS5 polymorphisms with musculoskeletal degenerative diseases: A systematic review and meta-analysis","volume":"38","author":"Huo","year":"2018","journal-title":"Biosci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/nature03417","article-title":"ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and In Vitro","volume":"434","author":"Stanton","year":"2005","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"d4002","DOI":"10.1136\/bmj.d4002","article-title":"Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials","volume":"343","author":"Sterne","year":"2011","journal-title":"BMJ"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lin, C., Chu, C.M., Lin, J., Yang, H.Y., and Su, S.L. (2015). Gene-gene and gene-environment interactions in meta-analysis of genetic association studies. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124967"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/12\/1916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:37:01Z","timestamp":1760168221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/12\/1916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,28]]},"references-count":22,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["genes12121916"],"URL":"https:\/\/doi.org\/10.3390\/genes12121916","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,28]]}}}