{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:46:41Z","timestamp":1791600401265,"version":"4.3.4"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["115770"],"award-info":[{"award-number":["115770"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s Seventh Framework Programme","award":["FP7\/2007\u20132013"],"award-info":[{"award-number":["FP7\/2007\u20132013"]}]},{"name":"EFPIA companies","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec017\">\n<jats:title>Objective<\/jats:title>\n<jats:p>Knee osteoarthritis (OA) is a heterogeneous disease with different endotypes and phenotypes, resulting in patients\u2019 varying clinical and structural progression. Several genomic markers have been associated with knee OA <jats:italic>presence<\/jats:italic>. This study aimed to find new associations of these genetic markers with knee OA <jats:italic>progression<\/jats:italic> and to investigate the risk of knee OA <jats:italic>progression<\/jats:italic> using a polygenic risk score (PRS).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec018\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Data from knee OA patients (n\u2009=\u2009297) from the IMI-APPROACH cohort with detailed measurements on disease progression were used. Knee OA progression definitions were based on the decrease in minimum joint space width in mm (minJSW; primary outcome), increase in pain on the Knee injury and Osteoarthritis Outcome Score (KOOS), and presence of radiographic OA (based on the Kellgren-Lawrence score) over 24 months. 30 previously reported single nucleotide polymorphisms (SNPs) associated with <jats:italic>presence<\/jats:italic> of OA irrespective of affected joints or knee OA specifically were investigated. We performed a SNP based genome-wide association analysis using the disease <jats:italic>progression<\/jats:italic> definitions. Furthermore, a PRS was created using the 30 <jats:italic>presence<\/jats:italic> SNPs to predict knee OA <jats:italic>progression<\/jats:italic>.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec019\">\n<jats:title>Results<\/jats:title>\n<jats:p>Existing genetic markers for knee OA <jats:italic>presence<\/jats:italic> were not found to be associated with knee OA <jats:italic>progression<\/jats:italic>. The PRS of the SNPs for knee OA presence did also not show significant predictive value for knee OA progression. Unexpectedly, nineteen different variants were associated significantly (<jats:italic>P<\/jats:italic>\u2009&lt;\u20095\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>) with minJSW decrease. Ten SNPs are located near protein coding genes <jats:italic>PLCL2<\/jats:italic>, <jats:italic>CDYL2<\/jats:italic>, and <jats:italic>NTNG1<\/jats:italic>, and several SNPs are located in or near long non-coding RNAs (lncRNA).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec020\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The 30 OA risk SNPs individually and combined in a PRS are not associated with progression of knee OA in the IMI-APPROACH cohort. 19 different SNPs were associated with minJSW decrease. We demonstrated how to employ multiple bioinformatics tools to, despite a limited dataset, still prioritise potential biomarkers for associations to knee OA progression.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0325819","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T17:42:06Z","timestamp":1750786926000},"page":"e0325819","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic markers for knee osteoarthritis presence are not associated with disease progression - data from the IMI-APPROACH cohort"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5054-1569","authenticated-orcid":true,"given":"Mieke L. M.","family":"Bentvelzen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paco M.J.","family":"Welsing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Moingeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon C.","family":"Mastbergen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margreet","family":"Kloppenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9821-7635","authenticated-orcid":true,"given":"Francisco J.","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida K.","family":"Haugen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Berenbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae-Won","family":"Uh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1929-6350","authenticated-orcid":true,"given":"Myl\u00e8ne P.","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2279-4337","authenticated-orcid":true,"given":"Said","family":"el Bouhaddani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"issue":"9859","key":"pone.0325819.ref001","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/S0140-6736(12)61729-2","article-title":"Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global burden of disease study 2010","volume":"380","author":"T Vos","year":"2012","journal-title":"Lancet"},{"key":"pone.0325819.ref002","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.2147\/DDDT.S295224","article-title":"The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): the evidence to date","volume":"15","author":"WM Oo","year":"2021","journal-title":"Drug Des Devel Ther"},{"issue":"5","key":"pone.0325819.ref003","first-page":"64","article-title":"Phenotypes of osteoarthritis: current state and future implications","author":"LA Deveza","year":"2019","journal-title":"Clin Exp Rheumatol"},{"issue":"2","key":"pone.0325819.ref004","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.joca.2006.09.004","article-title":"Genetic influence on the progression of radiographic knee osteoarthritis: a longitudinal twin study","volume":"15","author":"G Zhai","year":"2007","journal-title":"Osteoarthritis Cartilage"},{"issue":"2","key":"pone.0325819.ref005","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/art.42696","article-title":"Genetic influence on osteoarthritis versus other rheumatic diseases","volume":"76","author":"K Magnusson","year":"2024","journal-title":"Arthritis Rheumatol"},{"issue":"7036","key":"pone.0325819.ref006","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":"TD Spector","year":"1996","journal-title":"BMJ"},{"issue":"18","key":"pone.0325819.ref007","article-title":"Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations","volume":"184","author":"CG Boer","year":"2021","journal-title":"Cell"},{"issue":"9","key":"pone.0325819.ref008","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1002\/art.42246","article-title":"Risk assessment for hip and knee osteoarthritis using polygenic risk scores","volume":"74","author":"B Sedaghati-Khayat","year":"2022","journal-title":"Arthritis Rheumatol"},{"issue":"5","key":"pone.0325819.ref009","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.joca.2021.03.002","article-title":"Genetics of osteoarthritis","volume":"30","author":"G Aubourg","year":"2022","journal-title":"Osteoarthritis Cartilage"},{"issue":"4","key":"pone.0325819.ref010","doi-asserted-by":"crossref","first-page":"101972","DOI":"10.1016\/j.berh.2024.101972","article-title":"Genetics of osteoarthritis","volume":"38","author":"G Zhai","year":"2024","journal-title":"Best Pract Res Clin Rheumatol"},{"issue":"11","key":"pone.0325819.ref011","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1016\/j.joca.2018.07.013","article-title":"Contribution of central and peripheral risk factors to prevalence, incidence and progression of knee pain: a community-based cohort study","volume":"26","author":"A Sarmanova","year":"2018","journal-title":"Osteoarthritis Cartilage"},{"issue":"7","key":"pone.0325819.ref012","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2019-035101","article-title":"Cohort profile: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) study: a 2-year, European, cohort study to describe, validate and predict phenotypes of osteoarthritis using clinical, imaging and biochemical markers","volume":"10","author":"EM van Helvoort","year":"2020","journal-title":"BMJ Open"},{"issue":"2","key":"pone.0325819.ref013","doi-asserted-by":"crossref","first-page":"88","DOI":"10.2519\/jospt.1998.28.2.88","article-title":"Knee Injury and Osteoarthritis Outcome Score (KOOS)--development of a self-administered outcome measure","volume":"28","author":"EM Roos","year":"1998","journal-title":"J Orthop Sports Phys Ther"},{"issue":"10","key":"pone.0325819.ref014","first-page":"1756","article-title":"Radiographic assessment of knee osteoarthritis: reproducibility and sensitivity to change","volume":"23","author":"P Ravaud","year":"1996","journal-title":"J Rheumatol"},{"issue":"8","key":"pone.0325819.ref015","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/art.1780290816","article-title":"Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the American rheumatism association","volume":"29","author":"R Altman","year":"1986","journal-title":"Arthritis Rheum"},{"issue":"4","key":"pone.0325819.ref016","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1136\/ard.16.4.494","article-title":"Radiological assessment of osteo-arthrosis","volume":"16","author":"JH Kellgren","year":"1957","journal-title":"Ann Rheum Dis"},{"issue":"2","key":"pone.0325819.ref017","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.joca.2007.06.009","article-title":"Knee Images Digital Analysis (KIDA): a novel method to quantify individual radiographic features of knee osteoarthritis in detail","volume":"16","author":"ACA Marijnissen","year":"2008","journal-title":"Osteoarthritis Cartilage"},{"issue":"8","key":"pone.0325819.ref018","first-page":"1588","article-title":"Reproducibility of the semiflexed (metatarsophalangeal) radiographic knee position and automated measurements of medial tibiofemoral joint space width in a multicenter clinical trial of knee osteoarthritis","volume":"31","author":"JC Buckland-Wright","year":"2004","journal-title":"J Rheumatol"},{"issue":"3","key":"pone.0325819.ref019","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2021-001759","article-title":"Baseline clinical characteristics of predicted structural and pain progressors in the IMI-APPROACH knee OA cohort","volume":"7","author":"EM van Helvoort","year":"2021","journal-title":"RMD Open"},{"issue":"7","key":"pone.0325819.ref020","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.joca.2009.01.007","article-title":"OARSI-OMERACT definition of relevant radiological progression in hip\/knee osteoarthritis","volume":"17","author":"P Ornetti","year":"2009","journal-title":"Osteoarthritis Cartilage"},{"issue":"3","key":"pone.0325819.ref021","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"S Purcell","year":"2007","journal-title":"Am J Hum Genet"},{"issue":"7571","key":"pone.0325819.ref022","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"1000 Genomes Project Consortium","year":"2015","journal-title":"Nature"},{"key":"pone.0325819.ref023","author":"R Core Team","year":"2016"},{"issue":"4","key":"pone.0325819.ref024","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/s41588-018-0079-y","article-title":"Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis","volume":"50","author":"E Zengini","year":"2018","journal-title":"Nat Genet"},{"issue":"8","key":"pone.0325819.ref025","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/ng.176","article-title":"Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis","volume":"40","author":"Y Miyamoto","year":"2008","journal-title":"Nat Genet"},{"issue":"9844","key":"pone.0325819.ref026","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/S0140-6736(12)60681-3","article-title":"Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study","volume":"380","author":"arcOGEN Consortium","year":"2012","journal-title":"Lancet"},{"issue":"2","key":"pone.0325819.ref027","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/s41588-018-0327-1","article-title":"Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data","volume":"51","author":"I Tachmazidou","year":"2019","journal-title":"Nat Genet"},{"issue":"3","key":"pone.0325819.ref028","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0009723","article-title":"New sequence variants in HLA class II\/III region associated with susceptibility to knee osteoarthritis identified by genome-wide association study","volume":"5","author":"M Nakajima","year":"2010","journal-title":"PLoS One"},{"issue":"4","key":"pone.0325819.ref029","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1136\/annrheumdis-2017-211848","article-title":"A novel variant in GLIS3 is associated with osteoarthritis","volume":"77","author":"E Casalone","year":"2018","journal-title":"Ann Rheum Dis"},{"issue":"12","key":"pone.0325819.ref030","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1038\/s41588-018-0247-0","article-title":"Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis","volume":"50","author":"U Styrkarsdottir","year":"2018","journal-title":"Nat Genet"},{"issue":"3","key":"pone.0325819.ref031","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.ajhg.2011.08.001","article-title":"A variant in MCF2L is associated with osteoarthritis","volume":"89","author":"AG Day-Williams","year":"2011","journal-title":"Am J Hum Genet"},{"issue":"19","key":"pone.0325819.ref032","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1093\/hmg\/ddx285","article-title":"Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus","volume":"26","author":"S Hackinger","year":"2017","journal-title":"Hum Mol Genet"},{"issue":"4","key":"pone.0325819.ref033","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/2005","article-title":"A functional polymorphism in the 5\u2019 UTR of GDF5 is associated with susceptibility to osteoarthritis","volume":"39","author":"Y Miyamoto","year":"2007","journal-title":"Nat Genet"},{"issue":"5","key":"pone.0325819.ref034","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1136\/ard.2010.134155","article-title":"The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance","volume":"70","author":"AM Valdes","year":"2011","journal-title":"Ann Rheum Dis"},{"issue":"25","key":"pone.0325819.ref035","doi-asserted-by":"crossref","first-page":"731","DOI":"10.21105\/joss.00731","article-title":"qqman: an R package for visualizing GWAS results using Q-Q and manhattan plots","volume":"3","author":"S D. Turner","year":"2018","journal-title":"J Open Sour Softw"},{"issue":"18","key":"pone.0325819.ref036","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1093\/bioinformatics\/btab186","article-title":"LocusZoom.js: interactive and embeddable visualization of genetic association study results","volume":"37","author":"AP Boughton","year":"2021","journal-title":"Bioinformatics"},{"key":"pone.0325819.ref037","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkab1112","article-title":"Database resources of the national center for biotechnology information","volume":"50","author":"EW Sayers","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"pone.0325819.ref038","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00018-022-04659-7","article-title":"Chromodomain on Y-like 2 (CDYL2) implicated in mitosis and genome stability regulation via interaction with CHAMP1 and POGZ","volume":"80","author":"M Siouda","year":"2023","journal-title":"Cell Mol Life Sci"},{"issue":"5","key":"pone.0325819.ref039","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1002\/acr.23005","article-title":"Knee extensor strength and risk of structural, symptomatic, and functional decline in knee osteoarthritis: a systematic review and meta-analysis","volume":"69","author":"AG Culvenor","year":"2017","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"2","key":"pone.0325819.ref040","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.joca.2013.12.009","article-title":"A gene expression study of normal and damaged cartilage in anteromedial gonarthrosis, a phenotype of osteoarthritis","volume":"22","author":"S Snelling","year":"2014","journal-title":"Osteoarthritis Cartilage"},{"issue":"3","key":"pone.0325819.ref041","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1111\/os.12690","article-title":"Role of MicroRNA, LncRNA, and exosomes in the progression of osteoarthritis: a review of recent literature","volume":"12","author":"F Xie","year":"2020","journal-title":"Orthop Surg"},{"key":"pone.0325819.ref042","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.cca.2022.05.030","article-title":"LncRNAs in osteoarthritis","volume":"532","author":"HM Okuyan","year":"2022","journal-title":"Clin Chim Acta"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0325819","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T17:42:21Z","timestamp":1750786941000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0325819"}},"subtitle":[],"editor":[{"given":"Germain","family":"Honvo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,24]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0325819","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,24]]}}}