{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:44:04Z","timestamp":1790315044139,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T00:00:00Z","timestamp":1534982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000341","name":"Arthritis Research UK","doi-asserted-by":"publisher","award":["20205"],"award-info":[{"award-number":["20205"]}],"id":[{"id":"10.13039\/501100000341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000341","name":"Arthritis Research UK","doi-asserted-by":"publisher","award":["20771"],"award-info":[{"award-number":["20771"]}],"id":[{"id":"10.13039\/501100000341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011102","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["305815"],"award-info":[{"award-number":["305815"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006662","name":"National Institute on Handicapped Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006662","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000774","name":"Newcastle University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000774","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify the functional single\u2010nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at the <jats:italic>ALDH1A2<\/jats:italic> locus, which is a retinoic acid regulatory gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Tissue samples from 247 patients with knee, hip, or hand OA who had undergone joint surgery were included. RNA\u2010sequencing analysis was used to investigate differential expression of <jats:italic>ALDH1A2<\/jats:italic> and other retinoic acid signaling pathway genes in cartilage. Expression of <jats:italic>ALDH1A2<\/jats:italic> in joint tissues obtained from multiple sites was quantified using quantitative reverse transcription\u2013polymerase chain reaction. Allelic expression imbalance (AEI) was measured by pyrosequencing. The consequences of <jats:italic>ALDH1A2<\/jats:italic> depletion by RNA interference were assessed in primary human chondrocytes. In silico and in vitro analyses were used to pinpoint which, among 62 highly correlated SNPs, could account for the association at the locus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>ALDH1A2<\/jats:italic> expression was observed across multiple joint tissue samples, including osteochondral tissue from the hand. The expression of <jats:italic>ALDH1A2<\/jats:italic> and of several retinoic acid signaling genes was different in diseased cartilage compared to non\u2010diseased cartilage, with <jats:italic>ALDH1A2<\/jats:italic> showing lower levels in OA cartilage. Experimental depletion of <jats:italic>ALDH1A2<\/jats:italic> resulted in changes in the expression levels of a number of chondrogenic markers, including <jats:italic>SOX9<\/jats:italic>. In addition, reduced expression of the OA risk\u2013conferring allele was witnessed in a number of joint tissues, with the strongest effect in cartilage. The intronic SNP rs12915901 recapitulated the AEI observed in patient tissues, while the Ets transcription factors were identified as potential mediators of this effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The <jats:italic>ALDH1A2<\/jats:italic> locus seems to increase the risk of hand OA through decreased expression of <jats:italic>ALDH1A2<\/jats:italic> in joint tissues, with the effect dependent on rs12915901. These findings indicate a mechanism that may now be targeted to modulate OA risk.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40545","type":"journal-article","created":{"date-parts":[[2018,5,7]],"date-time":"2018-05-07T01:10:41Z","timestamp":1525655441000},"page":"1577-1587","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Functional Characterization of the Osteoarthritis Genetic Risk Residing at <i>ALDH1A2<\/i> Identifies rs12915901 as a Key Target Variant"],"prefix":"10.1002","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3334-3379","authenticated-orcid":false,"given":"Colin","family":"Shepherd","sequence":"first","affiliation":[{"name":"Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Newcastle University, Newcastle upon Tyne, UK and Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, and Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Skelton","sequence":"additional","affiliation":[{"name":"Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Combe","sequence":"additional","affiliation":[{"name":"Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harrison","family":"Threadgold","sequence":"additional","affiliation":[{"name":"Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Arthritis Research UK Centre for OA Pathogenesis University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonia L.","family":"Vincent","sequence":"additional","affiliation":[{"name":"Arthritis Research UK Centre for OA Pathogenesis University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Stuart","sequence":"additional","affiliation":[{"name":"Newcastle University Teaching Hospitals NHS Trust Freeman Hospital Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise N.","family":"Reynard","sequence":"additional","affiliation":[{"name":"Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Loughlin","sequence":"additional","affiliation":[{"name":"Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,8,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34453"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjsm.2010.081059"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ken475"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2016.04.017"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2013.121"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2957"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrc.10010"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2010.04.014"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39278"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl488"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-015-0254-2"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-206367"},{"key":"e_1_2_7_14_1","unstructured":"AndrewsS.FastQC.2010. 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