{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:21:12Z","timestamp":1787822472468,"version":"build-2784847793"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A20362"],"award-info":[{"award-number":["U22A20362"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2020YFA0803900"],"award-info":[{"award-number":["2020YFA0803900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Integrative genetic approaches can combine Mendelian randomization, variant annotation, pathway\u2010level interpretation, and exploratory cellular measurements to investigate complex disease mechanisms. However, the relationship between genetic liability to insulin medication use and osteoarthritis (OA) remains incompletely characterized GWAS summary statistics for insulin medication use were obtained from the UK Biobank insulin medication\u2010use dataset. Insulin therapy\u2010associated SNPs were selected using a suggestive significance threshold (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20095\u2009\u00d7\u200910\n                    <jats:sup>\u22126<\/jats:sup>\n                    ) and clumped (\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009&lt;\u20090.001, 10,000\u2009kb). Two\u2010sample Mendelian randomization (MR) was performed using the inverse\u2010variance weighted (IVW) method as the primary analysis, supplemented by MR\u2010Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses included Cochran's\n                    <jats:italic>Q<\/jats:italic>\n                    test, MR\u2010Egger intercept, MR\u2010PRESSO global test, and leave\u2010one\u2010out analysis. Insulin\u2010associated genetic variants were functionally annotated using Ensembl VEP, ANNOVAR, FUMA, and Open Targets Genetics, and mapped genes were subjected to exploratory GO biological process and KEGG pathway enrichment analysis. A separate exploratory cellular experiment was performed in the immortalized human chondrocyte cell line TC28a2 using insulin treatment followed by Safranin O staining, RT\u2010qPCR, western blotting, and ELISA. After SNP selection and harmonization, 56 instrument\u2010outcome associations were retained, comprising 29 SNPs in the ukb\u2010a\u2010106 OA dataset and 27 SNPs in the ukb\u2010b\u201014,486 OA dataset. IVW analysis suggested an association between genetic liability to insulin medication use and increased OA susceptibility (ukb\u2010a\u2010106: OR\u2009=\u20091.195, 95% CI\u2009=\u20091.062\u20131.344,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003; ukb\u2010b\u201014,486: OR\u2009=\u20091.179, 95% CI\u2009=\u20091.066\u20131.305,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.001). Sensitivity tests did not detect statistically significant heterogeneity or directional horizontal pleiotropy; however, indication\u2010related genetic liability, correlated pleiotropy, and biologically plausible alternative pathways remain important concerns. Seven mapped genes were used for exploratory enrichment analysis. In a separate exploratory cellular experiment, insulin\u2010treated TC28a2 cells under high\u2010glucose conditions showed reduced proteoglycan staining, increased matrix\u2010degrading and inflammatory markers, and reduced NRF2 protein expression. This study suggests an association between genetic liability to insulin medication use and OA susceptibility and provides exploratory functional\u2010annotation and cellular observations for further investigation.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70384","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T14:07:32Z","timestamp":1787753252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Multi\u2010Omics\u2010Informed Analysis Identifies Insulin Therapy\u2013Associated Loci Implicated in Osteoarthritis Susceptibility"],"prefix":"10.1111","volume":"108","author":[{"given":"Lingbo","family":"Rong","sequence":"first","affiliation":[{"name":"Department of Pharmacology Wuhan University School of Basic Medical Sciences  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9432-1088","authenticated-orcid":false,"given":"Jiayong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7909-115X","authenticated-orcid":false,"given":"Yifan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8778-1457","authenticated-orcid":false,"given":"Liaobin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Department of Pediatric Surgery Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5300-8661","authenticated-orcid":false,"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Wuhan University School of Basic Medical Sciences  Wuhan China"},{"name":"Hubei Provincial Key Laboratory of Developmentally Originated Disease  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.MCNA.2019.10.007"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.ADDR.2006.01.008"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ACR.25252"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000161"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PMED.1001775"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.MEHY.2016.12.010"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(18)31064\u2010X"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/AOGS.13309"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/CSHPERSPECT.A041302"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/GEPI.21965"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyy258"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/JRSM.1346"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/IJE\/DYV080"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/S10654\u2010015\u20100011\u2010Z"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/S10654\u2010017\u20100255\u2010X"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/S10067\u2010014\u20102708\u2010X"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.JBSPIN.2023.105684"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/S00394\u2010023\u201003239\u20100"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/IJE\/DYT110"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/IJE\/DYAB251"},{"issue":"120","key":"e_1_2_11_22_1","first-page":"S3","article-title":"Osteoarthritis Is a Serious Disease","volume":"37","author":"Hawker G. 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