{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T16:46:18Z","timestamp":1782405978604,"version":"3.54.5"},"reference-count":64,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["501100011747"],"award-info":[{"award-number":["501100011747"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005036","name":"Universitetet i Bergen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005036","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018562","name":"Steno Diabetes Center Copenhagen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018562","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Ophthalmologica"],"abstract":"Abstract<\/jats:title>\n \n Purpose<\/jats:title>\n Proliferative diabetic retinopathy (PDR) is one of the leading causes of blindness in working\u2010age adults. We have previously shown that the risk of PDR is significantly elevated in individuals with intrauterine exposure to famine. However, the genetic mechanisms mediating this association remain unknown. The aim of the current study was to investigate the molecular underpinnings of famine\u2010related PDR by performing genome\u2010wide association (GWAS) and interaction studies (GWIS).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We analysed\n n<\/jats:italic>\n \u2009=\u20092925 patients with type 2 diabetes from the DOLCE cohort of Northern Ukraine, of whom\n n<\/jats:italic>\n \u2009=\u20091364 were born during historical famine periods (1929\u20131949, including the Holodomor and World War II). PDR cases were defined as individuals with either diagnosed proliferative retinopathy, laser\u2010treated diabetic retinopathy (DR) or blindness in either eye. GWAS and GWIS were performed using linear mixed model (LMM) adjusted for established risk factors and genetic relationship matrix.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n GWAS identified rs3795299 in\n IL22RA1<\/jats:italic>\n as the top signal (\n p<\/jats:italic>\n LMM<\/jats:sub>\n \u2009=\u20091.05\u2009\u00d7\u200910\n \u22126<\/jats:sup>\n ), which was also the strongest gene in the gene\u2010based analysis (\n p<\/jats:italic>\n \u2009=\u20093.19\u2009\u00d7\u200910\n \u22125<\/jats:sup>\n ), with suggestive enrichment of response to ketones (GO) and base excision repair (KEGG) pathways. In the GWIS, the strongest signal was rs1506783 in\n PAPPA2<\/jats:italic>\n (\n p<\/jats:italic>\n LMM<\/jats:sub>\n \u2009=\u20091.29\u2009\u00d7\u200910\n \u22127<\/jats:sup>\n ). A second biologically credible candidate was rs2230805 in\n ABCA1<\/jats:italic>\n (\n p<\/jats:italic>\n LMM<\/jats:sub>\n \u2009=\u20094.44\u2009\u00d7\u200910\n \u22126<\/jats:sup>\n ), reaching borderline genome\u2010wide significance in gene\u2010based analysis (\n p<\/jats:italic>\n \u2009=\u20094.31\u2009\u00d7\u200910\n \u22126<\/jats:sup>\n ). Interaction analyses showed suggestive enrichment for nucleosomal DNA binding (GO), tryptophan metabolism and glycerolipid metabolism (KEGG) pathways. Furthermore, at nominal significance, we validated variants in previously reported diabetic retinopathy\u2010associated genes, including\n TCF7L2<\/jats:italic>\n ,\n SLC2A1<\/jats:italic>\n ,\n SLC2A11<\/jats:italic>\n and\n VDR<\/jats:italic>\n in the GWAS, as well as 13 variants in genes including\n VEGF<\/jats:italic>\n ,\n VEGFR1<\/jats:italic>\n ,\n ANGPT1<\/jats:italic>\n ,\n PLXDC2<\/jats:italic>\n ,\n SELP<\/jats:italic>\n and\n PON2<\/jats:italic>\n in the GWIS.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Our findings suggest that famine\u2010related PDR susceptibility involves distinct developmental programming mechanisms, including altered insulin\u2010growth signalling (\n PAPPA2<\/jats:italic>\n ) and lipid metabolism (\n ABCA1<\/jats:italic>\n ), whereas immune\u2010related pathways (\n IL22RA1<\/jats:italic>\n ) may contribute to the conventional glycaemia\u2010driven route to PDR through VEGF\u2010mediated angiogenesis. These genes represent potential therapeutic targets and emphasize the importance of the perinatal environment in lifelong vascular health and disease.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/aos.70187","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T15:50:24Z","timestamp":1782402624000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome\u2010wide association and interaction analysis for proliferative retinopathy in adults with type 2 diabetes born during famine: The\n DOLCE<\/scp>\n study in Ukraine"],"prefix":"10.1111","author":[{"given":"Olena","family":"Fedotkina","sequence":"first","affiliation":[{"name":"Department of Clinical Science, Center for Diabetes Research University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Most Champa","family":"Begum","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Center for Diabetes Research University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan Tung","family":"Trinh","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Center for Diabetes Research University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Turkuler","family":"\u00d6zgumus","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Center for Diabetes Research University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael","family":"\u00c5kerlund","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Lund University, Sk\u00e5ne University Hospital Malm\u00f6 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Lund University, Sk\u00e5ne University Hospital Malm\u00f6 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia Maria","family":"Spindola","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Center for Diabetes Research University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0198-6524","authenticated-orcid":false,"given":"Valeriya","family":"Lyssenko","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Center for Diabetes Research University of Bergen Bergen Norway"},{"name":"Department of Clinical Sciences Lund University, Sk\u00e5ne University Hospital Malm\u00f6 Sweden"},{"name":"Steno Diabetes Center Copenhagen Herlev Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.2337\/dc09-1893","article-title":"Aldose reductase gene polymorphisms and diabetic retinopathy susceptibility","volume":"33","author":"Abhary S.","year":"2010","journal-title":"Diabetes Care"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1210\/js.2018-00106","article-title":"PAPPA2 as a therapeutic modulator of IGF\u2010I bioavailability: in\u00a0vivo and in\u00a0vitro evidence","volume":"2","author":"Andrew M.","year":"2018","journal-title":"Journal of the Endocrine Society"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"3839","DOI":"10.1167\/iovs.07-1633","article-title":"Heritability of the severity of diabetic retinopathy: the FIND\u2010eye study","volume":"49","author":"Arar 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