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Helsinki","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007797","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>DNA methylation has been shown to be associated with kidney function and diabetic kidney disease (DKD), but prospective studies are scarce. Therefore, we conducted epigenome-wide association studies (EWASs) on early- and late-stage DKD progression using DNA methylation data obtained by analysing baseline blood samples from participants in the Finnish Diabetic Nephropathy Study type 1 diabetes cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We included 403 individuals with normal AER (early-stage progression group) and 372 individuals with severe albuminuria (late-stage progression group), and followed up DKD progression, defined as a decrease in eGFR to &lt;60 ml\/min per 1.73 m\n                      <jats:sup>2<\/jats:sup>\n                      in the early-stage progression group, and end-stage kidney disease (ESKD) in the late-stage group. Replication was conducted in two type 1 diabetes cohorts in addition to publicly available EWAS summary statistics from diabetes and general population cohorts. Significant loci were further characterised by integration with genetic and proteomic data.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 11 methylation sites associated with DKD progression (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;9.4 \u00d7 10\n                      <jats:sup>\u22128<\/jats:sup>\n                      ). Methylation at cg01730944 near the podocyte-specific gene\n                      <jats:italic>CDKN1C<\/jats:italic>\n                      and three other CpGs associated with early-stage DKD progression were independent of baseline eGFR, whereas late-stage progression CpGs were strongly associated with eGFR. The identified lead ESKD risk locus cg17944885 (chr19p13.2,\n                      <jats:italic>p<\/jats:italic>\n                      =2.6\u00a0\u00d7\u00a010\n                      <jats:sup>\u221217<\/jats:sup>\n                      ) and several novel methylation sites associated with late-stage DKD progression were supported by the results of previous studies. Proteomic analysis of\n                      <jats:italic>cis<\/jats:italic>\n                      proteins identified potential target genes for two CpGs: cg14999724 methylation was associated with PRG3 and PRG2, and cg12272104 was associated with BSG, FSTL3 and PALM. Furthermore, UK Biobank data show associations between these proteins and severe kidney endpoints. Finally, survival models that included methylation markers in addition to clinical risk factors significantly improved the identification of individuals at risk of early-stage DKD progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>The current study detected 11 loci associated with DKD progression, identifying methylation changes predictive of early-stage DKD progression in type 1 diabetes for the first time. Future research is needed to establish prognostic DNA methylation markers for DKD progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06661-7","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T06:14:35Z","timestamp":1769062475000},"page":"1317-1336","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Blood DNA methylation markers are associated with diabetic kidney disease progression in type 1 diabetes"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1857-2560","authenticated-orcid":false,"given":"Anna","family":"Syreeni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1271-8696","authenticated-orcid":false,"given":"Emma H.","family":"Dahlstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6419-4826","authenticated-orcid":false,"given":"Laura J.","family":"Smyth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2481-5162","authenticated-orcid":false,"given":"Claire","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8293-6982","authenticated-orcid":false,"given":"Stefan","family":"Mutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3568-9779","authenticated-orcid":false,"given":"Valma","family":"Harjutsalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3522-9660","authenticated-orcid":false,"given":"Zhuo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4494-1788","authenticated-orcid":false,"given":"Rama","family":"Natarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1705-2953","authenticated-orcid":false,"given":"Andrzej S.","family":"Krolewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel N.","family":"Hirschhorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1730-9325","authenticated-orcid":false,"given":"Jose C.","family":"Florez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"GENIE Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6110-7253","authenticated-orcid":false,"given":"Alexander P.","family":"Maxwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4055-6954","authenticated-orcid":false,"given":"Per-Henrik","family":"Groop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7482-709X","authenticated-orcid":false,"given":"Amy Jayne","family":"McKnight","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4322-6942","authenticated-orcid":false,"given":"Niina","family":"Sandholm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the FinnDiane Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"issue":"7","key":"6661_CR1","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/S2213-8587(22)00099-7","volume":"10","author":"F Jansson Sigfrids","year":"2022","unstructured":"Jansson Sigfrids F, Groop PH, Harjutsalo V (2022) Incidence rate patterns, cumulative incidence, and time trends for moderate and severe albuminuria in individuals diagnosed with type 1 diabetes aged 0\u201314 years: a population-based retrospective cohort study. 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Forsblom (1964\u20132022) for his considerable contribution to the FinnDiane study. We thank all FinnDiane participants and study nurses and physicians at the study centres (ESM Table\n                      \n                      ). We also wish to acknowledge the ELIXIR Finland node hosted at the CSC \u2013 IT Center for ICT Resources (Espoo, Finland), which enabled computational analysis. The participants and researchers for all look-up replication cohorts and datasets used in this study are greatly appreciated. We also wish to acknowledge the participants and investigators of the FinnGen study. Members of the GENIE Consortium are listed in ESM Table\n                      \n                      . Preliminary results of this study were presented in abstract form at the 34th Annual Meeting of the European Diabetic Nephropathy Study Group in Salzburg, Austria (May 2022).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The informed consent written by the participants does not allow public sharing of the FinnDiane data analysed during the current study. Summary statistics on associations with\n                      p\n                      <1\u00d710\n                      \u22124\n                      from the main analyses (EWAS) are available in ESM Table\n                      \n                      . For replication of our significant key findings, we accessed EWAS summary statistics from the Susztaklab Kidney Biobank (\n                      \n                      ;\n                      \n                      : eGFR, eGFR slope, AER and HbA\n                      1c\n                      in diabetes) [\n                      \n                      ],\n                      \n                      (eGFR and eGFR slope) [\n                      \n                      ],\n                      \n                      (pha004652 [eGFR]; pha004653 [incident CKD]; pha004651 [prevalent CKD]) [\n                      \n                      ],\n                      \n                      (albumin to creatinine ratio and eGFR) [\n                      \n                      ], and\n                      \n                      (eGFR) [\n                      \n                      ]. Look-ups on meQTL, eQTM, kidney single-cell gene expression and kidney gene expression datasets are based on published summary statistics that are downloadable or browsable online. In brief, meQTL data were obtained from\n                      \n                      (Genetics of DNA Methylation Consortium data; last accessed 5 May 2025) [\n                      \n                      ] and\n                      \n                      [\n                      \n                      ], eQTM data were obtained from\n                      \n                      (EWAS Toolkit; multiple tissues; last accessed 10 March 2025),\n                      \n                      (chronic renal insufficiency cohort, kidney) [\n                      \n                      ],\n                      \n                      (whole blood) [\n                      \n                      ],\n                      \n                      (monocytes) [\n                      \n                      ],\n                      \n                      (whole blood, children) [\n                      \n                      ] and\n                      \n                      (kidney) [\n                      \n                      ]. Kidney single-cell expression data were obtained from the Kidney Interactive Transcriptomics online analysis platform (\n                      \n                      ; last accessed 14 March 2025), human kidney transcriptomics data were accessed using Nephroseq version\u00a05 (\n                      \n                      ; last accessed 17 March 2025) and human kidney RNA sequencing data were obtained from\n                      \n                      [\n                      \n                      ] and\n                      \n                      [\n                      \n                      ]. GTEx version\u00a08 data were accessed through the GTEx Portal at\n                      \n                      (last accessed 19 April 2025) and used to study genetic variant association with gene expression. UKBB results on plasma proteome vs kidney outcome analyses [\n                      \n                      ] were accessed from\n                      \n                      (last accessed 13 May 2025). UKBB protein quantitative trait locus data for the chr19p13.3 locus were obtained from\n                      \n                      [\n                      \n                      ], the Type 1 Diabetes Knowledge Portal was accessed at\n                      \n                      (last accessed 14 August 2025) and GWAS summary statistics from the Finnish biobank (FinnGen) study data freeze 10 were accessed at\n                      \n                      (last accessed 10 March 2025). eGFR GWAS summary statistics (multiethnic, whole cohort) [\n                      \n                      ] were downloaded from\n                      \n                      . EWAS loci associated with incident CKD in type 2 diabetes are available in ESM Table\n                      \n                      , and were downloaded from\n                      \n                      [\n                      \n                      ]. Data for TF binding overlap with the CpGs were obtained from the University of California Santa Cruz Genome browser, GrCh37 (hg19) at\n                      \n                      (last accessed 19 March 2025) and the eFORGE-TF database (\n                      \n                      ; last accessed 4 May 2024).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open Access funding provided by University of Helsinki (including Helsinki University Central Hospital). The research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH under award numbers R01DK105154, R01DK132299, R01DK065073 and R01DK081705. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The FinnDiane study was supported by grants from Folkh\u00e4lsan Research Foundation and the Wilhelm and Else Stockmann Foundation, the Liv och H\u00e4lsa Society, by state funding for university-level health research by Helsinki University Hospital (TYH2023403), and by grants from the Sigrid Jus\u00e9lius Foundation (220027, 250214), the Novo Nordisk Foundation (NNF23OC0082732), the Academy of Finland (316664), the Finnish Diabetes Research Foundation and the Medical Society of Finland (Finska\u202fL\u00e4kares\u00e4llskapet). LJS was the recipient of a Northern Ireland Kidney Research Fund Fellowship. LJS, CH and AJM were supported by awards from HSC R&D Division (STL\/5569\/19) and the UK Research and Innovation Medical Research Council (MC_PC_20026). The Joslin Kidney Study was funded by NIH grants R01DK041526, R01DK110350, R01DK126799 and R01DK131061 (to ASK). For the Joslin Kidney Study, support was also obtained from the Wanek Family Project for Type 1 Diabetes at the City of Hope Beckman Research Institute (to RN).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"P-HG has received investigator-initiated research grants from Eli Lilly and Roche, is an advisory board member for AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme, Mundipharma, Nestl\u00e9, Novartis, Novo Nordisk and Sanofi, and has received lecture fees from Astellas, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Eli Lilly, ELO Water, Genzyme, Merck Sharp & Dohme, Medscape, Menarini, Mundipharma, Novartis, Novo Nordisk, PeerVoice, Sanofi and Sciarc. SM has received lecture honoraria from Encore Medical Education. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"AS designed the study, analysed the FinnDiane EWAS data, performed the downstream analyses and wrote the first draft of the manuscript. EHD participated in the FinnDiane methylation data collection and QC, and ran meQTL analyses. LJS generated the MethylationEPIC data for the FinnDiane and UK-ROI cohorts, and quality-controlled and analysed the EWAS data for the UK-ROI and NICOLA cohorts. CH analysed the human kidney expression data of Fan et\u00a0al [\n                      \n                      ] and Levin et\u00a0al [\n                      \n                      ]. SM contributed to the sample selection and QC for the FinnDiane OLINK protein data. VH and P-HG obtained funding and phenotypic data for the FinnDiane study. ZC ran the EWAS in the JKS cohort, and provided the replication results. RN contributed the EWAS data from the JKS. ASK contributed to the JKS cohort data acquisition and analysis. JNH and JCF contributed to obtaining funding for the GENIE Consortium, the study design and interpretation of the results. APM contributed to overall interpretation of the results of the study and analysis of the UK-ROI cohort data. AJM designed the study, acquired and analysed UK-ROI collection data and contributed to interpretation of the results of the study. NS designed the study, and contributed to the FinnDiane data collection and investigation and interpretation of the results of the study. AS, EHD, LJS, CH, SM, VH, ZC, RN, ASK, JNH, JCF, APM, P-HG, AJM and NS read and reviewed the manuscript draft, and all authors approved the final version. NS is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}