{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T14:38:23Z","timestamp":1786372703461,"version":"build-2736575974"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01HL163972"],"award-info":[{"award-number":["R01HL163972"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902 and U24DK060990"],"award-info":[{"award-number":["U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902 and U24DK060990"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"crossref","award":["UL1TR000003,UL1 TR-000424,GCRC M01 RR-16500, UL1TR000439,UL1TR000433, UL1RR029879, P20 GM109036, UL1 RR-024131, NM R01DK119199"],"award-info":[{"award-number":["UL1TR000003,UL1 TR-000424,GCRC M01 RR-16500, UL1TR000439,UL1TR000433, UL1RR029879, P20 GM109036, UL1 RR-024131, NM R01DK119199"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Manchester Biomedical Research Center","award":["NIHR"],"award-info":[{"award-number":["NIHR"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["CJASN"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:sec>\n                    <jats:title>Key Points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Type 2 diabetes partitioned polygenic scores capture metabolic profiles for obesity,\n                            <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                            -cell with positive proinsulin, and lipodystrophy clusters in CKD.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The type 2 diabetes obesity genetic cluster was associated with higher risk of overall mortality among individuals with CKD.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Type 2 diabetes (T2D) exhibits biologic and pathophysiologic heterogeneity, which may contribute to variations in diabetes-related complications, particularly in high-risk populations such as individuals with CKD. Prior research has explored T2D mechanisms using partitioned polygenic scores (pPGS), derived from distinct clusters of variants according to their associations with cardiometabolic traits. In this study, we investigated whether cluster-specific pPGS are associated with cardiovascular outcomes and CKD progression in individuals with CKD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used genome-wide genotype data from the Chronic Renal Insufficiency Cohort (CRIC) to calculate both a total polygenic score for T2D and pPGS for T2D clusters. We examined their associations with cardiometabolic traits and conducted time-to-event analysis to assess their association with mortality (overall and cardiovascular), incident cardiovascular outcomes (myocardial infarction, stroke, heart failure, atrial fibrillation [AFIB], peripheral artery disease, and a composite of major cardiovascular events), and CKD progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 3577 CRIC participants (mean age 58 years, 45% were women, 49% had T2D), the total polygenic score was significantly associated with higher hemoglobin A1c (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 4.8\u00d710\n                      <jats:sup>\u221221<\/jats:sup>\n                      ) among nondiabetic participants. Cluster-specific pPGS in CRIC captured distinct cardiometabolic profiles corresponding to T2D mechanistic subtypes, particularly the obesity cluster, the\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -cell dysfunction with positive proinsulin cluster, and the lipodystrophy cluster. The obesity cluster pPGS was significantly associated with incident AFIB (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 2.89\u00d710\n                      <jats:sup>\u22124<\/jats:sup>\n                      ) and overall mortality (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 4.29\u00d710\n                      <jats:sup>\u22124<\/jats:sup>\n                      ), but the association with AFIB was attenuated when accounting for competing risk of death (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.002). The\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -cell dysfunction with negative proinsulin cluster was inversely associated with CKD progression (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 2.48\u00d710\n                      <jats:sup>\u22125<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that T2D driven by insulin resistance and obesity contributes to a higher risk of overall death in individuals with CKD and explain in part the higher risk of AFIB. These results highlight the importance of considering T2D heterogeneity when assessing cardiovascular risk in this population.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2215\/cjn.0000000882","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T17:00:18Z","timestamp":1764090018000},"page":"221-228","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Diabetes Genetic Clusters and Clinical Outcomes in the Chronic Renal Insufficiency Cohort"],"prefix":"10.2215","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8563-6339","authenticated-orcid":false,"given":"Kaylia M.","family":"Reynolds","sequence":"first","affiliation":[{"name":"Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daohang","family":"Sha","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Epidemiology and Biostatistics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-2803","authenticated-orcid":false,"given":"Quan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina"},{"name":"Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshin","family":"Parsa","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9035-9126","authenticated-orcid":false,"given":"Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3559-4374","authenticated-orcid":false,"given":"Hernan","family":"Rincon-Choles","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine and Neurology, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0498-1980","authenticated-orcid":false,"given":"Ruth","family":"Dubin","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8286-9652","authenticated-orcid":false,"given":"Jiang","family":"He","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Departments of Internal Medicine and Neurology, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8182-1238","authenticated-orcid":false,"given":"Chi-Yuan","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University of California, San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0919-3825","authenticated-orcid":false,"given":"Kristine","family":"Yaffe","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry, Neurology and Epidemiology and Biostatistics, University of California, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3584-4057","authenticated-orcid":false,"given":"Vallabh","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9647-083X","authenticated-orcid":false,"given":"Dominic","family":"Raj","sequence":"additional","affiliation":[{"name":"Division of Renal Diseases and Hypertension, George Washington University School of Medicine and Health Sciences, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-4002","authenticated-orcid":false,"given":"Sylvia E.","family":"Rosas","sequence":"additional","affiliation":[{"name":"Joslin Diabetes Center and Harvard University, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6580-4080","authenticated-orcid":false,"given":"James P.","family":"Lash","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University of Illinois Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Morris","sequence":"additional","affiliation":[{"name":"Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, United Kingdom"},{"name":"NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8346-3662","authenticated-orcid":false,"given":"Nora","family":"Franceschini","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina"},{"name":"Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the CRIC Study Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"issue":"49","key":"B2-20260318","article-title":"Percentage of adults aged 18 years or older with diagnosed diabetes, by urbanization level and age group - national health interview survey, United States, 2022","volume":"73","year":"2024","journal-title":"MMWR Morb Mortal Wkly Rep."},{"issue":"10397","key":"B3-20260318","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0140-6736(23)01301-6","article-title":"Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the global Burden of disease Study 2021","volume":"402","author":"Ong","year":"2023","journal-title":"Lancet."},{"issue":"1","key":"B4-20260318","doi-asserted-by":"crossref","first-page":"26","DOI":"10.2337\/dci23-0085","article-title":"Economic costs of diabetes in the U.S. in 2022","volume":"47","author":"Parker","year":"2024","journal-title":"Diabetes Care."},{"issue":"1 suppl 1","key":"B5-20260318","first-page":"S27","article-title":"2. Diagnosis and classification of diabetes: standards of care in diabetes-2025","volume":"48","author":"ElSayed","year":"2025","journal-title":"Diabetes Care."},{"issue":"13","key":"B6-20260318","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1056\/NEJMoa041031","article-title":"Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization","volume":"351","author":"Go","year":"2004","journal-title":"N Engl J Med."},{"issue":"1","key":"B7-20260318","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41591-024-03413-9","article-title":"Genetic insights into global heterogeneity of type 2 diabetes","volume":"31","author":"Udler","year":"2025","journal-title":"Nat Med."},{"issue":"5","key":"B8-20260318","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S2213-8587(18)30051-2","article-title":"Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables","volume":"6","author":"Ahlqvist","year":"2018","journal-title":"Lancet Diabetes Endocrinol."},{"issue":"7","key":"B9-20260318","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.3390\/jcm9072083","article-title":"Factors associated with risk of diabetic complications in novel cluster-based diabetes subgroups: a Japanese Retrospective Cohort Study","volume":"9","author":"Tanabe","year":"2020","journal-title":"J Clin Med."},{"key":"B10-20260318","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/s41591-024-02865-3","article-title":"Multi-ancestry polygenic mechanisms of type 2 diabetes","volume":"30","author":"Smith","year":"2024","journal-title":"Nat Med."},{"issue":"3","key":"B11-20260318","doi-asserted-by":"crossref","first-page":"674","DOI":"10.2337\/dc21-1395","article-title":"Type 2 diabetes partitioned polygenic scores associate with disease outcomes in 454,193 individuals across 13 cohorts","volume":"45","author":"DiCorpo","year":"2022","journal-title":"Diabetes Care."},{"issue":"8003","key":"B12-20260318","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","article-title":"Genetic drivers of heterogeneity in type 2 diabetes pathophysiology","volume":"627","author":"Suzuki","year":"2024","journal-title":"Nature."},{"issue":"7 suppl 2","key":"B13-20260318","doi-asserted-by":"crossref","first-page":"S148","DOI":"10.1097\/01.ASN.0000070149.78399.CE","article-title":"The Chronic Renal Insufficiency Cohort (CRIC) Study: design and methods","volume":"14","author":"Feldman","year":"2003","journal-title":"J Am Soc Nephrol."},{"issue":"8","key":"B14-20260318","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.2215\/CJN.00070109","article-title":"Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function","volume":"4","author":"Lash","year":"2009","journal-title":"Clin J Am Soc Nephrol."},{"issue":"2","key":"B15-20260318","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1053\/j.ajkd.2012.04.012","article-title":"Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) Study","volume":"60","author":"Anderson","year":"2012","journal-title":"Am J Kidney Dis."},{"issue":"2","key":"B16-20260318","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1681\/ASN.2013050465","article-title":"Fibroblast growth factor-23 and cardiovascular events in CKD","volume":"25","author":"Scialla","year":"2014","journal-title":"J Am Soc Nephrol."},{"issue":"2 suppl 1","key":"B17-20260318","first-page":"S86","article-title":"Sex differences in the incidence of peripheral artery disease in the chronic renal insufficiency cohort","volume":"9","author":"Wang","year":"2016","journal-title":"Circ Cardiovasc Qual Outcomes."},{"issue":"6","key":"B18-20260318","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.ahj.2010.03.027","article-title":"Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC)","volume":"159","author":"Soliman","year":"2010","journal-title":"Am Heart J."},{"issue":"23","key":"B19-20260318","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1056\/NEJMoa1310345","article-title":"APOL1 risk variants, race, and progression of chronic kidney disease","volume":"369","author":"Parsa","year":"2013","journal-title":"N Engl J Med."},{"issue":"8","key":"B20-20260318","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/ng1847","article-title":"Principal components analysis corrects for stratification in genome-wide association studies","volume":"38","author":"Price","year":"2006","journal-title":"Nat Genet."},{"issue":"5","key":"B21-20260318","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1093\/bioinformatics\/btu704","article-title":"minimac2: faster genotype imputation","volume":"31","author":"Fuchsberger","year":"2015","journal-title":"Bioinformatics."},{"issue":"4","key":"B22-20260318","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.ajhg.2019.08.012","article-title":"Harmonizing genetic ancestry and self-identified race\/ethnicity in genome-wide association studies","volume":"105","author":"Fang","year":"2019","journal-title":"Am J Hum Genet."},{"issue":"446","key":"B23-20260318","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","article-title":"A proportional hazards model for the subdistribution of a competing risk","volume":"94","author":"Fine","year":"1999","journal-title":"J Am Stat Assoc."},{"issue":"5","key":"B24-20260318","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1097\/01.ASN.0000123691.46138.E2","article-title":"Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies","volume":"15","author":"Weiner","year":"2004","journal-title":"J Am Soc Nephrol."},{"issue":"5","key":"B25-20260318","doi-asserted-by":"crossref","first-page":"e001303","DOI":"10.1161\/JAHA.114.001303","article-title":"Incident atrial fibrillation and risk of death in adults with chronic kidney disease","volume":"3","author":"Bansal","year":"2014","journal-title":"J Am Heart Assoc."},{"issue":"4","key":"B26-20260318","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1001\/jama.2024.22451","article-title":"Atrial fibrillation: a Review","volume":"333","author":"Ko","year":"2025","journal-title":"JAMA."},{"issue":"3","key":"B27-20260318","doi-asserted-by":"crossref","first-page":"105","DOI":"10.31083\/j.rcm2303105","article-title":"Insights into concomitant atrial fibrillation and chronic kidney disease","volume":"23","author":"Wang","year":"2022","journal-title":"Rev Cardiovasc Med."},{"issue":"11","key":"B28-20260318","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.2215\/CJN.04260415","article-title":"Chronic Renal Insufficiency Cohort Study (CRIC): overview and summary of selected findings","volume":"10","author":"Denker","year":"2015","journal-title":"Clin J Am Soc Nephrol."},{"issue":"14","key":"B29-20260318","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1016\/j.jacc.2019.08.1017","article-title":"Chronic kidney disease and coronary artery disease: JACC state-of-the-art review","volume":"74","author":"Sarnak","year":"2019","journal-title":"J Am Coll Cardiol."}],"container-title":["Clinical Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.2215\/CJN.0000000882","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T13:37:00Z","timestamp":1786369020000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.2215\/CJN.0000000882"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.2215\/cjn.0000000882","relation":{},"ISSN":["1555-9041","1555-905X"],"issn-type":[{"value":"1555-9041","type":"print"},{"value":"1555-905X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]},"assertion":[{"value":"2025-05-16","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-20","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}