{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:01:59Z","timestamp":1791295319830,"version":"4.1.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011291","name":"National Key Laboratory of Science and Technology on Communications","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011291","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>It remains unclear whether cardiovascular-kidney-metabolic (CKM) syndrome and genetic susceptibility are associated with cancer incidence. This study aims to evaluate the associations between CKM health status, genetic susceptibility, and cancer incidence, and to develop a machine learning-based prediction model for cancer risk in patients with advanced CKM syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study included 399,034 UK Biobank participants (389,289 with genetic data). CKM health was categorized into stages 0\u20134. Genetic susceptibility was assessed via a polygenic risk score (PRS). Associations were evaluated using Cox proportional hazard models. For participants with advanced CKM, candidate predictors were screened via the Boruta algorithm, LASSO regression, and multivariable logistic regression. Eight machine learning models were constructed and validated, and their predictive discrimination, calibration performance, and clinical practical value were further assessed. Additionally, Shapley Additive Explanations (SHAP) were adopted to interpret the internal mechanism of the optimal model. The dose\u2013response relationship was assessed using restricted cubic splines (RCS), and mediation analysis was further performed to explore the underlying mechanism of the observed associations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      During a median follow-up of 13.7 years, 48,247 incident cancer cases were identified. Compared to CKM stage 0, multivariable-adjusted hazard ratios (HRs) were 1.01 (95% CI: 0.91-1.12) for stage 1, 1.21 (1.10\u20131.33) for stage 2, and 2.17 (1.95\u20132.42) for advanced CKM (stage 3\u20134). Participants with high PRS and advanced CKM faced the highest cancer risk (HR 3.24, 95% CI 2.68\u20133.93). A total of 14 predictors were retained after screening. The GBM model achieved the best predictive performance (test AUC\u00a0=\u00a00.801). A web-based calculator was developed to realize individualized cancer risk prediction. RCS analyses indicated that diastolic blood pressure (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>nonlinearity<\/jats:sub>\n                      &amp;lt;0.05), neutrophil count(\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>nonlinearity<\/jats:sub>\n                      &amp;lt;0.05), alkaline phosphatase (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>nonlinearity<\/jats:sub>\n                      =0.001), and TyG-BMI (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>nonlinearity<\/jats:sub>\n                      &amp;lt;0.05) were significantly and nonlinearly associated with cancer risk. Total bilirubin the strongest positive mediating effect, explaining 44.45% of the total association (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Advanced CKM syndrome independently increases incident cancer risk, and this elevated risk is significantly amplified by high genetic susceptibility. The validated GBM model provides an interpretable tool for individualized risk estimation, which serves as a valuable complementary tool for clinical risk stratification and cancer patients with, cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1884752","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T04:27:53Z","timestamp":1785731273000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiovascular-kidney-metabolic health, genetic susceptibility, and incident cancer risk: a prospective UK biobank cohort and machine learning study"],"prefix":"10.3389","volume":"17","author":[{"given":"Xue","family":"He","sequence":"first","affiliation":[{"name":"Graduate School, Beijing University of Chinese Medicine","place":["Beijing, China"]},{"name":"Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqiao","family":"An","sequence":"additional","affiliation":[{"name":"Graduate School, Beijing University of Chinese Medicine","place":["Beijing, China"]},{"name":"Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunjia","family":"Yan","sequence":"additional","affiliation":[{"name":"Graduate School, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Graduate School, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Graduate School, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Xu","sequence":"additional","affiliation":[{"name":"Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyong","family":"He","sequence":"additional","affiliation":[{"name":"Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000001184","article-title":"Cardiovascular-kidney-metabolic health: A presidential advisory from the American Heart Association","volume":"148","author":"Ndumele","year":"2023","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.6892","article-title":"Prevalence of cardiovascular-kidney-metabolic syndrome stages in US adults, 2011-2020","volume":"331","author":"Aggarwal","year":"2024","journal-title":"Jama"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000140677.20606.0e","article-title":"Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults","volume":"110","author":"Malik","year":"2004","journal-title":"Circulation"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/hypertensionaha.113.01925","article-title":"Metabolic syndrome and risk of incident peripheral artery disease: The cardiovascular health study","volume":"63","author":"Garg","year":"2014","journal-title":"Hypertension"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.744466","article-title":"Metabolic syndrome and risk of development of atrial fibrillation: The Niigata preventive medicine study","volume":"117","author":"Watanabe","year":"2008","journal-title":"Circulation"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfae200","article-title":"Metabolic syndrome and kidney disease: A systematic review and meta-analysis","volume":"6","author":"Thomas","year":"2011","journal-title":"Clin J Am Soc Nephrol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-8587(14)70032-4","article-title":"Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome","volume":"2","author":"Yki-J\u00e4rvinen","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2015.4899","article-title":"Metabolic syndrome and the risk of mild cognitive impairment and progression to dementia: Follow-up of the Singapore longitudinal ageing study cohort","volume":"73","author":"Ng","year":"2016","journal-title":"JAMA Neurol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.117.017709","article-title":"Type 2 diabetes mellitus and impaired renal function are associated with brain alterations and poststroke cognitive decline","volume":"48","author":"Ben Assayag","year":"2017","journal-title":"Stroke"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ehj.2004.02.021","article-title":"Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome","volume":"25","author":"Coughlin","year":"2004","journal-title":"Eur Heart J"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-0336","article-title":"Metabolic syndrome and risk of cancer: A systematic review and meta-analysis","volume":"35","author":"Esposito","year":"2012","journal-title":"Diabetes Care"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.4916046","article-title":"Association of metabolic syndrome with risk of lung cancer: A population-based prospective cohort study","volume":"165","author":"Li","year":"2024","journal-title":"Chest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/mou.0000000000001041","article-title":"Metabolic syndrome, obesity and cancer risk","volume":"32","author":"Belladelli","year":"2022","journal-title":"Curr Opin Urol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.jacc.2022.04.042","article-title":"Cardiovascular disease risk among cancer survivors: The atherosclerosis risk in communities (ARIC) study","volume":"80","author":"Florido","year":"2022","journal-title":"J Am Coll Cardiol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2020.04.080","article-title":"Cardiovascular disease burden in adult patients with cancer: An 11-year nationwide population-based cohort study","volume":"317","author":"Youn","year":"2020","journal-title":"Int J Cardiol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.06.531330","article-title":"Atherosclerosis is a smooth muscle cell-driven tumor-like disease","volume":"149","author":"Pan","year":"2024","journal-title":"Circulation"},{"key":"B17","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.jtho.2023.09.004","article-title":"Bidirectional association between cardiovascular disease and lung cancer in a prospective cohort study","volume":"19","author":"Zhang","year":"2024","journal-title":"J Thorac Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjpad.2025.100325","article-title":"Cardiovascular-kidney-metabolic health, genetic susceptibility, and the risk of dementia: A prospective cohort study","volume":"13","author":"Zhang","year":"2026","journal-title":"J Prev Alzheimers Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000001241","article-title":"Correction to: Cardiovascular-kidney-metabolic health: A presidential advisory from the American Heart Association","volume":"149","year":"2024","journal-title":"Circulation"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0800-0","article-title":"Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers","volume":"26","author":"Mars","year":"2020","journal-title":"Nat Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1158\/2159-8290.cd-21-1059","article-title":"Hallmarks of cancer: New dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov"},{"key":"B23","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/s41392-021-00658-5","article-title":"Inflammation and tumor progression: Signaling pathways and targeted intervention","volume":"6","author":"Zhao","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0295-5","article-title":"Hyperinsulinaemia in cancer","volume":"20","author":"Gallagher","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2790","DOI":"10.3390\/nu16162790","article-title":"Cancer and the microbiome of the human body","volume":"16","author":"Herrera-Quintana","year":"2024","journal-title":"Nutrients"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2020.07.003","article-title":"EMT, MET, plasticity, and tumor metastasis","volume":"30","author":"Bakir","year":"2020","journal-title":"Trends Cell Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00783-5","article-title":"The polygenic score catalog as an open database for reproducibility and systematic evaluation","volume":"53","author":"Lambert","year":"2021","journal-title":"Nat Genet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0252-y","article-title":"Artificial intelligence in digital pathology - new tools for diagnosis and precision oncology","volume":"16","author":"Bera","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/s41586-019-1799-6","article-title":"International evaluation of an AI system for breast cancer screening","volume":"577","author":"McKinney","year":"2020","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s42256-019-0138-9","article-title":"From local explanations to global understanding with explainable AI for trees","volume":"2","author":"Lundberg","year":"2020","journal-title":"Nat Mach Intell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.3390\/antiox12081613","article-title":"Genetics of plasma bilirubin and associations between bilirubin and cardiometabolic risk profiles in Danish children and adolescents","volume":"12","author":"Ullah","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-8587(22)00172-3","article-title":"Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: An individual participant-level data meta-analysis","volume":"10","author":"Nazarzadeh","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1911793","article-title":"Reduced lung-cancer mortality with volume CT screening in a randomized trial","volume":"382","author":"de Koning","year":"2020","journal-title":"N Engl J Med"}],"updated-by":[{"DOI":"10.3389\/fendo.2026.2006958","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000}}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1884752\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:19:26Z","timestamp":1791292766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1884752\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":33,"alternative-id":["10.3389\/fendo.2026.1884752"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1884752","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]},"article-number":"1884752"}}