{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:52:07Z","timestamp":1785909127150,"version":"3.56.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although the triglyceride\u2013glucose (TyG) index is an established surrogate marker of insulin resistance and metabolic burden, its relationship with hyperhomocysteinemia (HHcy) within the cardiovascular\u2013kidney\u2013metabolic (CKM) framework remains insufficiently understood. This study aimed to investigate the association between TyG and HHcy and to prioritize CKM-related biomarkers using interpretable machine learning and epidemiological modeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective cross-sectional study included 31,116 adults undergoing health examinations. HHcy was defined as serum homocysteine &amp;gt;15\u202f\u03bcmol\/L. The relationships among CKM-related biomarkers were characterized using smooth curve fitting, Spearman correlation heatmaps, and network visualization. An extreme gradient boosting model coupled with SHapley Additive exPlanations was used to evaluate feature importance for HHcy identification. Sequential multivariable logistic regression and restricted cubic spline analyses were performed to assess the linear and nonlinear associations between TyG and HHcy. Subgroup and sensitivity analyses were conducted to assess the robustness of the observed associations, including alternative adiposity adjustment, creatinine-based estimated glomerular filtration rate substitution, and restriction of extreme TyG values.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Network analysis showed that TyG clustered predominantly with adiposity and metabolic indices, whereas homocysteine showed closer connectivity with renal-function-related markers. Within the prespecified CKM-related candidate feature set, creatinine ranked highest for HHcy identification, whereas TyG provided limited incremental discriminatory information beyond basic clinical characteristics. In sequential logistic regression, the TyG\u2013HHcy association changed substantially across adjustment models: a crude positive association was attenuated and became inverse after adjustment for CKM-related covariates. In Model 4, which additionally adjusted for log(C-reactive protein + 1) and serum creatinine, each one-unit increase in TyG was associated with lower odds of HHcy (OR\u202f=\u202f0.819, 95% CI: 0.765\u20130.877). Restricted cubic spline analysis indicated a significant nonlinear association (P-nonlinear &amp;lt; 0.001).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TyG appears to be embedded as a metabolic component within a broader CKM biomarker network, whereas renal-function-related markers, particularly creatinine, are more closely linked to the HHcy phenotype. These findings support a CKM network-based interpretation of the TyG\u2013HHcy relationship and highlight the relevance of metabolic\u2013renal interrelationships in cardiometabolic risk assessment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1898997","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:38:35Z","timestamp":1785908315000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Triglyceride\u2013glucose index and hyperhomocysteinemia within a cardiovascular\u2013kidney\u2013metabolic biomarker network: insights from interpretable machine learning and epidemiological modeling"],"prefix":"10.3389","volume":"13","author":[{"given":"Hongzhou","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Aerospace Center Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Beijing Jishuitan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huadan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Jinxiang Grand Hospital","place":["Jining, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Aerospace Center Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Aerospace Center Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manka","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Aerospace Center Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Aerospace Center Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangtong","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Second Medical Center, Chinese PLA General Hospital & National Clinical Research Center for Geriatric Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"4907","DOI":"10.1007\/s11010-025-05284-1","article-title":"Dysregulated homocysteine metabolism and cardiovascular disease and clinical treatments","volume":"480","author":"Cao","year":"2025","journal-title":"Mol Cell Biochem"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1109445","DOI":"10.3389\/fcvm.2022.1109445","article-title":"Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis","volume":"9","author":"Yuan","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"746","DOI":"10.3390\/ijms26020746","article-title":"Homocysteine metabolites, endothelial dysfunction, and cardiovascular disease","volume":"26","author":"Jakubowski","year":"2025","journal-title":"Int J Mol Sci"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1186\/s12882-023-03295-y","article-title":"Association of hyperhomocysteinemia and chronic kidney disease in the general population: a systematic review and meta-analysis","volume":"24","author":"Chen","year":"2023","journal-title":"BMC Nephrol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.1038\/s41440-024-01613-x","article-title":"Associations of total homocysteine and kidney function with all-cause and cause-specific mortality in hypertensive patients: a mediation and joint analysis","volume":"47","author":"Ding","year":"2024","journal-title":"Hypertens Res"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1007\/s10157-025-02762-0","article-title":"Combined effect of hyperhomocysteinemia and mild-to-moderate chronic kidney disease on mortality and cardiovascular events in the Japanese general population: the Yamagata (Takahata) study","volume":"29","author":"Takehara","year":"2025","journal-title":"Clin Exp Nephrol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e15573","DOI":"10.14814\/phy2.15573","article-title":"Homocysteine exchange across skeletal muscle in patients with chronic kidney disease","volume":"11","author":"Garibotto","year":"2023","journal-title":"Physiol Rep"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.pcad.2024.10.012","article-title":"Cardiovascular-kidney-metabolic syndrome - an integrative review","volume":"87","author":"Kittelson","year":"2024","journal-title":"Prog Cardiovasc Dis"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1606","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":"ref10","doi-asserted-by":"publisher","first-page":"2608","DOI":"10.1016\/j.ekir.2024.05.033","article-title":"Combination of cardiovascular, kidney, and metabolic diseases in a syndrome named cardiovascular-kidney-metabolic, with new risk prediction equations","volume":"9","author":"Massy","year":"2024","journal-title":"Kidney Int Rep"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"31352","DOI":"10.1038\/s41598-024-82881-y","article-title":"Elevated triglyceride glucose index is associated with advanced cardiovascular kidney metabolic syndrome","volume":"14","author":"Wu","year":"2024","journal-title":"Sci Rep"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.ccl.2025.03.001","article-title":"Cardiovascular-kidney-metabolic health: definition, staging, risk assessment, and therapeutic considerations","volume":"43","author":"Solomon","year":"2025","journal-title":"Cardiol Clin"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"961","DOI":"10.3904\/kjim.2025.082","article-title":"Association of the triglyceride-glucose index with cardiovascular outcomes across cardiovascular-kidney-metabolic syndrome stages","volume":"40","author":"Kim","year":"2025","journal-title":"Korean J Intern Med"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"3347","DOI":"10.1210\/jc.2010-0288","article-title":"The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp","volume":"95","author":"Guerrero-Romero","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1186\/s12933-024-02392-y","article-title":"Diagnostic and prognostic value of triglyceride glucose index: a comprehensive evaluation of meta-analysis","volume":"23","author":"Nayak","year":"2024","journal-title":"Cardiovasc Diabetol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1186\/s12944-024-02412-6","article-title":"The role of the triglyceride-glucose index as a biomarker of cardio-metabolic syndromes","volume":"23","author":"Gounden","year":"2024","journal-title":"Lipids Health Dis"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1656800","DOI":"10.3389\/fendo.2025.1656800","article-title":"Predictive value of the triglyceride-glucose index for adverse clinical outcomes in chronic kidney disease","volume":"16","author":"Lee","year":"2025","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"3035","DOI":"10.1007\/s11357-023-01044-5","article-title":"Baseline and usual triglyceride-glucose index and the risk of chronic kidney disease: a prospective cohort study","volume":"46","author":"Kunutsor","year":"2024","journal-title":"Geroscience"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s12882-025-04714-y","article-title":"Homocysteine levels alter the TyG index-CKD link in Chinese hypertensive patients","volume":"27","author":"Zhou","year":"2025","journal-title":"BMC Nephrol"},{"key":"ref20","first-page":"83","article-title":"Predictive values of body mass index and waist circumference for risk factors of certain related diseases in Chinese adults--study on optimal cut-off points of body mass index and waist circumference in Chinese adults","volume":"15","author":"Zhou","year":"2002","journal-title":"Biomed Environ Sci"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1145\/2939672.2939785","volume-title":"Proceedings of the 22nd ACM SIGKDD international conference on knowledge discovery and data mining","author":"Chen","year":"2016"},{"key":"ref22","author":"Lundberg","year":"2017"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1002\/sim.3841","article-title":"Dose-response analyses using restricted cubic spline functions in public health research","volume":"29","author":"Desquilbet","year":"2010","journal-title":"Stat Med"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1056\/NEJMoa2102953","article-title":"New creatinine- and cystatin C-based equations to estimate GFR without race","volume":"385","author":"Inker","year":"2021","journal-title":"N Engl J Med"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1016\/j.numecd.2024.01.030","article-title":"Triglyceride glucose index combined with body mass index and its 4-year change with the risk of hypertension in middle-aged and older Chinese: a prospective cohort study","volume":"34","author":"Liu","year":"2024","journal-title":"Nutr Metab Cardiovasc Dis"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"17687","DOI":"10.1038\/s41598-025-02342-y","article-title":"Association of body mass index combined with triglyceride-glucose index in cardiovascular disease risk: a prospective cohort study","volume":"15","author":"Cheng","year":"2025","journal-title":"Sci Rep"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"413","DOI":"10.3760\/cma.j.cn112148-20230911-00149","article-title":"Association of triglyceride glucose index and risk of incident hypertension: a prospective cohort study","volume":"52","author":"Chen","year":"2024","journal-title":"Zhonghua Xin Xue Guan Bing Za Zhi"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1177\/00033197251390139","article-title":"Triglyceride-glucose index mediated by metabolic burden predicts cardiovascular events in patients with complex coronary lesions: a prospective cohort study","volume":"77","author":"Zheng","year":"2026","journal-title":"Angiology"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"492","DOI":"10.3390\/nu17030492","article-title":"The association between the triglyceride-glucose index, its combination with the body roundness index, and chronic kidney disease in patients with type 2 diabetes in eastern China: a preliminary study","volume":"17","author":"Chen","year":"2025","journal-title":"Nutrients"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1018083","DOI":"10.3389\/fmed.2022.1018083","article-title":"The non-linear relationship between triglyceride-glucose index and risk of chronic kidney disease in hypertensive patients with abnormal glucose metabolism: a cohort study","volume":"9","author":"Zhu","year":"2022","journal-title":"Front Med (Lausanne)"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/s12933-024-02215-0","article-title":"Association between triglyceride-glucose related indices with the all-cause and cause-specific mortality among the population with metabolic syndrome","volume":"23","author":"Wei","year":"2024","journal-title":"Cardiovasc Diabetol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s12933-023-01843-2","article-title":"Association between the triglyceride glucose index and in-hospital and 1-year mortality in patients with chronic kidney disease and coronary artery disease in the intensive care unit","volume":"22","author":"Ye","year":"2023","journal-title":"Cardiovasc Diabetol"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1159\/000142725","article-title":"Two cardiovascular risk factors in one? Homocysteine and its relation to glomerular filtration rate. A meta-analysis of 41 studies with 27,000 participants","volume":"31","author":"Kielstein","year":"2008","journal-title":"Kidney Blood Press Res"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1159\/000114300","article-title":"Positive association between plasma homocysteine level and chronic kidney disease","volume":"31","author":"Shankar","year":"2008","journal-title":"Kidney Blood Press Res"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1046\/j.1523-1755.63.s84.7.x","article-title":"Homocysteine, renal function, and risk of cardiovascular disease","author":"Clarke","year":"2003","journal-title":"Kidney Int Suppl"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"231","DOI":"10.3967\/bes2023.026","article-title":"Association between serum uric acid and the early marker of kidney function decline among Chinese middle-aged and older population: evidence from the China health and retirement longitudinal study","volume":"36","author":"Tang","year":"2023","journal-title":"Biomed Environ Sci"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1161\/CIRCULATIONAHA.120.050686","article-title":"Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options","volume":"143","author":"Jankowski","year":"2021","journal-title":"Circulation"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.2147\/DMSO.S425511","article-title":"Serum uric acid is a better indicator of kidney impairment than serum uric acid-to-creatinine ratio and serum uric acid-to-high-density lipoprotein ratio: a cross-sectional study of type 2 diabetes mellitus patients","volume":"16","author":"Han","year":"2023","journal-title":"Diabetes Metab Syndr Obes"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e40577","DOI":"10.1097\/MD.0000000000040577","article-title":"Serum homocysteine and left ventricular hypertrophy in adults with chronic kidney disease: a case-control study","volume":"103","author":"Lei","year":"2024","journal-title":"Medicine (Baltimore)"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1111\/jch.13398","article-title":"Association between plasma homocysteine and hypertension: results from a cross-sectional and longitudinal analysis in Beijing\u2019s adult population from 2012 to 2017","volume":"20","author":"Tao","year":"2018","journal-title":"J Clin Hypertens (Greenwich)"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"e16110","DOI":"10.1016\/j.heliyon.2023.e16110","article-title":"Essential properties and explanation effectiveness of explainable artificial intelligence in healthcare: a systematic review","volume":"9","author":"Jung","year":"2023","journal-title":"Heliyon"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"2798","DOI":"10.1002\/ehf2.14834","article-title":"Development of interpretable machine learning models to predict in-hospital prognosis of acute heart failure patients","volume":"11","author":"Tanaka","year":"2024","journal-title":"ESC Heart Fail"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"17728","DOI":"10.1038\/s41598-024-67844-7","article-title":"SHAP based predictive modeling for 1 year all-cause readmission risk in elderly heart failure patients: feature selection and model interpretation","volume":"14","author":"Luo","year":"2024","journal-title":"Sci Rep"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"e045732","DOI":"10.1136\/bmjopen-2020-045732","article-title":"Association between dietary antioxidant vitamins intake and homocysteine levels in middle-aged and older adults with hypertension: a cross-sectional study","volume":"11","author":"Peng","year":"2021","journal-title":"BMJ Open"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"e090223213539","DOI":"10.2174\/1573403X19666230209111854","article-title":"Homocysteine, vitamin B12 and folate level: possible risk factors in the progression of chronic heart and kidney disorders","volume":"19","author":"Mohan","year":"2023","journal-title":"Curr Cardiol Rev"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1186\/s13148-026-02169-y","article-title":"Exercise-specific epigenetic effects on cardiovascular health","volume":"18","author":"Huang","year":"2026","journal-title":"Clin Epigenetics"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1016\/j.scib.2025.05.017","article-title":"Intermittent fasting and cardiovascular health: a circadian rhythm-based approach","volume":"70","author":"Zhang","year":"2025","journal-title":"Sci Bull (Beijing)"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/s41538-026-00862-z","article-title":"The association of time-restricted eating and indices of organ-specific aging in relation to metabolic health and obesity","volume":"10","author":"Sheng","year":"2026","journal-title":"NPJ Sci Food"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s12877-025-06727-6","article-title":"Association of atherosclerosis cardiovascular diseases with hearing loss in older people: a cross-sectional age-stratified analyses of 4,441 participants","volume":"26","author":"Sheng","year":"2026","journal-title":"BMC Geriatr"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"102907","DOI":"10.1016\/j.xcrm.2026.102907","article-title":"Metabolomic and lifestyle profiles refine BMI-metabolic phenotypes in older adults","volume":"7","author":"Chen","year":"2026","journal-title":"Cell Rep Med"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1898997\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:38:38Z","timestamp":1785908318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1898997\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":50,"alternative-id":["10.3389\/fnut.2026.1898997"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2026.1898997","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"article-number":"1898997"}}