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Department of Epidemiology, Center for Public Health, Medical University of Vienna, 1090. Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115. Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA 02115. Centre for Biological Timing, Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, United Kingdom. Diabetes, Endocrinology and Metabolism Centre, National Institute for Health and Care Research Manchester Biomedical Research Centre, Manchester University National Health Service Foundation Trust, Manchester M13 9WU, United Kingdom. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USAObjectives To prospectively evaluate the association between combined circadian imbalance related traits and cardiovascular-kidney-metabolic (CKM) disease incidence, and their interaction with night shift work.Methods 191,764 UK Biobank participants employed and without major chronic diseases at baseline were included. Our novel score incorporates factors that may adversely affect the circadian system – the Circadian Imbalance Index (CII), with evening chronotype, short or long sleep duration (≥9 or ≤6 hours/day), high neuroticism score (≥7), atypical caffeine consumption (0 or ≥5 caffeinated coffee cups/day), and low vitamin D levels (<50 nmol/L), each contributing 1 point if present, resulting in a scale ranging from 0-5. Current night shift work status was categorized as day workers, shift workers and night shift workers. The CKM outcome comprised type 2 diabetes, cardiovascular diseases and chronic kidney diseases, identified via inpatient ICD codes, self-reports, or death records. Cox models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), investigating associations between the CII and CKM incidence, and effect modification by night shift work.Results During a median follow-up of 13.5 years, 16,907 incident CKM cases were identified. A significant trend of CKM risk with increasing CII was observed in participants of European (Ptrend<0.001) and Asian (Ptrend<0.001), but not in African ancestry. Among Europeans, the adjusted HR for CKM comparing participants scoring highest to those scoring 0-1 on CII was 1.95 (95%CI: 1.70-2.23; Ptrend<0.001). The joint effect of high CII and night shift work on CKM was HR=2.22 (95%CI: 1.95-2.53), with a significant additive interaction (P<0.05).Conclusion We observed an association between CII and CKM incidence in Europeans and Asians. Among Europeans, a high CII combined with night shift work was associated with the highest CKM rate, suggesting that maintaining low CII may help prevent CKM disease, with greater benefits observed for night shift workers.