A newly developed circadian imbalance index (CII) and risk of cardiovascular-kidney-metabolic disease in the UK biobank

To examine the association between combined circadian imbalance related traits and cardiovascular-kidney-metabolic (CKM) disease risk, and their potential interaction with night shift work. This study included 191,764 UK Biobank participants without major chronic diseases who were employed at baseline (2006–2010). The Circadian Imbalance Index (CII) was developed by combining several factors indicative of a propensity for circadian misalignment. One point was assigned for each of the following components if present: evening chronotype, sleep duration ≤ 6 or ≥ 9 h/day, high neuroticism (score ≥ 7), atypical caffeinated coffee consumption (0 or ≥ 5 cups/day), and vitamin D (< 50 nmol/L), resulting in a composite scale from 0 to 5. CKM outcome (type 2 diabetes, cardiovascular diseases, chronic kidney diseases) identified by ICD codes, self-reports, or death records. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the multivariable (MV)-adjusted association between the CII and CKM risk, including effect modification by night shift work. During a median follow-up of 13.5 years (through 2022), 16,907 incident CKM cases were identified. Among participants with European ancestry, for highest versus lowest (0–1) CII, the MV-adjusted risk of CKM was 1.95 (95%CI: 1.70–2.23; Ptrend<0.001). A significant positive relationship between CII and CKM risk was also observed in participants of Asian (HR = 2.03, 95%CI, 1.07–3.86; Ptrend=0.002), but not African ancestry (HR = 1.43, 95%CI, 0.67–3.06; Ptrend=0.35). Risks were higher in shift and night workers than day workers. Among Europeans, the HR for highest CII combined with current night shift work was 2.22 (95%CI, 1.95–2.53), with significant additive interaction (P < 0.05). In this large prospective study, Circadian Imbalance Index (CII) was associated with higher CKM risk in Europeans and Asians. Among Europeans, high CII plus night shift work posed the greatest risk.