Misalignment between circadian preference and accelerometer-derived actual sleep-wake cycle is associated with increased risk of cardiometabolic diseases: a prospective cohort study in UK Biobank

BackgroundEvidence has linked several circadian disruption indicators, such as social jetlag and shift work, to adverse health outcomes, however, associations of misalignment between circadian preference and actual sleep-wake cycle with cardiometabolic diseases (CMDs) remains unclear. We aimed to prospectively investigate the associations of the circadian misalignment with CMDs including type 2 diabetes (T2D), chronic heart diseases (CHD), and stroke, and to uncover potential mechanisms linking circadian misalignment and CMDs. MethodsA total of 60,965 participants from the UK Biobank study without baseline CMDs and followed-up for an average of 7.9 years were included in the current analysis. Circadian misalignment was defined as discrepancies between self-reported chronotype and accelerometer-derived midpoint of sleep to detect its association with CMDs. Incident CMDs were derived from primary care, hospital inpatient, death registry, and self-reported source of data. Cox proportional hazards regression models were used to compute the hazard ratio (HR) and confidence intervals (CIs) on the association between circadian misalignment (quintiles of residuals of midsleep on chronotype) and incident CMDs. ResultsU-shaped associations were found of the circadian misalignment with incident T2D and CHD after adjusting the potential confounders. Compared to individuals with aligned midsleep and circadian preferences (Q3), those with advanced and delayed circadian misalignment had higher risks of T2D [HR (95%CI) 1.22 (1.03, 1.45) in Q1 and 1.39 (1.18, 1.62) in Q5]. However, only delayed circadian misalignment was significantly associated with an increased risk of CHD [HR (95%CI) 1.15 (1.01, 1.31) in Q4 and 1.16 (1.02, 1.33) in Q5]. Liver function, lipid and glucose metabolism, and inflammatory markers partially explained the observed circadian misalignment and CMDs association (mediation proportion 12.3-44.6% for T2D, 8.8-20.5% for CHD). Moreover, the association between delayed circadian misalignment and CMDs was more prominent in women (for T2D, Pinteraction=0.03) and in younger adults (for CHD, Pinteraction=0.02) compared to their counterparts. Additionally, early chronotype [HR (95%CI): 1.19 (1.06, 1.34)] rather than late chronotype was associated with an increased risk of incident T2D. ConclusionBoth advanced and delayed circadian misalignment were associated with increased risks of CMDs, suggesting potential benefits of aligning actual sleep-wake cycles with individual circadian preferences. Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABSO_LICardiometabolic diseases such as type 2 diabetes, coronary heart disease, and cerebrovascular diseases have become major concerns in global public health over recent decades. C_LIO_LIEvidence has linked several circadian disruption indicators to adverse health outcomes: People living with late chronotype (circadian preference), late sleep timing, long social jetlag (the difference between midsleep on work-free days and work days), and shift work were prone to introduce circadian disruptions and had higher risks of cardiometabolic diseases. C_LIO_LILittle is known about whether and how the misalignment between circadian preference and actual sleep-wake cycle is associated with cardiometabolic diseases, particularly in large prospective cohort studies. C_LI What New Information Does This Article Contribute?O_LIThis is the first study to propose a new metrics (misalignment between circadian preference and actual sleep-wake cycle) to shed some lights on quantifying human circadian disruption in general population of differed work schedule and in population with less disrupted circadian rhythm. C_LIO_LIBoth advanced and delayed sleep-wake cycle comparing to individual circadian preference were associated with increased risks of cardiometabolic diseases. Population may benefit from keeping an actual sleep-wake cycle in accordance with their circadian preference. C_LIO_LIEarly chronotype rather than late chronotype were found to associate with an increased risk of incident T2D, independent of actual sleep-wake cycle. C_LIO_LIAge and sex modified the associations between circadian misalignment and cardiometabolic diseases, while liver function, lipid and glucose metabolism, and inflammatory markers partially mediated the associations. C_LI