Circadian imbalance and incident hypertension in the UK Biobank with exploratory molecular analyses

Circadian imbalance may contribute to hypertension, but its association with incident hypertension, genetic susceptibility, and molecular pathways remains unclear. This prospective study included 107,270 UK Biobank participants free of hypertension at baseline. The circadian imbalance index (CII) was constructed from 5 factors: chronotype, sleep duration, neuroticism, caffeinated coffee intake, and serum vitamin D levels. During 1,690,083 person-years of follow-up, 10,311 cases occurred. Each 1-point increase in CII was associated with higher hypertension risk (hazard ratio [HR] 1.08 [95% CI 1.06–1.10]). Compared with the low CII group, the HRs were 1.10 (95% CI 1.05–1.14) for the middle CII group and 1.34 (95% CI 1.25–1.44) for the high CII group. Participants with both high CII and high genetic risk had the highest risk (HR 2.43, 95% CI 2.11–2.81), with evidence of additive interaction at high CII levels. Exploratory proteomic and metabolomic analyses identified 15 proteins and 58 metabolites as potential statistical mediators related to lipid, inflammatory, and vascular pathways.