Impact of sleep problems on the cardiometabolic risks: an integrated epidemiological and metabolomics study.

Background: We investigated the association between sleep problems and cardiometabolic risks and the potential linking effect of metabolites and metabolic pathways based on multi-layered research, including observational, mendelian randomization (MR), and metabolomics analysis.

Methods: A cross-sectional analysis of the 2015-2018 National Health and Nutrition Examination Survey (NHANES) dataset was conducted to identify the association between sleep problems and cardiometabolic risks. A subsequent MR study based on genetic data was performed to explore the causal correlation of significant associations in the NHANES study. The underlying alteration of metabolism was explored by constructing zebrafish models and wide-targeted metabolomics analysis.

Results: The cross-sectional analysis of the NHANES database revealed a significant association of snoring with obesity [OR = 2.65, 95% confidence intervals (CI): 1.87, 3.74]; sleep apnea with hypertension (OR = 1.68, 95% CI: 1.14, 2.48) and obesity (OR = 1.44, 95% CI: 1.05, 1.96); trouble sleeping with hypertension (OR = 1.84, 95% CI: 1.18, 2.86), obesity (OR = 1.56, 95% CI: 1.07, 2.26), and type 2 diabetes (T2DM) (OR = 1.52, 95% CI: 1.02, 2.25). MR analysis verified the causal relationship between genetically proxied sleep apnea or snoring and obesity. The decreased activity levels and altered expression levels of six circadian genes (bmal1b, cry1aa, cry1ab, clock1a, per1b, per2) were identified in the zebrafish of the sleep disorder group. Multiple metabolites related to disturbed glucose metabolism (e.g., 20-HETE), lipid metabolism (e.g., inosine), and vascular-related metabolites (e.g., riboflavin) were finally identified, indicating the latent effect of metabolism.

Conclusions: This study identified the chain of sleep-circadian rhythm-metabolism-cardiometabolic risks. These findings can promote improved prevention implementation and therapeutic strategies.