Circadian gene expression in adolescents: Associations with concurrent circadian disruption and subsequent changes in cardiometabolic risk measures

OBJECTIVES: Circadian disruption has been linked to adverse metabolic health. Adolescents are particularly susceptible to circadian disruptors, such as delayed sleep onset and social jetlag, which may have sex-specific effects. However, evidence linking these disruptors with circadian gene expression and subsequent cardiometabolic risk remains limited. METHODS: Our study included 203 adolescents (53% females, median age 13.6 years) from the ELEMENT cohort in Mexico City. Sleep was assessed via 7-day wrist actigraphy. A fasting venipuncture blood sample was collected between 8:00 a.m. and 12:00 p.m. RNA was isolated from blood leukocytes and sequenced to determine the relative expression of genes. We conducted differential gene expression analysis for 12 core clock genes in relation to sleep midpoint and social jetlag, adjusting for sleep duration and other potential confounders. We further evaluated how circadian gene expression associated with changes in adiposity, glucose metabolism, blood pressure, and lipid profiles over two years using linear regression. RESULTS: Later sleep midpoint (per 1-h increase) was associated with reduced mid-morning expression of four circadian genes: RORA (log2 fold change [LFC]: -0.190; P value: 0.001), RORC (LFC: -0.147; P value: 0.039), CLOCK (LFC: -0.141; P value: 0.019), and NR1D2 (LFC: -0.093; P value: 0.029). Additionally, expression levels of several clock genes (CRY1, NR1D2, BMAL1, and PER1-3) were associated with changes in metabolic biomarkers over two years in sex-specific patterns. For instance, NR1D2 showed a negative association with fasting glucose among females (β: -0.0012; P value: 0.020), while demonstrating positive associations with LDL cholesterol (β: 0.0023; P value: 0.002) and total cholesterol (β: 0.0016; P value: 0.028) among males. CONCLUSIONS: Expression of core clock genes was linked to circadian disruption and changes in cardiometabolic risk factors in a sex-specific manner among adolescents. Our findings provide novel insights into potential biological mechanisms underlying associations of circadian disruption with cardiometabolic health.