Circadian disruption and circulating TGF-β1 in workers: evidence from Mendelian randomization and observational data.

Background: Circadian disruption is increasingly recognized as an important biological stressor underlying chronic disease, yet its direct immunological effects remain unclear. Observational studies are limited by residual confounding and reverse causation. Methods: We integrated two-sample Mendelian randomization (MR) with an exploratory observational biomarker study. Genetic instruments for genetically proxied shift-work propensity were derived from the UK Biobank GWAS, and outcome data for 46 circulating proteins were obtained from the AGES-Reykjavik Study in Iceland. Inverse-variance weighted (IVW) was primary estimator, with four additional MR estimators and sensitivity analyses assessed consistency and potential violations of MR assumptions. False discovery rate (FDR) correction was applied across the 46 primary IVW tests. We also measured eight circulating immune mediators among 61 Korean workers to obtain complementary observational evidence relevant to the MR findings. Results: MR demonstrated that genetic predisposition to shift work causally increases circulating TGF-β1 (β=1.15, 95% CI 0.28-2.02) and SMAD4 (β=1.12, 95% CI 0.20-2.05), with no evidence of heterogeneity, horizontal pleiotropy, or reverse causation. MR-PRESSO detected no outlier variants. In the observational analysis, shift workers exhibited higher serum TGF-β1, providing consistent supportive evidence, while pro-inflammatory cytokines measured in EDTA plasma showed no consistent differences. Conclusions: Circulating TGF-β1 emerged as a candidate immune signal associated with genetically proxied shift-work propensity. However, neither association survived FDR correction, SMAD2 and SMAD3 estimates were discordant, and the observational association attenuated after age adjustment. Further longitudinal studies are needed to clarify biological and mechanistic relevance.