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Some studies reported that mildly elevated serum bilirubin levels were associated with decreased risk of cardiovascular disease (CVD) and diabetes. Whether these are causal relationships remains unclear. This study aims to examine the causal effects of bilirubin on CVD, diabetes and their subtypes. The data we used in this study includes individual data from the UK Biobank cohort with 331,002 white British participants, and summary data from published genome wide associations studies (GWAS) findings. We used individual data to perform logistic regression for the observational study and two-stage least squares method for the Mendelian randomization (MR) study. We also performed several traditional MR methods and MR-TRYX by summary data. The observational study supported the association relationships between bilirubin and CVD and diabetes and their subtypes. Results of MR showed strong evidence for negative causal associations of log e total bilirubin with CVD [OR 0.92, 95%CI 0.88–0.95, p -value 2.15 × 10−6], coronary heart disease [OR 0.90, 95%CI 0.85–0.96, p -value 1.54 × 10−3] and hypertensive diseases [OR 0.91, 95%CI 0.88–0.95, p -value 5.89 × 10−6], but no evidence for diabetes [OR 0.94, 95%CI 0.86–1.02, p -value 0.14] and its subtypes. We also obtained similar results for direct bilirubin. We found that blood pressure, cholesterol, C-reactive protein, alcohol and white blood cell count played important roles in the causal pathway from bilirubin to CVD. Two sample MR and sensitivity analyses showed consistent results with one sample MR. Genetically determined bilirubin was negatively associated with the risk of CVD but had no evident causal association with diabetes in the UK Biobank cohort of white British. • Genetic determined bilirubin is negatively associated with the risk of cardiovascular disease (CVD). • Bilirubin has no evident causal association with diabetes in white British. • We identified the mediators of the causal pathway from bilirubin to CVD. [ABSTRACT FROM AUTHOR]

Objectives To explore the longitudinal effect of metabolic syndrome (MetS) and its components on the development of non-alcoholic fatty liver disease (NAFLD) and to evaluate the significance of MetS and its components as early markers of NAFLD risk in a northern urban Han Chinese population. Materials and methods A total of 15,791 cohort members without NAFLD at baseline were included in the current study between 2005 and 2011. The baseline characteristics of the cohort were compared by MetS status at baseline and NAFLD status after follow-up. Cox proportional hazards models were used to estimate the unadjusted or adjusted hazard ratios (HRs) for development of NAFLD among individuals with MetS compared with individuals without MetS at baseline. Results During 51,652 person-years of follow-up, 3913 (24.78%) new cases of NAFLD occurred between 2005 and 2011. In the unadjusted model, the HR (95% confidence interval [CI]) for NAFLD was 2.51 (2.30, 2.73). After adjusting for gender, age, diet, smoking status, and regular exercise, the HR was 1.94 (1.78, 2.13). Gender differences were observed, with adjusted HRs (95% CIs) of 1.89 (1.71, 2.09) and 1.72 (1.43, 2.07) among males and females, respectively. Compared with individuals without MetS components, the HRs were 1.92 (1.76, 2.09), 2.64 (2.40, 2.90) and 3.51 (3.15, 3.91) for individuals with one, two, or three or more MetS components, respectively. Moreover, participants with obesity or hyperlipidemia had a higher risk of NAFLD than patients with hypertension or hyperglycemia, with HRs of 2.03 (1.83, 2.25) for obesity, 1.94 (1.72, 2.19) for hyperlipidemia, and 3.01 (2.68, 3.37) for these factors in combination. Conclusion The present study indicates that MetS and its components independently predict the risk of NAFLD in a northern urban Han Chinese population and suggests that people with MetS or its component should initiate lifestyle changes to prevent the development of NAFLD. [ABSTRACT FROM AUTHOR]