INTRODUCTION AND AIM: It has been proposed that plasma concentration of bilirubin, an endogenous antioxidant, is protective against diseases mediated by increased oxidative stress, including cardiovascular diseases (CVD) and cancer. To examine this hypothesis, we investigated the relationship between plasma bilirubin concentrations and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variations (associated with increased bilirubin concentrations) with total/CVD and cancer mortality. MATERIALS AND METHODS: A nested case-control study was conducted within the Polish arm of the HAPIEE cohort. At baseline in 2002-2005, participants were examined in detail. Mortality follow-up (median (IQR) between blood draw and death was 3.7 (2.1-5.1) years) was performed by linkage with regional and national death registers. Plasma biomarkers were analysed in all subjects who died from any cause (cases, n=447) and in a random subsample of survivors (controls, n=1423). RESULTS: There was a strong negative association between plasma bilirubin levels and total and cancer mortality, expressed more profoundly in men. The adjusted OR of deaths from all causes and cancer, comparing the highest vs. lowest plasma bilirubin categories were 0.61 (95% CI: 0.42-0.87) and 0.39 (0.24-0.65), respectively. There was no association of bilirubin with CVD mortality. The UGT1A1*28 allele, a genetic marker of raised bilirubin, was also negatively associated with total/cancer mortality, although the associations were not statistically significant. DISCUSSION: Both the observational and genetic associations support the negative relationship between bilirubin and total mortality; this association appears to be driven by cancer mortality, while that with CVD mortality is not evident.

4th Department of Internal Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

Chair of Epidemiology and Population Studies Institute of Public Health Faculty of Health Sciences Jagiellonian University Krakow Poland

Department of Epidemiology and Public Health University College of London UK

Institute of Medical Biochemistry and Laboratory Diagnostics and 4th Department of Internal Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

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Higher bilirubin on admission predicts better outcome in refractory cardiac arrest: A Prague OHCA trial analysis focused on the antioxidant effect of bilirubin