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OBJECTIVES  Bilirubin is an endogenous antioxidant that protects cells against oxidative stress. Increased plasma levels of bilirubin have been associated with a reduced risk of ischemic heart disease (IHD) in previous studies. Nonetheless, whether those associations reflect a true protective effect of bilirubin on IHD, rather than confounding or reverse causation, remains unknown. Therefore, we applied two-sample Mendelian randomization to evaluate the causal association between bilirubin levels and IHD risk in a Korean population.    METHODS  A total of 5 genetic variants— TRPM8  (rs10490012),   USP40   (rs12993249),  ATG16L1  (rs2119503),  SLCO1B1  (rs4149014), and  SLCO1B3  (rs73233620)—were selected as genetic instruments for serum bilirubin levels using a communitybased cohort, the Korean Genome and Epidemiology Study, comprising 33,598 subjects. We then evaluated their impact on IHD using the Korean Cancer Prevention Study-II cohort.    RESULTS  Among the 5 instrumental variables that showed significant associations with serum bilirubin levels, rs12993249 (  USP40  ) showed the most significant association (p<2.36×10 -105 ). However, we found no significant association between serum bilirubin levels and IHD. Sensitivity analyses demonstrated a consistent association, suggesting that our observations were robust.    CONCLUSIONS  Using two-sample Mendelian randomization, we found no association between serum bilirubin levels and IHD. Further studies that confirm the observed interactions among other ethnicities are warranted.

Bilirubin and risk of ischemic heart disease in Korea: a two-sample Mendelian randomization study