Abstract
OBJECTIVESBilirubin 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.METHODSA 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.RESULTSAmong 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.CONCLUSIONSUsing 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.
Highlights
Bilirubin is an endogenous antioxidant that protects cells against oxidative stress [1]
We conducted a two-sample Mendelian randomization (MR) study and found that 5 genetic variants were significantly associated with bilirubin levels
single-nucleotide polymorphism (SNP) effect on bilirubin though our results do not provide evidence for a positive effect of bilirubin levels on Ischemic heart disease (IHD) risk, to our knowledge, this is the first two-sample MR study to examine the effect of bilirubin levels on IHD risk among an East Asian population
Summary
Bilirubin is an endogenous antioxidant that protects cells against oxidative stress [1]. In previous studies, increased plasma levels of bilirubin have been associated with a reduced risk of IHD [4,5]. Whether those associations reflect a true protective effect of bilirubin on IHD, rather than confounding or reverse causation, remains unknown [6]. Some of those studies were conducted in populations at high risk. The relationship between bilirubin levels and IHD is not well-characterized
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