Causal associations between serum bilirubin levels and decreased stroke risk: A two-sample Mendelian randomization study

Objective: A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization (MR) analyses conducted using a single sample have shown no evidence of association.
Approach and Results: A two-sample summary MR study was performed by obtaining exposure and outcome data from separate non-overlapping samples. We utilised data from the Korean Genome and Epidemiology Study (KoGES) (n=25,406) and Korean Cancer Prevention Study-II (KCPS-II) (n=14,541) biobank for serum bilirubin and stroke respectively. Using KoGES, a total of 1,784 single nucleotide polymorphisms (SNPs) associated with serum bilirubin levels were discovered using a genome-wide significancethreshold (p < 5´10-8), of which 10 SNPs were identified as independent (R2 < 0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1,489 and n=686), with 12,366 acting as controls. Various two-sample summary MR methods were employed, with MR estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (Odds ratio=0.481, 95% confidence interval=0.234-0.988. p=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (Odds ratio=0.302, 95% confidence interval=0.105-0.868, p=0.026).
Conclusions: Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke, and suggests that previous findings were not a consequence of unmeasured confounding.