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 analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10-8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 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% CI, 0.105-0.868]; P=0.026).

25,406 Korean ancestry individuals