Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta‐analysis

BACKGROUND: Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear. OBJECTIVE: We tested the hypothesis that elevated plasma bilirubin is causally related to decreased risk of IHD and MI. DESIGN: We used a Mendelian randomization approach and three independent studies from Copenhagen, Denmark. We measured bilirubin in 43 708 white individuals from the general population, and genotyped rs6742078 G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in 67 068 individuals, of whom 11 686 had IHD. RESULTS: Third versus first tertile of baseline bilirubin levels was associated with 134% increased bilirubin levels, with sex- and age-adjusted hazard ratios (HRs) of 0.86 [95% confidence interval (CI), 0.76-0.98; P = 0.02] for IHD and 0.81 (95% CI, 0.66-0.99; P = 0.04) for MI, but with corresponding multifactorially adjusted HRs of 0.93 (95% CI, 0.82-1.06; P = 0.29) and 0.90 (95% CI, 0.73-1.12; P = 0.35). UGT1A1 rs6742078 TT versus GG genotype was associated with 95% increased bilirubin levels (P < 0.001); TT versus GG genotype was associated with odds ratios (ORs) of 1.03 (95% CI, 0.96-1.11; P = 0.73) for IHD and 1.01 (95% CI, 0.92-1.12; P = 0.68) for MI. Finally, in a meta-analysis of the present three studies and eight previous studies including a total of 14 711 cases and 60 324 controls, the random effects OR for ischaemic cardiovascular disease for genotypes with approximately 100% increased bilirubin levels versus reference genotypes was 1.01 (95% CI, 0.88-1.16). CONCLUSION: These data suggest that plasma bilirubin is not causally associated with risk of IHD.