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

Abstract

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.

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  • Publisher Full Text

    • Authors

    Stender S, Frikke-Schmidt R, Nordestgaard BG, Grande P, Tybjaerg-Hansen A

    Institution

    Department of Clinical Biochemistry, Copenhagen University, Copenhagen, Denmark.

    Source

    Journal of internal medicine 273:1 2013 Jan pg 59-68

    MeSH

    Adult
    Aged
    Bilirubin
    Confidence Intervals
    Denmark
    Female
    Genotype
    Glucuronosyltransferase
    Humans
    Incidence
    Male
    Mendelian Randomization Analysis
    Middle Aged
    Myocardial Ischemia
    Odds Ratio
    Polymorphism, Genetic
    Risk Factors

    Pub Type(s)

    Journal Article
    Meta-Analysis
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22805420