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

Authors

  • S. Stender,

    1. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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  • R. Frikke-Schmidt,

    1. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    2. The Copenhagen General Population Study, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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  • B. G. Nordestgaard,

    1. The Copenhagen General Population Study, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    2. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    3. The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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  • P. Grande,

    1. Department of Cardiology, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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  • A. Tybjærg-Hansen

    Corresponding author
    1. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    2. The Copenhagen General Population Study, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    3. The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    • Correspondence: Anne Tybjærg-Hansen MD, DMSc, Department of Clinical Biochemistry, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. (fax: +45 3545 4160; e-mail: at-h@rh.regionh.dk).

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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 (< 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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