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

Stefan Stender; R Frikke-Schmidt; B G Nordestgaard; P Grande; A Tybjaerg-Hansen

doi:10.1111/j.1365-2796.2012.02576.x

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

Stefan Stender, R Frikke-Schmidt, B G Nordestgaard, P Grande, A Tybjaerg-Hansen

64 Citations (Scopus)

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 43708 white individuals from the general population, and genotyped rs6742078G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1*) gene in 67068 individuals, of whom 11686 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 14711 cases and 60324 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.

Original language	English
Journal	The Internet Journal of Internal Medicine
Volume	273
Issue number	1
Pages (from-to)	59-68
Number of pages	10
ISSN	1528-8382
DOIs	https://doi.org/10.1111/j.1365-2796.2012.02576.x
Publication status	Published - Jan 2013

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10.1111/j.1365-2796.2012.02576.x

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@article{f61b2736e40d4018b256402a4336449f,

title = "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 43708 white individuals from the general population, and genotyped rs6742078G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1*) gene in 67068 individuals, of whom 11686 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 14711 cases and 60324 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.",

author = "Stefan Stender and R Frikke-Schmidt and Nordestgaard, {B G} and P Grande and A Tybjaerg-Hansen",

note = "{\textcopyright} 2012 The Association for the Publication of the Journal of Internal Medicine.",

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doi = "10.1111/j.1365-2796.2012.02576.x",

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T1 - Genetically elevated bilirubin and risk of ischaemic heart disease

T2 - three Mendelian randomization studies and a meta-analysis

AU - Stender, Stefan

AU - Frikke-Schmidt, R

AU - Nordestgaard, B G

AU - Grande, P

AU - Tybjaerg-Hansen, A

PY - 2013/1

Y1 - 2013/1

N2 - 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 43708 white individuals from the general population, and genotyped rs6742078G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1*) gene in 67068 individuals, of whom 11686 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 14711 cases and 60324 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.

AB - 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 43708 white individuals from the general population, and genotyped rs6742078G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1*) gene in 67068 individuals, of whom 11686 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 14711 cases and 60324 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.

U2 - 10.1111/j.1365-2796.2012.02576.x

DO - 10.1111/j.1365-2796.2012.02576.x

M3 - Journal article

C2 - 22805420

SN - 1528-8382

VL - 273

SP - 59

EP - 68

JO - The Internet Journal of Internal Medicine

JF - The Internet Journal of Internal Medicine

IS - 1

ER -

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

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