title: Serum total bilirubin levels and coronary heart disease--Causal association or epiphenomenon?
abstract: Observational epidemiological evidence supports a linear inverse and independent association between serum total bilirubin levels and coronary heart disease (CHD) risk, but whether this association is causal remains to be ascertained. A Mendelian randomization approach was employed to test whether serum total bilirubin is causally linked to CHD. The genetic variant rs6742078--well known to specifically modify levels of serum total bilirubin and accounting for up to 20% of the variance in circulating serum total bilirubin levels--was used as an instrumental variable. In pooled analysis of estimates reported from published genome-wide association studies, every copy of the T allele of rs6742078 was associated with 0.42 standard deviation (SD) higher levels of serum total bilirubin (95% confidence interval, 0.40 to 0.43). Based on combined data from the Coronary Artery Disease Genome wide Replication and Meta-analyses and the Coronary Artery Disease (C4D) Genetics Consortium involving a total of 36,763 CHD cases and 76,997 controls, the odds ratio for CHD per copy of the T allele was 1.01 (95% confidence interval, 0.99 to 1.04). The odds ratio of CHD for a 1 SD genetically elevated serum total bilirubin level was 1.03 (95% confidence interval, 0.98 to 1.09). The current findings casts doubt on a strong causal association of serum total bilirubin levels with CHD. The inverse associations demonstrated in observational studies may be driven by biases such as unmeasured confounding and/or reverse causation. However, further research in large-scale consortia is needed.
authors.affiliation: School of Clinical Sciences, University of Bristol, Learning & Research Building (Level 1), Southmead Hospital, Southmead Road, Bristol BS10 5NB, UK. Electronic address: skk31@cantab.net.
authors.forename: Setor K
authors.initials: SK
authors.lastname: Kunutsor
mesh_terms: D001663:Bilirubin / Q000097:blood*; D015984:Causality; D003324:Coronary Artery Disease / Q000097:blood* / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D057182:Mendelian Randomization Analysis / Q000379:methods*; D016017:Odds Ratio
chemical_list: D001663:Bilirubin
keywords: Bilirubin; Coronary heart disease; Mendelian randomization