Abstract
BackgroundElevated serum bilirubin has been associated with reduced risk of cardiovascular disease (CVD). However, serum bilirubin is also related with several potential confounders related to CVD, such as obesity. Mendelian randomization has been proposed as a method to address challenges to validity from confounding and reverse causality. It utilizes genotype to estimate causal relationships between a gene product and physiological outcomes. In this report, we demonstrate its use in assessing direct causal relations between serum bilirubin levels and CVD risk factors, including obesity, cholesterol, measures of vascular function and blood pressure.MethodsStudy subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels.ResultsSerum bilirubin levels were inversely associated with levels of several cardiovascular disease risk factors, including body mass index (p = 0.003), LDL (p = 0.0005) and total cholesterol (p = 0.0002). In contrast, UGT1A1*28 genotype, a known cause of elevated bilirubin levels, was not significantly associated with any of these traditional CVD risk factors. We did observe an association between genotype and brachial artery diameter (p = 0.003) and cold pressor reactivity (p = 0.01).ConclusionsOur findings imply that the observed association of serum bilirubin levels with body mass index and cholesterol are likely due to confounding and suggest that previously established CVD benefits of increased bilirubin may in part be mediated by the early regulation of vascular structure and reactivity.
Highlights
Elevated serum bilirubin has been associated with reduced risk of cardiovascular disease (CVD)
High levels of bilirubin are associated with decreased risk of coronary heart disease (CHD) and cardiovascular disease (CVD) [1]
We describe use of the Mendelian randomization approach to evaluate relations of serum bilirubin levels with CVD risk factors and subclinical atherosclerosis in a sample of relatively healthy Old Order Amish individuals from Lancaster County, PA
Summary
Elevated serum bilirubin has been associated with reduced risk of cardiovascular disease (CVD). It utilizes genotype to estimate causal relationships between a gene product and physiological outcomes. We demonstrate its use in assessing direct causal relations between serum bilirubin levels and CVD risk factors, including obesity, cholesterol, measures of vascular function and blood pressure. If a genetic variant is strongly causal of a measured exposure, the variant can be used as a proxy for exposure during modeling This approach, known as Mendelian randomization, can provide evidence of causal inference between two variables [9]. Mendelian randomization has particular utility for evaluation of biomarkers that are highly influenced by a single gene, are of interest in a disease process, and are highly subject to confounding
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