Background: Elevated 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.
Methods: Study subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels.
Results: Serum 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).
Conclusions: Our 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.