Abstract 15466: Genetically Elevated Bilirubin and Risk of Ischemic Heart Disease: a Mendelian Randomization Study of the General Population
Background: Elevated plasma bilirubin, an endogenous antioxidant, has been associated with reduced risk of ischemic heart disease(IHD) and myocardial infarction(MI) in mainly case-control studies. We used Mendelian randomization to test whether these associations are causal.
Methods: Gilbert's Syndrome, caused by genetic variation in UGT1A1, is a common cause of moderate hyperbilirubinemia. We genotyped the Gilbert's Syndrome variant UGT1A1 rs6742078 (minor allele frequency 32%) in two general population studies, the prospective Copenhagen City Heart Study (CCHS, n=10,300) and the mainly cross-sectional Copenhagen General Population Study (n=46,500), and in the Copenhagen Ischemic Heart Disease Study (n=5,200 IHD cases and 5,200 controls). We tested 1) whether baseline bilirubin predicted risk of IHD and MI in the prospective CCHS, 2) whether UGT1A1 rs6742078 associated with plasma bilirubin, and 3) whether UGT1A1 genotype predicted risk of IHD and MI in the general population.
Results: In the CCHS, baseline plasma bilirubin (adjusted for sex and age) predicted an increased risk of IHD and MI (hazard ratios for 3rd tertile versus 1st tertile: 1.3 [P<0.001] and 1.2 [P<0.05], respectively). However, these associations were no longer significant after extensive multifactorial adjustments for potential confounders (sex, age, body mass index, diabetes, smoking, hypertension, alcohol consumption, physical activity, lipid lowering therapy, LDL-cholesterol, HDL-cholesterol, triglycerides, CRP). UGT1A1 rs6742078 associated with stepwise increased plasma bilirubin of up to 93% in homozygotes versus non-carriers (P<0.001). UGT1A1 rs6742078 genotype did not associate with risk of IHD or MI in any of the three studies including a total number of 11,373 cases of IHD and 5,548 MIs.
Conclusion: UGT1A1 rs6742078 associated with elevated plasma bilirubin, but did not associate with risk of IHD or MI in the general population, indicating that moderately elevated plasma bilirubin neither protects against nor causes ischemic vascular disease.
- © 2011 by American Heart Association, Inc.