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(Circulation. 2006;114:1476-1481.)
© 2006 American Heart Association, Inc.

Epidemiology

Association Between the UGT1A1*28 Allele, Bilirubin Levels, and Coronary Heart Disease in the Framingham Heart Study

Jing-Ping Lin, MD, PhD; Christopher J. O’Donnell, MD, MPH; Johannes P. Schwaiger, MD; L. Adrienne Cupples, PhD; Arno Lingenhel, PhD; Steven C. Hunt, PhD; Song Yang, PhD; Florian Kronenberg, MD

From the Office of Biostatistics Research (J.-P.L., S.Y.) and Framingham Heart Study (C.J.O.), Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; Division of Genetic Epidemiology/Department of Medical Genetics, Molecular and Clinical Pharmacology (J.P.S., A.L., F.K.), Innsbruck Medical University, Innsbruck, Austria; Department of Biostatistics (L.A.C.), Boston University School of Public Health, Boston, Mass; and Department of Internal Medicine (S.C.H.), University of Utah, Salt Lake City, Utah.

Correspondence to Jing-Ping Lin, MD, PhD, NHLBI/NIH, 6701 Rockledge Dr, Suite 8110, Bethesda, MD 20892-7938. E-mail linj{at}nhlbi.nih.gov

Received April 17, 2006; revision received July 20, 2006; accepted July 25, 2006.

Background— Bilirubin is an antioxidant that suppresses lipid oxidation and retards atherosclerosis formation. An inverse association between serum bilirubin and coronary heart disease has been reported. Linkage studies have identified a major locus at the chromosome 2q telomere that affects bilirubin concentrations. A candidate gene in the linkage region encodes hepatic bilirubin uridine diphosphate–glucuronosyltransferase (UGT1A1). The insertion of a TA in the TATAA box of the gene, an allele designated UGT1A1*28, decreases gene transcription. Individuals homozygous for UGT1A1*28 (genotype 7/7) have increased serum bilirubin levels compared with carriers of the 6 allele. To date, no significant association between UGT1A1*28 and cardiovascular disease (CVD) events has been reported. We performed an association study in the Framingham Heart Study population to investigate whether UGT1A1*28 is associated with the risk of CVD events.

Methods and Results— The study population included 1780 unrelated individuals from the Offspring cohort (49% males, mean age 36 years at entry) who had been followed up for 24 years. Individuals with genotype 7/7 had significantly higher bilirubin levels (mean±SD 1.14±0.44 mg/dL) than those with genotypes 6/6 and 6/7 (mean±SD 0.69±0.27 mg/dL, P<0.01). Using the Cox proportional hazards model, we found significant associations between the UGT1A1*28 allele and decreased risk of CVD. Individuals with genotype 7/7 (population frequency of 11%) had approximately one third the risk for CVD and coronary heart disease as carriers of the 6 allele, which resulted in a hazard ratio (95% confidence interval) of 0.36 (0.18 to 0.74) and 0.30 (0.12 to 0.74), respectively.

Conclusions— Homozygote UGT1A1*28 allele carriers with higher serum bilirubin concentrations exhibit a strong association with lower risk of CVD.

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