title: Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study.
abstract: 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.
  
  
  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.
authors.affiliation: Office of Biostatistics Research, NHLBI/NIH, 6701 Rockledge Dr, Suite 8110, Bethesda, MD 20892-7938, USA. linj@nhlbi.nih.gov
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Lin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Johannes P
authors.initials: JP
authors.lastname: Schwaiger
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Arno
authors.initials: A
authors.lastname: Lingenhel
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Song
authors.initials: S
authors.lastname: Yang
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
mesh_terms: D000328:Adult; D000483:Alleles; D001663:Bilirubin / Q000032:analysis*; D003327:Coronary Disease / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D016016:Proportional Hazards Models; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme