Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study

Jing Ping Lin, Christopher J. O'Donnell, Johannes P. Schwaiger, L. Adrienne Cupples, Arno Lingenhel, Steven Hunt, Song Yang, Florian Kronenberg

Research output: Contribution to journalArticle

208 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)1476-1481
Number of pages6
JournalCirculation
Volume114
Issue number14
DOIs
Publication statusPublished - Oct 2006
Externally publishedYes

Fingerprint

Bilirubin
Coronary Disease
Alleles
Cardiovascular Diseases
Genotype
Serum
Population
Genes
Glucuronosyltransferase
Uridine Diphosphate
Telomere
Homozygote
Proportional Hazards Models
Atherosclerosis
Antioxidants
Chromosomes
Confidence Intervals
Lipids
Liver

Keywords

  • Atherosclerosis
  • Cardiovascular diseases
  • Enzymes
  • Epidemiology
  • Genes
  • Genetics
  • Survival

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Lin, J. P., O'Donnell, C. J., Schwaiger, J. P., Cupples, L. A., Lingenhel, A., Hunt, S., ... Kronenberg, F. (2006). Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation, 114(14), 1476-1481. https://doi.org/10.1161/CIRCULATIONAHA.106.633206

Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. / Lin, Jing Ping; O'Donnell, Christopher J.; Schwaiger, Johannes P.; Cupples, L. Adrienne; Lingenhel, Arno; Hunt, Steven; Yang, Song; Kronenberg, Florian.

In: Circulation, Vol. 114, No. 14, 10.2006, p. 1476-1481.

Research output: Contribution to journalArticle

Lin, JP, O'Donnell, CJ, Schwaiger, JP, Cupples, LA, Lingenhel, A, Hunt, S, Yang, S & Kronenberg, F 2006, 'Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study', Circulation, vol. 114, no. 14, pp. 1476-1481. https://doi.org/10.1161/CIRCULATIONAHA.106.633206
Lin, Jing Ping ; O'Donnell, Christopher J. ; Schwaiger, Johannes P. ; Cupples, L. Adrienne ; Lingenhel, Arno ; Hunt, Steven ; Yang, Song ; Kronenberg, Florian. / Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. In: Circulation. 2006 ; Vol. 114, No. 14. pp. 1476-1481.
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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. 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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AU - Cupples, L. Adrienne

AU - Lingenhel, Arno

AU - Hunt, Steven

AU - Yang, Song

AU - Kronenberg, Florian

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N2 - 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.

AB - 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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