Conditional linkage and genome-wide association studies identify UGT1A1 as a major gene for anti-atherogenic serum bilirubin levels-The Framingham Heart Study

Jing Ping Lin, Johannes P. Schwaiger, L. Adrienne Cupples, Christopher J. O'Donnell, Gang Zheng, Veit Schoenborn, Steven Hunt, Jungnam Joo, Florian Kronenberg

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Objective and methods: Low bilirubin levels are significantly associated with cardiovascular diseases (CVD). In previous genome-wide linkage studies we identified a major locus on chromosome 2q harboring the candidate gene UDP-glucuronosyltransferase (UGT1A1). The activity of this enzyme is significantly influenced by a TA-repeat polymorphism in the promoter of the gene. In a prospective study individuals with genotype (TA)7/(TA)7 had significantly higher bilirubin levels and approximately one-third the risk of CVD as carriers of the wildtype (TA)6 allele. In the present study we performed a conditional linkage study to investigate whether this polymorphism explains the observed linkage peak and extended our analysis by a genome-wide association study on bilirubin levels in 1345 individuals. Results: After adjustment for the bilirubin variance explained by this polymorphism, the LOD score on chromosome 2q dropped from 3.8 to 0.4, demonstrating that this polymorphism explains the previous linkage result. For the genome-wide association study, the closest marker to UGT1A1 was in the top ranking SNPs. The association became even stronger when we considered the TA-repeat polymorphism in the analysis (p = 2.68 × 10-53). Five other SNPs in other regions reached genome-wide significance without obvious connection to bilirubin metabolism. Conclusions: Our studies suggest that UGT1A1 may be the major gene with strong effects on bilirubin levels and the TA-repeat polymorphism might be the key polymorphism within the gene controlling bilirubin levels. Since this polymorphism has a high frequency and a substantial impact on the development of CVD, the gene might be an important drug target.

Original languageEnglish
Pages (from-to)228-233
Number of pages6
JournalAtherosclerosis
Volume206
Issue number1
DOIs
Publication statusPublished - Sep 2009
Externally publishedYes

Fingerprint

Genome-Wide Association Study
Bilirubin
Serum
Genes
Cardiovascular Diseases
Single Nucleotide Polymorphism
Chromosomes
Genome
Glucuronosyltransferase
Alleles
Genotype
Prospective Studies
Enzymes
Pharmaceutical Preparations

Keywords

  • Bilirubin
  • Genome-wide association study
  • Linkage analysis
  • UGT1A1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Conditional linkage and genome-wide association studies identify UGT1A1 as a major gene for anti-atherogenic serum bilirubin levels-The Framingham Heart Study. / Lin, Jing Ping; Schwaiger, Johannes P.; Cupples, L. Adrienne; O'Donnell, Christopher J.; Zheng, Gang; Schoenborn, Veit; Hunt, Steven; Joo, Jungnam; Kronenberg, Florian.

In: Atherosclerosis, Vol. 206, No. 1, 09.2009, p. 228-233.

Research output: Contribution to journalArticle

Lin, Jing Ping ; Schwaiger, Johannes P. ; Cupples, L. Adrienne ; O'Donnell, Christopher J. ; Zheng, Gang ; Schoenborn, Veit ; Hunt, Steven ; Joo, Jungnam ; Kronenberg, Florian. / Conditional linkage and genome-wide association studies identify UGT1A1 as a major gene for anti-atherogenic serum bilirubin levels-The Framingham Heart Study. In: Atherosclerosis. 2009 ; Vol. 206, No. 1. pp. 228-233.
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abstract = "Objective and methods: Low bilirubin levels are significantly associated with cardiovascular diseases (CVD). In previous genome-wide linkage studies we identified a major locus on chromosome 2q harboring the candidate gene UDP-glucuronosyltransferase (UGT1A1). The activity of this enzyme is significantly influenced by a TA-repeat polymorphism in the promoter of the gene. In a prospective study individuals with genotype (TA)7/(TA)7 had significantly higher bilirubin levels and approximately one-third the risk of CVD as carriers of the wildtype (TA)6 allele. In the present study we performed a conditional linkage study to investigate whether this polymorphism explains the observed linkage peak and extended our analysis by a genome-wide association study on bilirubin levels in 1345 individuals. Results: After adjustment for the bilirubin variance explained by this polymorphism, the LOD score on chromosome 2q dropped from 3.8 to 0.4, demonstrating that this polymorphism explains the previous linkage result. For the genome-wide association study, the closest marker to UGT1A1 was in the top ranking SNPs. The association became even stronger when we considered the TA-repeat polymorphism in the analysis (p = 2.68 × 10-53). Five other SNPs in other regions reached genome-wide significance without obvious connection to bilirubin metabolism. Conclusions: Our studies suggest that UGT1A1 may be the major gene with strong effects on bilirubin levels and the TA-repeat polymorphism might be the key polymorphism within the gene controlling bilirubin levels. Since this polymorphism has a high frequency and a substantial impact on the development of CVD, the gene might be an important drug target.",
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AB - Objective and methods: Low bilirubin levels are significantly associated with cardiovascular diseases (CVD). In previous genome-wide linkage studies we identified a major locus on chromosome 2q harboring the candidate gene UDP-glucuronosyltransferase (UGT1A1). The activity of this enzyme is significantly influenced by a TA-repeat polymorphism in the promoter of the gene. In a prospective study individuals with genotype (TA)7/(TA)7 had significantly higher bilirubin levels and approximately one-third the risk of CVD as carriers of the wildtype (TA)6 allele. In the present study we performed a conditional linkage study to investigate whether this polymorphism explains the observed linkage peak and extended our analysis by a genome-wide association study on bilirubin levels in 1345 individuals. Results: After adjustment for the bilirubin variance explained by this polymorphism, the LOD score on chromosome 2q dropped from 3.8 to 0.4, demonstrating that this polymorphism explains the previous linkage result. For the genome-wide association study, the closest marker to UGT1A1 was in the top ranking SNPs. The association became even stronger when we considered the TA-repeat polymorphism in the analysis (p = 2.68 × 10-53). Five other SNPs in other regions reached genome-wide significance without obvious connection to bilirubin metabolism. Conclusions: Our studies suggest that UGT1A1 may be the major gene with strong effects on bilirubin levels and the TA-repeat polymorphism might be the key polymorphism within the gene controlling bilirubin levels. Since this polymorphism has a high frequency and a substantial impact on the development of CVD, the gene might be an important drug target.

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