+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Atherosclerosis 206(1): 228-233

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. 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 x 10(-53)). Five other SNPs in other regions reached genome-wide significance without obvious connection to bilirubin metabolism. 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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 052287785

Download citation: RISBibTeXText

PMID: 19389676

DOI: 10.1016/j.atherosclerosis.2009.02.039

Related references

Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation 114(14): 1476-1481, 2006

Genome-wide linkage and association scans for quantitative trait Loci of serum lactate dehydrogenase-the framingham heart study. Human Genomics and Proteomics 2010: 905237-905237, 2010

Genome-wide association analyses of North American Rheumatoid Arthritis Consortium and Framingham Heart Study data utilizing genome-wide linkage results. Bmc Proceedings 3 Suppl 7: S103-S103, 2009

A genome-wide association study for serum bilirubin levels and gene-environment interaction in a Chinese population. Genetic Epidemiology 37(3): 293-300, 2013

Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study. Bmc Medical Genetics 8 Suppl 1: S12-S12, 2007

Evidence for a gene influencing serum bilirubin on chromosome 2q telomere A genome-wide scan in the Framingham Offspring Study. American Journal of Human Genetics 71(4 Supplement): 215, October, 2002

Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study. Bmc Medical Genetics 8 Suppl 1: S4-S4, 2007

Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. American Journal of Human Genetics 82(2): 411-423, 2008

Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism: Clinical and Experimental 54(11): 1435-1441, 2005

QT interval is a heritable quantitative trait with evidence of linkage to chromosome 3 in a genome-wide linkage analysis: The Framingham Heart Study. Heart Rhythm 2(3): 277-284, 2005

A genome-wide search for non-UGT1A1 markers associated with unconjugated bilirubin level reveals significant association with a polymorphic marker near a gene of the nucleoporin family. Annals of Human Genetics 76(1): 33-41, 2012

Influence of control selection in genome-wide association studies: the example of diabetes in the Framingham Heart Study. Bmc Proceedings 3 Suppl 7: S113-S113, 2009

A 100K genome-wide association scan for diabetes and related traits in the Framingham Heart Study: replication and integration with other genome-wide datasets. Diabetes 56(12): 3063-3074, 2007

Gene-environment interaction effects on lung function- a genome-wide association study within the Framingham heart study. Environmental Health 12(): 101-101, 2015

A genome scan for loci influencing anti-atherogenic serum bilirubin levels. European Journal of Human Genetics 10(9): 539-546, September, 2002