Conditional linkage and genome-wide association studies identify UGT1A1 as a major gene for anti-atherogenic serum bilirubin levels--the Framingham Heart Study.
OBJECTIVE
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 x 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.
Lin
Jing-Ping
JP
Office of Biostatistics Research, Department of Population and Public Science, National Heart Lung and Blood Institute, National Institutes of Health, 6701 Rockledge Drive, Bethesda, MD 20892-7913, USA. linj@nhlbi.nih.gov
Schwaiger
Johannes P
JP
Cupples
L Adrienne
LA
O'Donnell
Christopher J
CJ
Zheng
Gang
G
Schoenborn
Veit
V
Hunt
Steven C
SC
Joo
Jungnam
J
Kronenberg
Florian
F
D000328:Adult; D001663:Bilirubin / Q000097:blood*; D002889:Chromosomes, Human, Pair 2; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D020641:Polymorphism, Single Nucleotide; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme