Genome-wide association meta-analysis for total serum bilirubin levels.
Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 x 10(-324)) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 x 10(-13)), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain approximately 18.0 and approximately 1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 x 10(-13)), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.
Johnson
Andrew D
AD
National Heart Lung and Blood Institute's The Framingham Heart Study, 73 Mt. Wayte Avenue, Suite #2, Framingham, MA 01702, USA.
Kavousi
Maryam
M
Smith
Albert V
AV
Chen
Ming-Huei
MH
Dehghan
Abbas
A
Aspelund
Thor
T
Lin
Jing-Ping
JP
van Duijn
Cornelia M
CM
Harris
Tamara B
TB
Cupples
L Adrienne
LA
Uitterlinden
Andre G
AG
Launer
Lenore
L
Hofman
Albert
A
Rivadeneira
Fernando
F
Stricker
Bruno
B
Yang
Qiong
Q
O'Donnell
Christopher J
CJ
Gudnason
Vilmundur
V
Witteman
Jacqueline C
JC
D000328:Adult; D000368:Aged; D001663:Bilirubin / Q000097:blood*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D044465:White People / Q000235:genetics; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D014453:Glucuronosyltransferase; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D000099148:UGT1A1 Enzyme; C503999:SLCO1B1 protein, human