Genome-wide association meta-analysis for total serum bilirubin levels

Abstract

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.

Evidence for Extensive Pleiotropy Among Pharmacogenes

“…We robustly reproduced two associations between ADME genes and physiological traits: ABCG2 and gout and SLCO1B1 and jaundice [47,49]. The remaining replications are signals driven by the impact of ADME variants on the metabolism of xenobiotics (CYP2A6 on nicotine, CYP2C19 and NAT1 on carcinogens).…”

“…In previous studies of European populations, rs4149056 has been associated with elevated serum bilirubin concentrations [49], a known cause of jaundice. The CAF was 0.23 for cases (n = 154) and 0.15 for controls (n = 5058).…”

Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism

“…Concurrent elevations of transaminases were not seen in these six patients. A recent genome-wide association study identified OATP1B1 (alternative symbol SLCO1B1) as one of the top loci associated with bilirubin levels (Johnson et al, 2009). Genetic markers in the OATP1B1 gene were also evaluated in this study and were not found to be associated with pazopanib-related bilirubin elevation.…”

The emerging role of transport systems in liver function tests

“…Corroboratively, recent pharmacogenetic studies have linked polymorphisms in the SLCO1B1 and SLCO1B3 genes with unconjugated and conjugated plasma bilirubin levels (Johnson et al, 2009;Sanna et al, 2009;Zhang et al, 2007). A role of Oatps in hepatocellular bilirubin uptake is further supported by experiments with mice with deleted Slco1a and Slco1b genes.…”