Human Molecular Genetics Advance Access originally published online on May 4, 2009
Human Molecular Genetics 2009 18(14):2700-2710; doi:10.1093/hmg/ddp202
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Published by Oxford University Press 2009
Genome-wide association meta-analysis for total serum bilirubin levels
1 National Heart Lung and Blood Institute's The Framingham Heart Study, 73 Mt. Wayte Avenue, Suite #2, Framingham, MA 01702, USA 2 Department of Epidemiology 3 Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands 4 Member of the Netherlands Consortium on Healthy Aging (NCHA), The Hague, The Netherlands 5 The Icelandic Heart Association, Reykjavik, Iceland 6 Department of Neurology, Boston University School of Medicine, Boston, MA, USA 7 University of Iceland, Reykjavik, Iceland 8 National Heart Lung and Blood Institute's Office of Biostatistics Research, Bethesda, MD, USA 9 National Institute on Aging's Age, Gene/Environment Susceptibility Study, Reykjavik, Iceland 10 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA 11 Inspectorate of Health Care, The Hague, The Netherlands 12 Cardiology Division, Massachusetts General Hospital, Boston, MA, USA
* To whom correspondence should be addressed at: National Heart Lung and Blood Institute's The Framingham Heart Study, 73 Mount Wayte Avenue, Suite #2, Framingham, MA 01702, USA. Tel: +1 5089353435; Fax: +1 5088722678; Email: codonnell{at}nih.gov
Received February 5, 2009; Revised March 31, 2009; Accepted April 28, 2009
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 
18.0 and 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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors and the last three authors should be regarded as joint Last Authors.