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Human Molecular Genetics Advance Access published online on May 6, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp203
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia

Serena Sanna1,7, Fabio Busonero1,7, Andrea Maschio1, Patrick F. McArdle2, Gianluca Usala1, Mariano Dei1, Sandra Lai1, Antonella Mulas1, Maria Grazia Piras1, Lucia Perseu1, Marco Masala1, Mara Marongiu1, Laura Crisponi1, Silvia Naitza1, Renzo Galanello3, Gonçalo R. Abecasis4, Alan R. Shuldiner2,5, David Schlessinger6, Antonio Cao1 and Manuela Uda1,*

1 Istituto di Neurogenetica e Neurofarmacologia del Consiglio Nazionale delle Ricerche, Monserrato, 09042, Cagliari, Italy 2 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 3 Clinica Pediatrica, Ospedale Regionale delle Microcitemie, Dipartimento di Scienze Biomediche e Biotecnologie-Università degli Studi di Cagliari, 09121, Cagliari, Italy 4 Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor 48109, MI, USA 5 Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland 6 Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA

* Corresponding author: Manuela Uda, Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Monserrato 09042, Cagliari, Italy, Tel +39 070 675 4591, Fax +39 070 6754652 email: manuela.uda{at}inn.cnr.it

Received February 5, 2009; Revised April 28, 2009; Accepted April 28, 2009

Bilirubin, resulting largely from the turnover of hemoglobin, is found in the plasma in two main forms: unconjugated or conjugated with glucuronic acid. Unconjugated bilirubin is transported into hepatocytes. There, it is glucuronidated by UGT1A1 and secreted into the bile canaliculi. We report a genome wide association scan in 4300 Sardinian individuals for total serum bilirubin levels. In addition to the two known loci previously involved in the regulation of bilirubin levels, UGT1A1 (p=6.2x10–62) and G6PD (p=2.5x10–8), we observed a strong association on chromosome 12 within the SLCO1B3 gene (p=3.9x10–9). Our findings were replicated in an independent sample of 1860 Sardinians and in 832 subjects from the Old Order Amish (combined p<5x10–14). We also show that SLC01B3 variants contribute to idiopathic mild unconjugated hyperbilirubinemia. Thus, SLC01B3 appears to be involved in the regulation of serum bilirubin levels in healthy individuals and in some bilirubin-related disorders that are only partially explained by other known gene variants.

7 S.S. and F.B. equally contributed to this work.


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