Human Mutation RESEARCH ARTICLE Association of Polymorphisms in Four Bilirubin Metabolism Genes with Serum Bilirubin in Three Asian Populations Rong Lin, 1 Xiaofeng Wang, 1 Yi Wang, 1 Feng Zhang, 1 Ying Wang, 3 Wenqing Fu, 1 Ting Yu, 1 Shilin Li, 1 Momiao Xiong, 4 Wei Huang, 3 and Li Jin 1,2Ã 1 Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China 2 Chinese Academy of Sciences-Max Planck Gesellschaft Partner Institute of Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 3 Chinese National Human Genome Center at Shanghai, Shanghai, China 4 Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas Communicated by Daniel W. Nebert Received 22 April 2008; accepted revised manuscript 25 July 2008. Published online 25 February 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/humu.20895 ABSTRACT: Numerous studies have shown that the (TA)n repeat polymorphism in the uridine diphosphate glycosyltransferase 1 (UGT1A1) gene promoter is associated with hyperbilirubinemia. Several studies also indicated that single nucleotide polymorphism (SNP) rs4148323:G4A at Exon 1 of UGT1A1 is associated with hyperbilirubinemia. However, it remains unclear what role the polymorphisms play in influencing serum total bilirubin (TBIL) levels in general populations, and whether polymorphisms in other genes involved in the bilirubin metabolism pathway are associated with TBIL levels. The present study addressed these questions by investigating the association of four bilirubin metabolism genes with TBIL levels in three Asian populations: 11 genetic polymorphisms in heme oxygenase-1 (HMOX1); biliverdin reductase A (BLVRA); solute carrier organic anion transporter family member 1B1 (SLCO1B1); and UGT1A1. The populations consisted of 502 Kazak herdsmen, 769 Uyghur farmers, and 789 Han farmers, with distinct genetic backgrounds. UGT1A1 was found to be associated with the (TA) 7 allele of the (TA)n repeat polymorphism. We also showed that the A allele of SNP rs4148323:G4A was strongly associated with high TBIL levels in all three populations (each Po0.005). Among polymorphisms in other genes, only the (GT)n repeat polymorphism in the HMOX1 promoter region showed association with TBIL levels in the Uyghur population, but not in the Han and Kazak populations. We also assessed the contributions of (TA)n polymorphism and rs4148323:G4A to phenotypic variations in all three populations. Finally, we observed that significant differ- ences of TBIL levels existed among the three popula- tions; however, this could not be completely explained by the differences at the (TA)n repeat polymorphism and SNP rs4148323:G4A. Hum Mutat 30, 609–615, 2009. & 2009 Wiley-Liss, Inc. KEY WORDS: bilirubin; UGT1A1; genetic polymorph- ism; genetic contribution Introduction Bilirubin, a water-insoluble compound, causes hyperbilirubi- nemia when in excess. Hyperbilirubinemia subsequently increases the risk of schizophrenia [Miyaoka et al., 2000] or leads to acute unconjugated bilirubin encephalopathy, even kernicterus [Brito et al., 2006]. Hence, the genetic mechanism of hyperbilirubinemia has been pursued for decades. However, increasing evidence from experimental data indicated that bilirubin is an effective antioxidant within the normal/mild-increased range. Bilirubin scavenges peroxyl radicals efficiently, suppresses the oxidation of lipids and lipoproteins, especially low density lipoprotein, and thus acts against plaque formation and subsequent atherosclerosis [Mayer, 2000]. Epidemiological studies also showed that serum bilirubin levels are inversely associated with cancer mortality [Temme et al., 2001], coronary artery disease, and mortality from myocardial infarction [Djousse et al., 2001; Mayer, 2000; Vitek et al., 2002]. Therefore, it is of great importance to identify the factors influencing serum bilirubin levels within the normal/mild- increased range. Serum bilirubin is derived primarily from hemoglobin in aging red blood cells, which is broken down to heme and globin. Heme oxygenases (HMOX) convert heme to biliverdin, which is reduced by biliverdin reductase A (BLVRA; MIM] 109750) to bilirubin. Bilirubin is carried by albumin in the blood and is taken into the liver by solute carrier organic anion transporter family member 1B1 (SLCO1B1; MIM] 604843). Within hepatocytes, the solubility of bilirubin is increased by the addition of one or two molecules of OFFICIAL JOURNAL www.hgvs.org & 2009 WILEY-LISS, INC. Additional Supporting Information may be found in the online version of this article. Contract grant sponsor: Science and Technology Commission of Shanghai Municipality; Grant number: 04dz14003; Contract grant sponsor: National Natural Science Foundation of China; Grant number: 30500291. Ã Correspondence to: Li Jin, PhD, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail: ljin007@gmail.com