Genomics & Informatics Vol. 6(4) 192-201, December 2008 *Corresponding author: E-mail kbkwack@cha.ac.kr, kbkwack@gmail.com Tel +82-31-725-8393, Fax +82-31-725-8350 Accepted 19 November 2008 Erythropoietin-producing Human Hepatocellular Carcinoma Receptor B1 Polymorphisms are Associated with HBV-infected Chronic Liver Disease and Hepatocellular Carcinoma in a Korean Population Kyoung-Yeon Kim 1 , Seung Ku Lee 1 , Min-Ho Kim 1 , Jae Youn Cheong 2 , Sung Won Cho 2 , Kap-Seok Yang 3 and KyuBum Kwack 1 * 1 Medical Genomics Laboratory, Graduate School of Life Science and Biotechnology, Pochon CHA University, Seongnam 463-836, Korea, 2 Department of Gastroen- terology, Genomic Research Center for Gastroenterolo- gy, Ajou University School of Medicine, Suwon 442- 721, Korea, 3 Macrogen Inc. 60-24, Gasan-dong, Gum- cheon-gu, Seoul 153-781, Korea Abstract Erythropoietin-producing human hepatocellular carcino- ma receptor B1 (EPHB1) is a member of the Eph family of receptor tyrosine kinases that mediate vascular sys- tem development. Eph receptor overexpression has been observed in various cancers and is related to the malignant transformation, metastasis, and differentiation of cancers, including hepatocellular carcinoma (HCC). Eph receptors regulate cell migration and attachment to the extracellular matrix by modulating integrin activity. EphrinB1, the ligand of EPHB1, has been shown to reg- ulate HCC carcinogenesis. Here, we sought to de- termine whether EPHB1 polymorphisms are associated with hepatitis B virus (HBV)-infected liver diseases, in- cluding chronic liver disease (CLD) and HCC. We geno- typed 26 EPHB1 single nucleotide polymorphisms (SNPs) in 399 Korean CLD, HCC, and LD (CLD+HCC) cases and seroconverted controls (HBV clearance, CLE) using the GoldenGate assay. Two SNPs (rs6793828 and rs11717042) and 1 haplotype that were composed of these SNPs were associated with an increased risk for CLD, HCC, and LD (CLD+HCC) compared with CLE. Haplotypes that could be associated with HBV-infected liver diseases by affecting downstream signaling were located in the Eph tyrosine kinase domain of EPHB1. Therefore, we suggest that EPHB1 SNPs, haplotypes, and diplotypes may be genetic markers for the pro- gression of HBV-associated acute hepatitis to CLD and HCC. Keywords: chronic liver disease, hepatocellular carcino- ma, Eph receptor, angiogenesis, polymorphism Introduction The single nucleotide polymorphism (SNP) is the most common genomic sequence variation and involves the stable substitution of a single base in the human genome. It was recently reported that various SNPs may increase susceptibility to risk factors for the develop- ment of a variety of cancers (Storey et al., 1998; Calin et al., 2005; Kiyohara & Yoshimasu, 2007; Dutt & Beroukhim, 2007; Zeng et al., 2006). Moreover, SNPs in various genes, such as the genes for cell division cycle protein 6 (Cdc6) (Xiong et al., 2008), patched homolog (PTCH) (Fu et al., 2008), interleukin (IL)-10, IL-19, IL-20 (Truelove et al., 2008), and Mdm2 p53 binding protein homolog (MDM2) (Yoon et al., 2008), are associated with the risk of developing HCC. Consequently, specific SNPs can be used as genetic markers in patients with chronic liver diseases, including chronic hepatitis B (CHB) infections, liver cirrhosis (LC), and hepatitis B vi- rus (HBV)-infected HCC. HCC is one of the most common malignant tumors worldwide and causes about 1 million deaths each year (Parkin et al., 2001; Marrero, 2006). The etiology of HCC seems to be multifactorial, and several events appear to be necessary for malignant transformation to occur. Hepatitis C virus (HCV) and HBV infections are im- portant risk factors for chronic liver diseases (Collier & Sherman, 1998). CHB infection is the most common eti- ology of HCC in Asian countries. In particular, cirrhosis is present in about 70% to 80% of HCC cases (Velazquez et al., 2003; Sy et al., 2005). Moreover, HCC is a highly hypervascular tumor that is associated with a high faculty for vascular invasion (Sun & Tang, 2004). Because tumor angiogenesis plays a critical role in the development and progression of cancers, including HCC (Sun & Tang, 2004; Pang & Poon, 2007), angiogenic factors have been used not only for diagnosis and prog- nosis but also as predictors in cancer patients.