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Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC-related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC-related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRA1, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC. M ore than 170 million people worldwide are estimated to have chronic hepatitis C virus (HCV) infection (http://www.who.int/inf-fs/ en/fact164.html). The most important sequelae of chronic HCV infection are progressive liver fibrosis leading to cirrhosis, and hepatocellular carcinoma (HCC), which is responsible for significant morbidity and mortality throughout the world. 1-4 Many factors, such as alcohol intake, older age at time of infection, male sex, and coinfection with hepatitis B virus, are reported to accelerate disease progression in HCV infection. [5][6][7][8] In addition, host genetic factors have been reported to affect the risk of developing HCC. [9][10][11][12][13][14][15] Recently, we reported that genetic polymorphisms in interleukin-1␤ 11 and uridine 5Ј-diphosphate-glucuronosyltransferase 1A7 12 are associated with the development of HCC in Japanese patients with chronic HCV infection. Genetic polymorphisms in CYP enzymes, 13 the microsomal epoxide hydrolase gene, 14 and the aldehyde dehydrogenase 2 gene 15 also have been reported to be associated with HCC and the severity of HCV-related liver disease. The number of candidate genes that have been examined is, however, rather limited.We performed a large-scale candidate-gene-based search of single-nucleotide polymorphisms (SNPs) to look for SNPs in genes associated with HCC susceptibility. A total of 393 SNPs in 171 candidate genes were examined in Japanese patients with chronic HCV infection.

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