title: Nine susceptibility loci for hepatitis B virus-related hepatocellular carcinoma identified by a pilot two-stage genome-wide association study.
abstract: Previous studies have indicated that complex interactions among viral, environmental and genetic factors lead to hepatocellular carcinoma (HCC). To identify susceptibility alleles for hepatitis B virus (HBV)-related HCC, the present study conducted a pilot two-phase genome-wide association study (GWAS) in 660 Han Chinese individuals. In phase 1, a total of 500,447 single-nucleotide polymorphisms (SNPs) were genotyped in 50 HCC cases and 50 controls using Affymetrix GeneChip 500k Array Set. In phase 2, 1,152 SNPs were selected from phase 1 and genotyped in 282 cases and 278 controls using the Illumina GoldenGate platform. The prior probability of HCC in control subjects was assigned at 0.01, and false-positive report probability (FPRP) was utilized to evaluate the statistical significance. In phase 1, one SNP (rs2212522) showed a significant association with HCC (Pallele=5.23×10-8; ORallele=4.96; 95% CI, 2.72-9.03). In phase 2, among 27 SNPs with unadjusted Pallele<0.05, 9 SNPs were associated with HCC based on FPRP criteria (FPRP <0.20). The strongest statistical evidence for an association signal was with rs2120243 (combined ORallele=1.76; 95% CI, 1.39-2.22; P=2.00×10-6), which maps within the fourth intron ofVEPH1. The second strongest statistical evidence for an association was identified for rs1350171 (combined ORallele=1.66; 95% CI, 1.33-2.07; P=6.48×10-6), which maps to the region downstream of theFZD4gene. The other potential susceptibility genes includedPCDH9,PRMT6,LHX1,KIF2BandL3MBTL4. In conclusion, this pilot two-phase GWAS provides the evidence for the existence of common susceptibility loci for HCC. These genes involved various signaling pathways, including those associated with transforming growth factor β, insulin/phosphoinositide 3 kinase, Wnt and epidermal growth factor receptor. These associations must be replicated and validated in larger studies.
authors: Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.
authors: Li-Shuai
authors: LS
authors: Qu
authors: Department of Gastroenterology, Shanghai Xuhui Central Hospital, Shanghai 200032, P.R. China.
authors: Fei
authors: F
authors: Jin
authors: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Yan-Mei
authors: YM
authors: Guo
authors: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Tao-Tao
authors: TT
authors: Liu
authors: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Ru-Yi
authors: RY
authors: Xue
authors: Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Xiao-Wu
authors: XW
authors: Huang
authors: Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Min
authors: M
authors: Xu
authors: Department of Liver Surgery, Qidong Liver Cancer Institute, Qidong, Jiangsu 226200, P.R. China.
authors: Tao-Yang
authors: TY
authors: Chen
authors: Department of Liver Surgery, Qidong Liver Cancer Institute, Qidong, Jiangsu 226200, P.R. China.
authors: Zheng-Ping
authors: ZP
authors: Ni
authors: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Xi-Zhong
authors: XZ
authors: Shen
keywords: hepatitis B virus; hepatocellular carcinoma; single-nucleotide polymorphisms