title: Evidence for association with hepatocellular carcinoma at the PAPSS1 locus on chromosome 4q25 in a family-based study.
abstract: A region on chromosome 4q25 has recently been highlighted as linked to hepatocellular carcinoma (HCC). In this study, we performed a family-based association analysis with 67 single-nucleotide polymorphisms (SNPs) to map this linkage region in 240 families with HCC, 212 (88.3%) of which were ascertained through hepatitis B virus surface antigen (HBsAg)-positive index cases. Individual SNP analysis with correction for multiple testing identified 10 SNPs in two correlated haplotype blocks, located in or around the 3'-phosphoadenosine 5'-phosphosulfate synthetase-1 (PAPSS1) gene (all P-values: <0.0075). Our linkage data and GIST (Genotype identity-by-descent sharing test) indicate that 6 of these 10 SNPs contributed to the linkage signal. The haplotype block of the strongest association with HCC extended from the intron 5 to the 3'-flanking region of PAPSS1; multiple consecutive three-SNP haplotypes in this region were significant. The most significant haplotype showed odd ratios of 3.41 (95% confidence interval (CI)=1.36-8.53) for homozygous individuals in a case-unaffected sibling analysis. This haplotype also revealed an association with elevated serum alpha-fetoprotein and with poor survival in familial cases and an independent series of HBsAg-positive cases with small tumor present at the time of hospital admission. These results implicate PAPSS1 as a candidate HCC-susceptibility gene in hepatitis B carriers.
authors.affiliation: Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Shih
authors.forename: Ming-Whei
authors.initials: MW
authors.lastname: Yu
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Tai-Wei
authors.initials: TW
authors.lastname: Wu
authors.forename: Chih-Lin
authors.initials: CL
authors.lastname: Lin
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Liu
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Lin
authors.forename: Dar-In
authors.initials: DI
authors.lastname: Tai
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
authors.forename: Yun-Fan
authors.initials: YF
authors.lastname: Liaw