Evidence for association with hepatocellular carcinoma at the PAPSS1 locus on chromosome 4q25 in a family-based study
Journal
European Journal of Human Genetics
Journal Volume
17
Journal Issue
10
Pages
1250-1259
Date Issued
2009
Author(s)
Wu T.-W.
Lin C.-L.
Lin S.-M.
Tai D.-I.
Lee S.-D.
Liaw Y.-F.
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 α-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.
SDGs
Other Subjects
adenosine 3' phosphate 5' phosphosulfate; adenosine 3' phosphate 5' phosphosulfate 1; alpha fetoprotein; hepatitis B surface antigen; unclassified drug; adult; aged; article; cancer survival; chromosome 4q; controlled study; DNA flanking region; gene locus; gene mapping; genetic association; genetic linkage; haplotype; homozygosity; human; intron; liver cell carcinoma; major clinical study; priority journal; protein blood level; single nucleotide polymorphism; Hepatitis B virus
Publisher
Nature Publishing Group
Type
journal article