Genetic Studies on Chromosome 4q and 13q in Familial Hepatocellular Carcinoma
Date Issued
2008
Date
2008
Author(s)
Shih, Wei-Liang
Abstract
Backgroundtudies of familial aggregation of hepatocellular carcinoma (HCC) and segregation analyses have suggested existence of genetic component in the etiology of familial HCC. High rates of loss-of-heterozygosity on chromosome 4q and 13q have been observed in hepatitis B-related HCC. The objective of this study was to use a hierarchical strategy with linkage and linkage disequilibrium (LD) approaches to identify HCC-susceptibility loci on chromosome 4q and 13q.ubjects and Methodse performed a two-stage genetic study in which linkage and family-based association mapping was followed up by association and replication studies in an independent sample of unrelated cases and controls. For stage 1, data were from 74 multiplex families and 166 singleton families. The majority of the affected individuals (86.7%) in the family sample were hepatitis B surface antigen (HBsAg) carriers. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test (PDT). For stage 2, promising single-nucleotide polymorphisms (SNPs) identified by stage 1 were examined in an independent set of 855 HBsAg-positive cases and 875 HBsAg-positive controls. Logistic and Cox regression analyses were used to study the relationship of SNPs representative of the implicated region with HCC development and with disease-specific survival determined in terms of HCC or cirrhosis deaths.esultse found evidence of linkage to microsatellite markers on 4q25 (peak multipoint heterogeneity LOD score =3.12 at marker D4S3240), 13q12.13-13.1, 13q14.3-21.31, and 13q31.1-32.2 (peak multipoint maximized LOD (MOD) =3.73 at marker D13S886 in 13q31.3). Fine mapping applied to the 4q25 region with SNPs across a 6.16-cM interval under peak resulted in significant association in ten SNPs (empirical P-value range: 0.0002 to 0.0045 from the PDT) from two adjacent haplotype blocks within or flanking the PAPSS1 gene, which encodes an enzyme involved in sulfation of a broad range of compounds. Our affected-sibship data and the genotype identity-by-descent sharing test suggest that six of these ten SNPs can account in part for the observed linkage signal. In the case-control analyses, multiple statistically significant SNP associations were identified in the PAPSS1 gene, particularly for the young-onset cases aged <45 years. In addition, the presence of a common haplotype containing the same alleles at four SNPs, which revealed overtransmission to HCC subjects in the PDT analyses, were associated with poor survival among patients with small tumor present at hospital admission (adjusted hazard ratio= 1.71; 95% confidence interval=1.10 to 2.65).onclusionsenetic variation in the PAPSS1 gene may play a role in the pathogenesis of HBV-related HCC. Further fine-mapping studies or positional candidate gene studies on 13q31.3 are warranted.
Subjects
Hepatocellular carcinoma
Linkage analysis
Association analysis
Linkage disequilibrium
Chromosome 4q
Chromosome 13q
PAPSS1 gene
SDGs
Type
thesis
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