染色體1p32.2-36.1區域肝癌易感受基因連鎖高峰之定位：候選基因策略

Abstract

Background: In hepatocellular carcinomas (HCCs), frequent allelic loss on chromosome 1p has been reported. Using linkage analysis on multiplex families, a HCC-susceptibility locus has been mapped to a broad region of chromosome 1p32.2-36.1. Materials and Methods: Here we have used a positional candidate gene strategy, based on association mapping with single nucleotide polymorphisms (SNPs) on 19 candidate genes within the linked region among 240 families with HCC, followed by a case-control analysis involving an independent set of 855 cases and 875 controls. Significance of the association was assessed by the false-discovery rate q value, which accounts for multiple testing. Results: In the family sample, we observed a significant association between HCC and five single-nucleotide polymorphisms (SNPs) in a haplotype block by using the pedigree disequilibrium test. SNP 13, located in the 3’ untranslated region (UTR) of the retinoblastoma binding protein 4 (RBBP4) gene, showed the strongest evidence (nominal P=0.0047; empirical P=0.0025; q=0.0188). Further case-control analysis confirmed the genetic association between SNP13 and HCC, and identified additional two SNPs in the same haplotype block. The C allele (minor allele) of SNP13 conferred an increased risk for HCC (odds ratio [95% confidence interval]: 1.36 [1.11-1.65] for heterozygotes; 1.29 [0.90-1.84] for homozygotes ). SNP13 and two neighboring SNPs fell on a common haplotype (‘C-A-C’ at SNP13-SNP14-SNP15), which was also associated with an increase risk of HCC. Conclusion: SNP13 was consistently associated with HCC in both family and case-control sample.