FAT10基因单体型与肝细胞癌的相关性研究

Association on the haplotypes of FAT10 gene and hepatocellular carcinoma

背景与目的:人类白细胞抗原FAT10是类泛素调节子蛋白家族中的一员,被认为与肝细胞癌(hepatocellular carcinoma,HCC)发生、发展密切相关。本研究探讨FAT10基因单体型与肝细胞癌的关系。方法:收集254例肝癌病例和268例健康对照人群外周血标本,提取DNA,通过DNA测序分析方法,检测两组人群FAT10基因外显子和侧翼序列单核苷酸多态性。应用Haploview统计软件分析研究对象的连锁不平衡和单体型,并应用病例对照分析方法进行相关性研究。结果:在肝癌组和对照组FAT10基因外显子和侧翼序列上共检测到10个多态性位点。遗传不平衡发现-143 A/G、-121 A/G、+3446 C/T、+3476 T/C、+3527 T/C、+3607 T/C、+3620 C/G、+3803 C/G、+3809 G/T 9个SNPs在同一个单体型块,其中-121 A/G、+3476 T/C、+3607 T/C、+3620 C/G和+3809 G/T多态位点完全连锁。进一步选择-143 A/G、+3476 T/C和+3527T/C 3个tagSNPs进行关联分析和单体型构建,发现-143 A/G和+3476 T/C基因型与相应的野生型纯合子相比能明显降低肝癌发病的风险(P<0.05)。进一步单体型分析发现ATT、ATC、GCT和ACT 4种单体型,其中肝癌患者的GCT和ACT单体型频率显著低于对照组(P<0.05),而ATT单体型频率显著高于对照组(P<0.05),经过1×108的随机置换检验校正后,ATT和GCT单体型与肝癌的发病风险仍然显著相关。结论:FAT10基因单体型可能与肝癌的发病风险相关,ATT单体型可能是肝癌的遗传标志。

Background and purpose： The human HLA-FAT10 gene is a member of the ubiquitin-likemodifier family of proteins, are thought to be associated with the development and progression of hepatocellular carcinoma （HCC）. This study aimed to assess the association between FAT10 gene haplotypes and hepatocellular carcinoma. Methods： Two hundred and sixty-eight healthy persons as control and 254 patients with HCC were recruited. Genotyping was done by using DNA sequencing. Haplotypes were determined through genotypic and disequilibrium analysis using identified single nucleotide polymorphisms （SNPs）. Results： Ten SNPs in FAT10 exonic and flanking sequence were identified, and -143 A/G, -121 A/G, ＋3446 C/T, ＋3476 T/C, ＋3527 T/C, ＋3607 T/C, ＋3620 C/G, ＋3803 C/G, ＋3809 G/T polymorphisms clustered in a block, the complete linkage disequilibrium （D＇=I） was also detected among -121 A/G, ＋3476 T/C, ＋3607 T/C, ＋3620 C/G, ＋3809 G/T. Further more, the -143 A/ G, ＋3476 T/C, ＋3527T/C SNPs were enrolled in the association analysis and haplotype analysis. The -143 A/G, ＋3476 T/C genotypes were associated with a decreased risk for HCC （P〈0.05）. A total of 4 haplotypes were found, namely ATT, ATC, GCT, ACT, the frequency of GCT and ACT haplotypes were significantly lower for HCC patients than for control subjects（P〈0.05）, and the frequency of ATT was significantly higher for HCC patients than for control subjects （P〈0.05）. Ten million permutation testing also indicated that the ATT and GCT haplotypes were associated with HCC susceptibility. Conclusion： The haplotypes of FTA10 gene may be involved in the susceptibility of HCC, the ATT might serve as genetic marker for HCC.