Systematic Exploration Of Functional Genetic Variation Which Can Impact Combination With Transcription Factor JunD And Association Study Of Susceptibility To Hepatocellular Carcinoma

It has been reported that transcription factor JunD plays an important role in the development and progression of hepatocellular carcinoma.The emphasis of this study lies in systematic exploration of functional genetic variation which can impact combination with JunD and provision of a complete and reliable research method.Based on the genome-wide ChIP-chip data,we screened the 84032 candidate SNPs and obtained 39 SNP ultimately which locate in conserved sequences and of which mutation frequency was more than five percent in Chinese population.They were the most promising SNP which can impact combination with JunD and we would not miss any meaningful SNP theoretically,which minimize false negative rate.Then we examined the association between the SNP and susceptibility to HCC by using case-control study.The results showed that the p value of rs4951541?rs2232965?rs281230?rs7820850 was less than 0.05,which means these SNPs associated with HCC development significantly and rs4951541 A>C polymorphism is a risk variation,that is,the individual having rs4951541 CC genotype had a 1.453-fold increased risk for HCC development compared with individual having the rs4951541 CC genotype.rs2232965 C>T polymorphism is a risk variation,that is,the individual having rs2232965 TT genotype had a 2.371-fold increased risk for HCC development compared with individual having the rs2232965 CC genotype.rs281230 G>A polymorphism is a protected variation,that is,the individual having rs281230 AA genotype had a 0.577-fold decreased risk for HCC development compared with individual having the rs281230 GG genotype.rs7820850 C>T polymorphism is a protected variation,that is,the individual having rs7820850 TT and TC genotype had a 0.683-fold decreased risk for HCC development compared with individual having the rs7820850 CC genotype.These four SNP are likely to play a part via impact JunD binding.Next,we explored downstream target genes of these four SNP mediated by JunD through tissue sample,and found that there was possible association between rs7820850 genotypes and PVT1 expression in non-tumor normal tissues.Then it has been verified that the binding of JunD to rs7820850 C genotype is much stronger compared with binding to T genotype by using electrophoretic mobility shift assay.As rs7820850 locate in 8q24 gene desert between c-Myc and PVT I,we inspected long-range interaction by using 3C technology.The result showed that there was interaction between rs7820850 and transcriptional initiation site of miR-1205.In conclusion,we found several functional genetic variation which associate with susceptibility to HCC,and the action mechanism of rs7820850 was studied in detail.They can be used as novel biomarkers and this study provided new strategies for diagnosis and individual-based treatment of HCC.