Integrative Genomic Analysis Identifies That SERPINA6-rs1998056 Regulated by FOXA/ERα Is Associated with Female Hepatocellular Carcinoma

The human forkhead box A1 (FOXA1) and A2 (FOXA2) transcription factors have been found to control estrogen and androgen signaling through co-regulating target genes with sex hormone receptors. Here we used an integrative strategy to examine the hypothesis that genetic variants at FOXA1/2 binding elements may be associated with sexual dimorphism of hepatocellular carcinoma (HCC) risk. Firstly we extracted chromatin immunoprecipitation-sequencing (ChIP-seq) data of FOXA1, FOXA2 and estrogen receptor 1(ERα) from ENCODE database to obtain dual target regions of FOXA/ERα, and further intersected these regions with genes' promoters. Then we used MATCH program to predict FOXA binding elements, in which genetic variants were retrieved by dbSNP database (NCBI, build 134). A total of 15 candidate variants were identified in this stage. Secondly we performed a case-control study with 1,081 HCC patients and 2,008 matched controls and found a significant association of SERPINA6-rs1998056 with female HCC risk under common genetic models (e.g. GG versus CC: OR = 2.03, 95% CI = 1.26-3.27, P = 0.004). Moreover, results from our real-time quantitative polymerase chain reaction (qPCR) using 72 normal liver tissues adjacent to the tumors showed that SERPINA6 expression was significantly different among different genotypes of this variant (GG versus CC: P = 0.032; Group test: P = 0.060). In summary, our study suggested that SERPINA6-rs1998056 regulated by FOXA/ERα might be associated with female HCC risk.