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. 2014 Sep 8;9(9):e107246.
doi: 10.1371/journal.pone.0107246. eCollection 2014.

Integrative genomic analysis identifies that SERPINA6-rs1998056 regulated by FOXA/ERα is associated with female hepatocellular carcinoma

Na Shen  1 , Jing Gong  2 , Ying Wang  3 , Jing Tian  4 , Jiaming Qian  5 , Li Zou  2 , Wei Chen  2 , Beibei Zhu  2 , Xinghua Lu  5 , Rong Zhong  2 , Anyuan Guo  6 , Li Wang  4 , Xiaoping Miao  2
Affiliations

Integrative genomic analysis identifies that SERPINA6-rs1998056 regulated by FOXA/ERα is associated with female hepatocellular carcinoma

Na Shen et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. A computational strategy for identifying candidate variants at FOXA1/2 binding elements.
Figure 2
Figure 2. SERPINA6 mRNA levels in liver tissues from different genotype carriers of rs1998056.
Vertical scatter plots indicated relative gene expression of SERPINA6 for 22 CC, 38 CG and 12 GG carriers. Horizontal line indicated median mRNA level of each genotype group.
See this image and copyright information in PMC

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Grants and funding

This study was supported by the National Natural Science Foundation of China (NSCF–81273182 to W.L.), Beijing Innovative Talent Development Project (2012D009008000004 to W.L.), Wuhan Innovative Talent Development Project for Ying Wang and General Financial Grant from the China Postdoctoral Science Foundation [2014M550395 to R.Z.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.