Abstract
FAS rs2234767 (−1377 G>A), rs1800682 (−670 A>G) and FASLG rs763110 (−844 C>T) promoter polymorphisms can influence transcriptional activities of the genes and thus multiple tumors susceptibility. To investigate their association with risk of colorectal cancer (CRC), the three SNPs were genotyped in 878 cases and 884 controls and the results showed that the FAS rs2234767 and rs1800682 were in a high linkage disequilibrium (LD) with each other (D’ = 0.994) and jointly contributed to an increased risk of CRC (without vs. with rs2234767 GG/rs1800682 AA genotypes, adjusted OR = 1.30, 95% CI = 1.05 − 1.61). In vivo ChIP assays evaluated the effect of rs2234767 and rs1800682 on recruitment of SP1 and STAT1, respectively, to chromatin. The results showed SP1 interacting specifically with STAT1 recruited to their respective motifs for transcriptional activation. The mutant alleles rs2234767 A and rs1800682 G jointly affected coupled SP1 and STAT1 recruitment to chromatin. The interplay between SP1 and STAT1 was critical for the functional outcome of rs2234767 and rs1800682 in view of their high LD. In conclusion, the FAS rs2234767 and rs1800682 polymorphisms were in high LD with each other, and they jointly contributed to an increased risk of CRC by altering recruitment of SP1/STAT1 complex to the FAS promoter for transcriptional activation.
Highlights
Functional SNPs within the promoter region of gene are capable of affecting transcription and subsequently modulating risk of disease[10,11]
When the rs2234767 GG genotype used as the reference, the heterozygous GA and AA genotypes were both associated with significantly increased risk of Colorectal cancer (CRC), and the risk did not change substantially under the assumption of a dominant genetic model
Our results indicated that SP1 and STAT1 contributed to activate the transcription of FAS in CRC and the interplay between these factor was critical for the functional outcome of FAS rs2234767 and rs1800682 in view of their high Linkage disequilibrium analysis (LD)
Summary
Functional SNPs within the promoter region of gene are capable of affecting transcription and subsequently modulating risk of disease[10,11]. It has been reported that there are two functional SNPs in the promoter of FAS www.nature.com/scientificreports/. Gene (FAS − 1377 G> A, rs2234767; − 670 A> G, rs1800682), which located within the consensus sequences of the SP1 and STAT1 transcription factors (TF) binding sites, respectively[12]. Wu et al.[14] first identified a T to C substitution at position − 844 in the promoter of FASLG gene (FASLG − 844 C> T, rs763110), which located in a putative binding motif for CAAT/enhancer-binding protein β (C/ EBPβ ). Functional study revealed that − 844 C allele could increase basal FASLG expression, suggesting the − 844 C> T polymorphism may affect the FASLG-mediated apoptotic signaling. We aimed to determine the association of the FAS rs2234767, rs1800682, and FASLG rs763110 polymorphisms with risk of CRC in a Chinese population and the molecular mechanism underlying the association
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