Single nucleotide polymorphism in the microRNA-199a binding site of HIF1A gene is associated with pancreatic ductal adenocarcinoma risk and worse clinical outcomes

Abstract

Hypoxia-inducible factor-1 alpha (HIF-1a) is over-expressed in many cancers including pancreatic ductal adenocarcinoma (PDAC) and correlated with poor prognosis. We aim to determine the effect of germline genetic variants on the regulation of the homeostasis of the miRNA-gene regulatory loop in HIF1A gene and PDAC risk. HIF1A rs2057482 single nucleotide polymorphism (SNP) was genotyped in 410 PDAC cases and 490 healthy controls. The CC genotype SNP HIF1A is significantly correlated with PDAC risk (OR = 1.719, 95% CI: 1.293-2.286) and shorter overall survival (OS, P<0.0001) compared with the CT/TT alleles group. The C/T variants of rs2057482, a SNP located near the miR-199a binding site in HIF1A, could lead to differential regulation of HIF1A by miR-199a. Specifically, the C allele of rs2057482 weakened miR-199a-induced repression of HIF-1a expression on both mRNA and protein levels. In the PDAC tissue, individuals with the rs2057482-CC genotype expressed significantly higher levels of HIF-1a protein than those with the rs2057482-CT/TT genotype (P<0.0001). Both the CC genotype of SNP HIF1A and increased HIF-1a expression are significantly associated with shorter OS of patients with PDAC. After adjusted by TNM staging, differentiation grade, and the levels of CA19-9, both SNP HIF1A and HIF-1a expression retained highly significance on OS (P<0.0001). Taken together, our study demonstrates that host genetic variants could disturb the regulation of the miR-199a/HIF1A regulatory loop and alter PDAC risk and poor prognosis. In conclusion, the rs2057482-CC genotype increases the susceptibility to PDAC and associated with cancer progression.