[Association and mechanism between genetic variants in binding region of pancreatic and duodenum homeobox-1 and susceptibility to pancreatic cancer].

Objective: To systematically investigate the association and regulatory mechanism between genetic variants in the binding region of pancreatic and duodenal homeobox 1 (PDX1) and pancreatic cancer susceptibility in the Chinese population. Methods: Chromatin immunoprecipitation sequencing (ChIP-seq) was performed using the human pancreatic cancer cell line BxPC-3 to identify and annotate genetic variants within the PDX1 binding region. A two-center case-control study was conducted, and logistic regression models were employed to analyze the association between PDX1-related variants and pancreatic cancer susceptibility. Functional experiments were performed to elucidate the molecular mechanisms of these genetic variants. Results: ChIP-seq analysis identified 1 608 PDX1 binding regions. SNPs within these regions were significantly enriched in susceptible areas of pancreatic cancer (P<0.001). The common variant rs154659, located within the most significant PDX1 binding peak, was further investigated. The multivariate logistic regression model showed that compared with individuals with TT genotype, individuals with CC genotype had a reduced risk of pancreatic cancer by 29.2% (OR=0.708, 95%CI: 0.589-0.850). Functional studies demonstrated that the rs154659[C] allele displayed higher relative luciferase activity than the rs154659[T] allele. Knockdown of PDX1 significantly attenuated the relative luciferase differences between the two alleles. Conclusion: Genetic variants in the PDX1 binding region are associated with pancreatic cancer risk. The rs154659 modulates pancreatic cancer susceptibility by specifically altering PDX1 binding activity.