Mapping Genetic Regulation of Transcription to Identify Functional Variants and Genes Associated with Pancreatic Cancer Risk

ABSTRACT Pancreatic cancer is one of the most lethal malignancies. Genome‐wide association studies (GWAS) identify multiple susceptibility loci, but most map to noncoding regions, leaving variant‐to‐gene links unresolved. In this study, a genome‐wide regulatory map is constructed using expression quantitative trait loci (eQTL) analysis of 482 pancreatic tissues, and integrated with a GWAS meta‐analysis to prioritize causal variants. A total of 82 significant variants and 15 target genes for pancreatic cancer risk are identified, with enrichment in cancer‐related pathways. The variant rs11102484 is validated in an independent cohort of 569 cases and 2691 controls. The combined analysis of 5699 cases and 8467 controls confirms that the G allele of rs11102484 significantly reduces pancreatic cancer risk (odds ratio = 0.85, 95% confidence interval = 0.80–0.90, P = 4.83 × 10 ⁻⁸ ). Functional assays demonstrate that the G allele impairs ZNF263 binding at rs11102484, thereby weakening a long‐range silencer‐promoter interaction and increasing ST7L expression. Elevated ST7L dampens AKT/β‐catenin signaling and suppresses pancreatic cancer cell proliferation, consistent with the protective association. Overall, this study implicates functional genes in pancreatic cancer risk and characterizes a regulatory variant that modulates ST7L expression, advancing the interpretation of GWAS findings and understanding of pancreatic cancer biology.