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

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.