Shared genetic susceptibility between autoimmune diseases and pancreatic ductal adenocarcinoma: A pathway-level analysis.

Abstract

689 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and limited options for early detection. Genetic susceptibility, including germline mutations and common variants identified through genome-wide association studies (GWAS), plays a critical role in PDAC risk. Emerging evidence suggests that autoimmune diseases—characterized by immune dysregulation potentially influencing its development. Understanding these shared genomic regions may offer new insights into PDAC susceptibility. We hypothesize that autoimmune diseases may share genetic architecture with PDAC. Methods: We analyzed GWAS summary statistics from 10,244 PDAC cases and 360,535 controls of European ancestry from the PanScan1–3, PanC4, and FinnGen consortia. Association analyses were adjusted for age, sex, study/batch effects, and population stratification using principal components, and results were combined via fixed-effect meta-analysis. Genome-wide significant SNPs (P < 5 × 10⁻⁸) associated with 14 autoimmune diseases were obtained from the largest available published GWAS. These included five gastrointestinal (GI) diseases—ulcerative colitis, inflammatory bowel disease (IBD), primary sclerosing cholangitis (PSC), Crohn’s disease, and celiac disease—and nine non-GI diseases—autoimmune thyroid disease (ATD), ankylosing spondylitis, multiple sclerosis, systemic sclerosis, myasthenia gravis, rheumatoid arthritis, psoriasis, Sjögren’s syndrome, and systemic lupus erythematosus (SLE). We examined the association between PDAC and genomic regions (±250 kb) surrounding the established common susceptibility variants for GWAS loci of each autoimmune disease using the summary data-based adaptive rank truncated product (sARTP) method. Sensitivity analyses were conducted excluding regions (± 500kb) surrounding the 20 identified PDAC GWAS loci. We used a false discovery rate threshold of .05. Results: Significant associations were observed between PDAC and genomic regions for both GI and non-GI autoimmune diseases (FDR=0.05). Among GI diseases, IBD (P=0.007) and Crohn’s disease (P= 0.008) were significantly associated with PDAC, with borderline significance observed for ulcerative colitis (P=0.053) and suggestive association with PSC (P=0.062). Among non-GI diseases, significant associations were found for ATD (P=0.0045) and SLE (0.013), with suggestive associations for myasthenia gravis (P=0.02).These associations remained after exclusion of known PDAC loci. Conclusions: Common variants in genomic regions associated with susceptibility to both GI (IBD, Crohn’s disease) and non-GI autoimmune (ATD and SLE) diseases were significantly associated with PDAC. These findings suggest shared genetic architecture, may enhance our understanding of PDAC etiology, and identify a new high-risk group of patients for PDAC.