Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk
Authors: Yuan Fangcheng , Hung Rayjean J. , Walsh Naomi , Zhang Han , Platz Elizabeth A. , Wheeler William , Song Lei , Arslan Alan A. , Beane Freeman Laura E. , Bracci Paige , Canzian Federico , Du Mengmeng , Gallinger Steven , Giles Graham G. , Goodman Phyllis J. , Kooperberg Charles , Le Marchand Loic , Neale Rachel E. , Rosendahl Jonas , Scelo Ghislaine , Shu Xiao-Ou , Visvanathan Kala , White Emily , Zheng Wei , Albanes Demetrius , Amiano Pilar , Andreotti Gabriella , Babic Ana , Bamlet William R. , Berndt Sonja I. , Brennan Paul , Bueno-de-Mesquita Bas , Buring Julie E. , Campbell Peter T. , Chanock Stephen J. , Fuchs Charles S. , Gaziano J. Michael , Goggins Michael G. , Hackert Thilo , Hartge Patricia , Hassan Manal M. , Holly Elizabeth A. , Hoover Robert N. , Katzke Verena , Kirsten Holger , Kurtz Robert C. , Lee I-Min , Malats Nuria , Milne Roger L. , Murphy Neil , Ng Kimmie , Oberg Ann L. , Porta Miquel , Rabe Kari G. , Real Francisco X. , Rothman Nathaniel , Sesso Howard D. , Silverman Debra T. , Thompson Ian M. , Wactawski-Wende Jean , Wang Xiaoliang , Wentzensen Nicolas , Wilkens Lynne R. , Yu Herbert , Zeleniuch-Jacquotte Anne , Shi Jianxin , Duell Eric J. , Amundadottir Laufey T. , Li Donghui , Petersen Gloria M. , Wolpin Brian M. , Risch Harvey A. , Yu Kai , Klein Alison P. , Stolzenberg-Solomon Rachael 
Published: July 2020

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values &lt; 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10−6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC.

Significance:

The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.