Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, p = 3.03 × 10-6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.

1st Department of Medicine Medical School University of Pécs Pécs Hungary

1st Faculty of Medicine Institute of Biology and Medical Genetics Charles University Prague Czechia

1st Propaedeutic University Surgery Clinic Hippocratio General Hospital Medical School National and Kapodistrian University of Athens Athens Greece

ARC NET Centre for Applied Research on Cancer University and Hospital Trust of Verona Verona Italy

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czechia

Biomedical Centre and Department of Surgery Faculty of Medicine in Pilsen Charles University Pilsen Czechia

Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Children's Hospital Florence Italy

Deparment of Pathology Cancer Center Amsterdam Amsterdam University Medical Centers University of Amsterdam Amsterdam Netherlands

Department for Determinants of Chronic Diseases Bilthoven Netherlands

Department of Biology University of Pisa Pisa Italy

Department of Biomedical Sciences Humanitas University Milan Italy

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

Department of Gastroenterology Institute for Digestive Research Medical Academy Lithuanian University of Health Sciences Kaunas Lithuania

Department of Gastroenterology San Carlo Hospital Potenza Italy

Department of General Surgery University of Heidelberg Heidelberg Germany

Department of General Visceral and Thoracic Surgery University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Hematology Institute of Hematology and Transfusion Medicine Warsaw Poland

Department of Medical Oncology Cancer Center Amsterdam Amsterdam University Medical Center University of Amsterdam Amsterdam Netherlands

Department of Medicine Centre for Translational Medicine University of Szeged Szeged Hungary

Department of Medicine DIMED Padua University Hospital Padua Italy

Department of Molecular and Clinical Cancer Medicine University of Liverpool Liverpool United Kingdom

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czechia

Department of Oncology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czechia

Department of Oncology Fondazione IRCCS Casa Sollievo della Sofferenza Hospital San Giovanni Rotondo Italy

Department of Radiology and Oncology Institute of Cancer of São Paulo São Paulo Brazil

Department of Surgery 1 Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czechia

Department of Surgery DiSCOG Padua University Hospital Padua Italy

Department of Surgery Erasmus Medical Center Erasmus University Rotterdam Netherlands

Department of Surgery Faculty Hospital Kralovske Vinohrady and 3rd Faculty of Medicine Charles University Prague Czechia

Digestive and Liver Disease Unit Sant'Andrea Hospital Rome Italy

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Experimental Oncology Gastroenterology and Gastrointestinal Endoscopy Unit Vita Salute San Raffaele University IRCCS San Raffaele Scientific Institute Milan Italy

Division of Gastroenterology and Digestive Endoscopy Department of Gastroenterology Humanitas Clinical and Research Center IRCCS Milan Italy

Division of Gastroenterology and Research Laboratory Fondazione IRCCS Casa Sollievo della Sofferenza Hospital San Giovanni Rotondo Italy

Division of General and Transplant Surgery University of Pisa Pisa Italy

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Endoscopic Surgery Department Hippocratio General Hospital of Athens Athens Greece

Faculty of Medicine and Psychology Sapienza University of Rome Rome Italy

Faculty of Medicine University of São Paulo São Paulo Brazil

Fundeni Clinical Institute Bucharest Romania

General Surgery Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa Pisa Italy

Genetic and Molecular Epidemiology Group Spanish National Cancer Research Centre Madrid Spain

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

German Cancer Consortium Heidelberg Germany

Institute for Risk Assessment Sciences Utrecht University Utrecht Netherlands

Institute for Translational Medicine Medical School University of Pécs Pécs Hungary

Laboratory for Applied Science and Technology in Health Carlos Chagas Institute Curitiba Brazil

Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece

Medical Faculty Heidelberg University of Heidelberg Heidelberg Germany

Oncological Department Azienda USL Toscana Nord Ovest Oncological Unit of Massa Carrara Carrara Italy

Pancreatic Surgery Unit Humanitas Clinical and Research Center IRCCS Milan Italy

Pancreato Biliary Endoscopy and Endosonography Division Pancreas Translational and Clinical Research Center IRSSC San Raffaele Scientific Institute Milan Italy

Szent György University Teaching Hospital of County Fejér Székesfehérvár Hungary

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