BACKGROUND: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. METHODS: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. RESULTS: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10-5). CONCLUSIONS: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. IMPACT: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

1st Department of Surgery University Hospital Olomouc Olomouc Czech Republic

1st Propaedeutic University Surgery Clinic Hippocratio General Hospital School of Medicine 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 Czech Republic

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

Clinica Chirurgica 1 Department DISCOG University of Padova Padua Italy

Clinica Chirurgica 3 Department DISCOG University of Padova Padua Italy

Department DIMED University of Padova Padua Italy

Department of Biology University of Pisa Pisa Italy

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

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

Department of General Visceral and Transplantation Surgery University Hospital Heidelberg Heidelberg Germany

Department of Hematology Transplantation and Internal Medicine Medical University of Warsaw Warsaw Poland

Department of Medical Biotechnologies University of Siena Siena Italy

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

Department of Oncology Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

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

Department of Surgery Cancer Center Amsterdam Amsterdam University Medical Center Amsterdam the Netherlands

Department of Surgery Erasmus Medical Center Erasmus University Rotterdam the Netherlands

Department of Surgery Unit of Experimental Surgical Pathology Pisa University Hospital Pisa Italy

Department of Surgery University Hospital Kralovske Vinohrady 3rd Faculty of Medicine Charles University Prague Czech Republic

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

Digestive and Liver Disease Unit Sant'Andrea University Hospital Faculty of Medicine and Psychology Sapienza University of Rome Rome Italy

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

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

Division of General and Transplant Surgery Pisa University Hospital Pisa Italy

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Endoscopic Unit Department of Gastroenterology IRCCS Humanitas Research Hospital Milan Italy

Former senior scientist Department for Determinants of Chronic Diseases Bilthoven the Netherlands

Fundeni Clinical Institute Bucharest Romania

Gastroenterology and Gastrointestinal Endoscopy Unit Vita Salute San Raffaele University IRCCS San Raffaele Scientific Institute Milan Italy

Gastroenterology Department Lithuanian University of Health Sciences Kaunas Lithuania

Gastroenterology Unit San Carlo Hospital Potenza Italy

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

Genomic Epidemiology Research Group German Cancer Research Center Heidelberg Germany

German Cancer Consortium Heidelberg Germany

Institute for Digestive Research Lithuanian University of Health Sciences Kaunas Lithuania

Institute for Translational Medicine Medical School University of Pécs Pécs Hungary

Institute of Biology and Medical Genetics 1st Medical Faculty Charles University and General University Hospital Prague Czech Republic

Institute of Experimental Medicine Czech Academy of Sciences Prague Czech Republic

Laboratory for Experimental Oncology and Radiobiology Amsterdam University Medical Centers University of Amsterdam Cancer Center Amsterdam Amsterdam the Netherlands

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

Medical Faculty Heidelberg University of Heidelberg Heidelberg Germany

Pál Heim National Institute of Pediatrics Budapest Hungary

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

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

Utrecht University Utrecht the Netherlands

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Genetic Susceptibility in Understanding of Pancreatic Ductal Adenocarcinoma Risk: A Decade-Long Effort of the PANDORA Consortium