Genetic Evidence Causally Linking Pancreas Fat to Pancreatic Cancer: A Mendelian Randomization Study

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and any clues to understanding its elusive etiology could lead to breakthroughs in prevention, early detection, or treatment. Observational studies have shown a relationship between pancreas fat accumulation and PDAC, but the causality of this link is unclear. We therefore investigated whether pancreas fat is causally associated with PDAC using two-sample Mendelian randomization. Methods: We leveraged eight genetic variants associated with pancreas fat (P<5×10-8) from a genome-wide association study (GWAS) in the UK Biobank (25,617 individuals), and assessed their association with PDAC in the Pancreatic Cancer Cohort Consortium I-III and the Pancreatic Cancer Case-Control Consortium dataset (8,275 PDAC cases and 6,723 non-cases). Causality was assessed using the inverse-variance weighted method. Although none of these genetic variants were associated with body mass index (BMI) at genome-wide significance, we further conducted a sensitivity analysis excluding genetic variants with a nominal BMI association in GWAS summary statistics from the UK Biobank and the Genetic Investigation of Anthropometric Traits consortium dataset (806,834 individuals). Results: Genetically determined higher levels of pancreas fat using the eight genetic variants was associated with increased risk of PDAC. For one standard deviation increase in pancreas fat levels (i.e., 7.9% increase in pancreas fat fraction), the odds ratio of PDAC was 2.46 (95%CI:1.38-4.40, P=0.002). Similar results were obtained after excluding genetic variants nominally linked to BMI (odds ratio:3.79, 95%CI:1.66-8.65, P=0.002). Conclusions: This study provides genetic evidence for a causal role of pancreas fat in the pathogenesis of PDAC. Thus, reducing pancreas fat could lower the risk of PDAC. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the following institutions. National Institutes of Health/National Cancer Institute (NIH/NCI) R00CA218892 (LW), T32CA229110 (SS), K99CA256525, U01CA164973 (LLM) and R00CA256525 (BH). Japan Society for the Promotion of Science KAKENHI grants JP22K15685. University of Hawaii Cancer Center. V Foundation V Scholar Award (V2021-023). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is approved by IRB in University of Hawaii at Manoa. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The pancreas fat genetic dataset is available from a previous study (reference 21): https://cdn.elifesciences.org/articles/65554/elife-65554-supp1-v1.xlsx. The pancreatic cancer genetic datasets used for the association analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through dbGaP accession phs000206.v5.p3 and phs000648.v1.p1. The BMI genetic dataset used for this study was obtained from a previous study (reference 25): https://zenodo.org/record/1251813#.Y9n8YnbP1D8.