Evidence for a causal link between intra-pancreatic fat deposition and pancreatic cancer: A prospective cohort and Mendelian randomization study.

Authors

Yamazaki H, Streicher SA, Wu L, Fukuhara S, Wagner R, Heni M, Grossman SR, Lenz HJ, Setiawan VW, Le Marchand L, Huang BZ

Affiliations

• Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Center for Innovative Research for Communities and Clinical Excellence (CiRC2LE), Fukushima Medical University, Fukushima, Japan. Electronic address: yamazaki.hajime.7n@kyoto-u.ac.jp.
• Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA.
• Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Center for Innovative Research for Communities and Clinical Excellence (CiRC2LE), Fukushima Medical University, Fukushima, Japan; Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
• Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
• Division of Endocrinology and Diabetology, Department of Internal Medicine I, Ulm University, Ulm, Germany; Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany.
• Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
• Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
• Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Abstract

Prior observational studies suggest an association between intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC); however, the causal relationship is unclear. To elucidate causality, we conduct a prospective observational study using magnetic resonance imaging (MRI)-measured IPFD data and also perform a Mendelian randomization study using genetic instruments for IPFD. In the observational study, we use UK Biobank data (N = 29,463, median follow-up: 4.5 years) and find that high IPFD (>10%) is associated with PDAC risk (adjusted hazard ratio [HR]: 3.35, 95% confidence interval [95% CI]: 1.60-7.00). In the Mendelian randomization study, we leverage eight out of nine IPFD-associated genetic variants (p < 5 × 10^-8) from a genome-wide association study in the UK Biobank (N = 25,617) and find that genetically determined IPFD is associated with PDAC (odds ratio [OR] per 1-standard deviation [SD] increase in IPFD: 2.46, 95% CI: 1.38-4.40) in the Pancreatic Cancer Cohort Consortium I, II, III (PanScan I-III)/Pancreatic Cancer Case-Control Consortium (PanC4) dataset (8,275 PDAC cases and 6,723 non-cases). This study provides evidence for a potential causal role of IPFD in the pathogenesis of PDAC. Thus, reducing IPFD may lower PDAC risk.