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

Cell Rep Med. 2024 Feb 20;5(2):101391. doi: 10.1016/j.xcrm.2023.101391. Epub 2024 Jan 26.

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.

Keywords: fatty pancreas; pancreas cancer; pancreas fat; pancreatic adenocarcinoma; pancreatic fat; pancreatic steatosis.

Publication types

  • Observational Study

MeSH terms

  • Carcinoma, Pancreatic Ductal* / epidemiology
  • Carcinoma, Pancreatic Ductal* / genetics
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis / methods
  • Pancreas / diagnostic imaging
  • Pancreatic Neoplasms* / epidemiology
  • Pancreatic Neoplasms* / genetics
  • Prospective Studies