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

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.

Graphical abstract

Figure 1

Data sources and selection of genetic instruments for the Mendelian randomization analysis ^aPalindromic SNPs are those where the alleles are complementary (G/C or A/T). ^bProxy genetic variants were used when selected genetic variants did not exist in PanScan I–III or PanC4. ^cAssociation of each genetic variant with BMI was evaluated using summary statistics obtained from meta-analysis results of the UK Biobank and GIANT consortium. Although none of the eight genetic variants were associated with BMI at the genome-wide significance, we further conducted a sensitivity analysis excluding the three genetic variants with a nominal BMI association. ^dThe estimates for the association of each genetic variant with PDAC were combined using the inverse-variance weighted method, with summary statistics for PDAC obtained from PanScan I–III and PanC4. IPFD, intra-pancreatic fat deposition; SNP, single-nucleotide polymorphism; MAF, minor allele frequency; GIANT, genetic investigation of anthropometric traits; BMI, body mass index; PanScan, Pancreatic Cancer Cohort Consortium; PanC4, Pancreatic Cancer Case-Control Consortium; PDAC, pancreatic ductal adenocarcinoma.

Figure 2

Primary Mendelian randomization estimates of the association between IPFD and PDAC ^aProxy SNPs were used for rs775103516 (rs113170275), chr9:136138765 (rs495828), rs751370420 (rs7307879), and rs7405380 (rs12444726). ^bAllele associated with increasing IPFD levels. ^cOR (95% CI) of PDAC per-1 SD increase in genetically determined IPFD levels (i.e., per 7.9% increase in fat fraction percentage within the pancreas). ^dRandom-effects inverse-variance weighted method was used to obtain the overall estimate for the association of genetically determined IPFD with PDAC. ^eData markers indicate the OR for the association of genetically determined IPFD with PDAC, which was estimated using each genetic variant. Error bars indicate 95% CIs. IPFD, intra-pancreatic fat deposition; PDAC, pancreatic ductal adenocarcinoma; OR, odds ratio; CI, confidence interval; SD, standard deviation.