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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.

SUBMITTER: Yamazaki H

PROVIDER: S-EPMC10897551 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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

Yamazaki Hajime H Streicher Samantha A SA Wu Lang L Fukuhara Shunichi S Wagner Róbert R Heni Martin M Grossman Steven R SR Lenz Heinz-Josef HJ Setiawan Veronica Wendy VW Le Marchand Loïc L Huang Brian Z BZ

Cell reports. Medicine 20240126 2

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 fin ...[more]

PMID: 38280379

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Project description:BackgroundRecent studies have increasingly emphasized the strong correlation between the lipidome and the risk of pancreatic diseases. To determine causality, a Mendelian randomization (MR) analysis was performed to identify connections between the lipidome and pancreatic diseases.MethodsStatistics from a genome-wide association study of the plasma lipidome, which included a diverse array of 179 lipid species, were obtained from the GeneRISK cohort study with 7,174 participants. Genetic associations with four types of pancreatitis and pancreatic cancer were sourced from the R11 release of the FinnGen consortium. Two pancreatitis datasets from UK Biobank were employed as the validation cohort. MR analysis was conducted to assess the relationship between the genetically predicted plasma lipidome and these pancreatic diseases. Inverse variance weighted was adopted as the main statistical method. Bayesian weighted MR was employed for further verification. The MR-Egger intercept test for pleiotropy and Cochrane's Q statistics test for heterogeneity were performed to ensure the robustness.ResultsMR analysis yielded significant evidence that 26, 25, 2, and 19 lipid species were correlated with diverse outcomes of pancreatitis, and 8 lipid species were correlated with pancreatic cancer. Notably, sterol ester (27:1/20:2) levels (OR: 0.84, 95% CI: 0.78-0.90, P = 5.79 × 10-7) were significantly associated with acute pancreatitis, and phosphatidylcholine (17:0_20:4) levels (OR: 0.89, 95% CI: 0.84-0.94, P = 1.78 × 10-4) and sterol ester (27:1/20:4) levels (OR: 0.90, 95% CI: 0.86-0.95, P = 2.71 × 10-4) levels were significantly associated with chronic pancreatitis after the Bonferroni-corrected test. As for validation, 14 and 9 lipid species were correlated with acute and chronic pancreatitis of UK Biobank. Some lipid classes showed significant effects both in the FinnGen consortium and UK Biobank datasets.ConclusionsThe findings of this study indicate a potential genetic predisposition linking the plasma lipidome to pancreatic diseases and good prospects for future pancreatic disease clinical trials.

Project description:IntroductionMetabolic syndrome (MetS) is significantly associated with osteoarthritis (OA), especially in MetS patients with blood glucose abnormalities, such as elevated fasting blood glucose (FG), which may increase OA risk. Dietary modifications, especially the intake of polyunsaturated fatty acids (PUFAs), are regarded as a potential means of preventing MetS and its complications. However, regarding the effects of FG, Omega-3s, and Omega-6s on OA, the research conclusions are conflicting, which is attributed to the complexity of the pathogenesis of OA. Therefore, it is imperative to thoroughly evaluate multiple factors to fully understand their role in OA, which needs further exploration and clarification.MethodsTwo-sample univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were employed to examine the causal effect of metabolic related factors on hip OA (HOA) or knee OA (KOA). The exposure and outcome datasets were obtained from Open GWAS IEU. All cases were independent European ancestry data. Three MR methods were performed to estimate the causal effect: inverse-variance weighting (IVW), weighted median method (WMM), and MR-Egger regression. Additionally, the intercept analysis in MR-Egger regression is used to estimate pleiotropy, and the IVW method and MR-Egger regression are used to test the heterogeneity.ResultsThe UVMR analysis revealed a causal relationship between FG and HOA. By MVMR analysis, the study discovered a significant link between FG (OR = 0.79, 95%CI: 0.64∼0.99, p = 0.036) and KOA after accounting for body mass index (BMI), age, and sex hormone-binding globulin (SHBG). However, no causal effects of FG on HOA were seen. Omega-3s and Omega-6s did not have a causal influence on HOA or KOA. No significant evidence of pleiotropy was identified.DiscussionThe MR investigation showed a protective effect of FG on KOA development but no causal relationship between FG and HOA. No causal effect of Omega-3s and Omega-6s on HOA and KOA was observed. Shared genetic overlaps might also exist between BMI and age, SHBG and PUFAs for OA development. This finding offers a novel insight into the treatment and prevention of KOA from glucose metabolism perspective. The FG cutoff value should be explored in the future, and consideration should be given to demonstrating the study in populations other than Europeans.

Dataset Information

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

Publications

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

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