Background
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality worldwide, with rising incidence. Beyond genetic susceptibility, metabolic disorders and lifestyle contribute to PDAC risk. Metabolic syndrome (MetS), defined by abdominal obesity, dyslipidemia, hypertension, and impaired glucose metabolism, is consistently associated with PDAC and is closely linked to dietary patterns that promote inflammation and insulin resistance.
Although diet has been widely studied in PDAC, results are inconsistent due to heterogeneous assessments, residual confounding, and a focus on single nutrients rather than overall dietary patterns. Composite indices, such as the Dietary Inflammatory Index (DII) and the Western Diet (WD) score, may better capture biologically relevant effects. Data jointly evaluating MetS and dietary patterns in PDAC risk remain limited, highlighting the need for integrative analyses.

Objectives
This study aimed to investigate relationships among MetS, dietary habits, and PDAC risk. We first assessed associations of MetS components with PDAC, then examined dietary factors—including inflammatory potential and adherence to a Western diet—in relation to PDAC risk.

?Methods
We used data from PanGenEU, a multicenter European case-control study of adults with PDAC and hospital-based controls with diagnoses unrelated to PDAC risk factors. Information on MetS components was self-reported. Two MetS definitions were applied: clinical (obesity, long-standing diabetes, hypertension, and hypercholesterolemia; n = 2,899) and biological (obesity, long-standing diabetes, low HDL-cholesterol, and elevated triglycerides; n = 1,199).
Dietary intake was assessed using a 149-item food frequency questionnaire referring to consumption two years earlier. Dietary data were available for 722 cases and 643 controls. DII was calculated from macro- and micronutrients, selected foods, and fatty acids, using energy-adjusted, standardized, literature-weighted scores. WD scores were derived from energy-adjusted intake of Western and Mediterranean foods, categorized into quintiles and summed. Associations with PDAC risk were evaluated using generalized linear models, adjusted for age, sex, and known PDAC risk factors.
 
Results
MetS (≥3 components) was associated with higher PDAC risk under both definitions: clinical (OR=1.39, p=0.003) and biological (OR=1.61, p<0.001). For individual components, long-standing diabetes predicted PDAC under the clinical definition (OR=1.73, p<0.001), with medication-treated diabetes further increasing risk (OR=2.01, p<0.001), whereas untreated diabetes did not. Under the biological definition, low HDL-cholesterol (OR=1.97, p<0.001) and elevated triglycerides (OR=1.53, p=0.001) were significant.
Regarding dietary factors, no overall association was observed between dietary scores and PDAC risk. However, a higher Dietary Inflammatory Index (DII) score was associated with increased PDAC risk among current smokers (OR per 1-SD increase = 1.36, 95% CI: 1.07–1.74), with a significant DII × smoking interaction (p = 0.026). Similar patterns were observed in younger participants and in subgroups without diabetes or a family history of pancreatic cancer, suggesting potential effect modification by these factors.

?Conclusions
MetS is associated with increased PDAC risk, driven by long-standing diabetes, low HDL-cholesterol, and elevated triglycerides. Dietary inflammatory potential may influence PDAC primarily among smokers or in low-risk populations, suggesting effect modification rather than a strong independent effect. Future analyses will integrate genetic susceptibility and the gut microbiome to further elucidate the interplay among diet, metabolic health and PDAC development.