Anthropometric traits, metabolic biomarkers, and pancreatic cancer risk: a causal mediation analysis in UK Biobank

BACKGROUND: Obesity is a risk factor for pancreatic cancer, but mechanisms remain unclear. We investigated how anthropometric traits, individually and combined, relate to pancreatic cancer risk and whether associations are mediated by metabolic biomarkers. METHODS: We analysed 462,300 adults (40-69 years) in the UK Biobank. Principal component analysis derived three body shape phenotypes combining body mass index (BMI), height, weight, waist and hip circumference, and waist-to-hip ratio (WHR). Mediation was assessed using four-way decomposition. RESULTS: Over a median follow-up of 10.9 years, 1115 pancreatic cancer cases occurred. Each one-standard-deviation (SD) increase in BMI or WHR was associated with a higher incidence of pancreatic cancer, with hazard ratios (HRs) of 1.20 (confidence interval, CI: 1.12-1.28) and 1.24 (CI: 1.14-1.36), respectively. Body shape characterizing overall obesity showed a similar association (HR = 1.20; CI: 1.12-1.28 per 1-SD), with glucose and HbA1c accounting for mediated proportions (mediated interaction + pure indirect effect) of 12.2% (CI: 3.4-21.0%) and 15.0% (CI: 5.7-24.2%), respectively. For BMI, glucose accounted for 15.9% (CI: 2.8-28.9%) and HbA1c for 20.0% (CI: 6.3-33.7%) of the association. CONCLUSIONS: Glucose and HbA1c mediate a large proportion of the obesity-pancreatic cancer association, highlighting the important role of glycemic control in obesity-related pancreatic carcinogenesis and targeted interventions in at-risk populations.