Abdominal obesity, rather than overall obesity, is a causal risk factor for pancreatic cancer

Abstract Obesity and type 2 diabetes (T2D) are associated with increased risk of pancreatic cancer. Here we assessed the relationship between pancreatic cancer and two distinct measures of obesity, namely total adiposity, using BMI, versus abdominal, using BMI adjusted waist-to-hip ratio (WHRadjBMI) using polygenic scores (PGS) and Mendelian randomization (MR). We constructed z-score weighted PGS for BMI and WHRadjBMI using publicly available data and tested for their association with pancreatic cancer defined in UK biobank (UKBB). Using publicly available summary statistics we then performed bi-directional MR analyses between the two obesity traits and pancreatic cancer. PGSBMI was significantly (multiple testing-corrected) associated with pancreatic cancer (OR[95%CI] = 1.077[1.023–1.13], P = 0.0052). The significance of association declined after T2D adjustment (OR[95%CI] = 1.069[1.015–1.079], P = 0.012). MR analyses showed a nominally significant causal effect of WHRadjBMI on pancreatic cancer (OR[95%CI] = 1.00095[1.00011–1.0018], P = 0.027). Overall, we show that abdominal adiposity measured using WHRadjBMI, is a more important causal risk factor for pancreatic cancer compared to total adiposity, with T2D being a potential driver of this relationship.