Causal Effects of Metabolic Factors on Pancreatic Ductal Adenocarcinoma Risk: A Mendelian Randomization Study

BACKGROUND: Epidemiological studies focusing on pancreatic ductal adenocarcinoma (PDAC) have consistently reported robust positive associations between metabolic factors and PDAC. In the realm of evaluating the causal implications of these factors on PDAC, Mendelian randomisation (MR) demonstrates distinct advantages over traditional observational research approaches. Therefore, an MR study was meticulously designed and executed to elucidate the causal relationship between obesity-related metabolic factors and PDAC. AIMS: This study aimed to explore the relationship between PDAC and obesity-related metabolic factors. MATERIALS AND METHODS: We identified instrumental variants corresponding to 30 exposures. These exposures could be classified into four distinct groups, namely traits related to glucose metabolism-related traits, lipid metabolism-related traits, body fat distribution and body mass index (BMI)-related traits. Summary-level data for PDAC were obtained from FinnGen consortia. MR analysis was conducted using three methods including inverse-variance weighted, weighted median and MR-Egger. Heterogeneity and horizontal pleiotropy were assessed to ensure result reliability. RESULTS: Our research findings demonstrated significant causal relationships among body fat distribution, BMI-related traits and PDAC. Specifically, parameters such as arm predicted mass, leg predicted mass, leg fat mass, trunk predicted mass, waist circumference, whole body fat mass, BMI, weight and basal metabolic rate exhibit positive associations with PDAC. Conversely, other risk factors, including the waist-to-hip ratio (WHR) and WHR adjusted for BMI, present negative associations. CONCLUSIONS: This study provided evidence that some obesity-related metabolic factors were correlated with PDAC. Specifically, significant correlations were observed between PDAC and certain body fat distribution as well as BMI-related traits.