Association of Intrapancreatic Fat Deposition with Mortality: A Prospective Cohort Study with Genetic Risk Profiling

BACKGROUND AND AIMS: Pancreatitis and pancreatic cancer lead to excess mortality in the general population. Excessive intrapancreatic fat deposition (IPFD) is a common driver of diseases of the exocrine pancreas according to the PANDORA hypothesis. However, the relationship of IPFD with mortality has never been investigated. We aimed to explore the association of IPFD with mortality. METHODS: Participants from the UK Biobank were divided into two cohorts based on the availability of IPFD quantified using MRI. The Kaplan-Meier survival analysis and multivariable Cox-proportional hazard model were used. Genome-wide association study (GWAS) on IPFD and Mendelian randomization analysis were performed. An IPFD-linked polygenic risk score (PRS) was applied in the MRI-naïve cohort. RESULTS: A total of 55,058 participants were analyzed, 695(1.26%) of whom died during a median follow-up of 4.9 years. Excessive baseline IPFD was significantly associated with an increased risk of all-cause mortality (HR=1.081, p<0.05) and mortality from vascular diseases (HR=1.247, p<0.001). GWAS identified 38 significant IPFD-associated SNPs. The PRS derived from these SNPs showed significant associations with all-cause mortality and mortality from vascular diseases. In the MRI-naïve cohort of 354,761 participants, consistent results were obtained using the PRS as a genetic proxy for IPFD. CONCLUSION: Excessive IPFD is associated with elevated risk of future mortality especially from vascular diseases in the general population.