Introduction Recent associative studies have linked intra-pancreatic fat deposition (IPFD) with risk of pancreatitis, but the causal relationship remains unclear.

Methods Utilizing Mendelian randomization, we evaluated the causal association between genetically predicted IPFD and pancreatitis. This approach utilized genetic variants from genome-wide association studies of IPFD (n=25,617), acute pancreatitis (n=6,787 cases/361,641 controls), and chronic pancreatitis (n=3,875 cases/361,641 controls).

Results Genetically predicted IPFD was significantly associated with acute pancreatitis (OR per 1-SD increase: 1.40[95%CI:1.12-1.76], p=0.0032) and chronic pancreatitis (OR:1.64[95%CI:1.13-2.39], p=0.0097).

Discussion Our findings support a causal role of IPFD in pancreatitis, suggesting that reducing IPFD could lower the risk of pancreatitis.

Outside of the current work, MH reports research grants from Boehringer Ingelheim and Sanofi to the University Hospital of Tuebingen, participation in advisory board for Boehringer Ingelheim, Sanofi, and Amryt, and lecture fees from Amryt, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, and Sanofi. L.W. provided consulting service to Pupil Bio, Inc. and reviewed manuscripts for Gastroenterology Report, and received honorarium.

We acknowledge the following grant support:T32CA229110 (S.A.S) and R00CA256525 (B.Z.H). Japan Society for the Promotion of Science KAKENHI grants JP22K15685.

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This study used only publicly available summary statistics from genome-wide association studies (GWAS). GWAS data for intra-pancreatic fat deposition, visceral adipose tissue, alcohol use, and cholelithiasis are accessible through the GWAS Catalog (https://www.ebi.ac.uk/gwas/). GWAS data for pancreatitis are available from FinnGen (https://www.finngen.fi/en).

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