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.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

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).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

GWAS data for IPFD, VAT, 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).