TOPLINE

A UK Biobank study showed that excessive intrapancreatic fat deposition (IPFD) was associated with an elevated risk for all-cause mortality, particularly from vascular causes, in the general population. A genome-wide analysis identified 38 variants linked to intrapancreatic fat, and a polygenic risk score (PRS) based on these variants was associated with higher risks for all-cause and vascular mortality, with the pattern replicated in a large independent group.

METHODOLOGY

• Although excessive IPFD has been linked to pancreatitis and pancreatic cancer, its association with mortality in the general population has remained unknown.
• Researchers analyzed 55,058 participants from the UK Biobank (median age, 65 years; 47.2% men) with MRI-derived measurements of IPFD to evaluate its association with mortality over a median follow-up of 4.9 years.
• IPFD was quantified using MRI-based deep learning segmentation of the pancreas to measure the fat content throughout the organ. Pancreatic fat levels above 9.54% were classified as excessive IPFD.
• A genome-wide association study identified genetic variants associated with IPFD in 46,265 participants and generated a PRS, which was then tested in an independent MRI-naive cohort of 354,761 participants to validate the association between genetically predicted IPFD and mortality.
• The primary outcome was all-cause mortality, while the secondary outcome was cause-specific mortality categorized as cancer, vascular, and nonvascular noncancer causes.

TAKEAWAY

• After adjusting for potential confounders, each SD increase in IPFD was associated with a higher risk for all-cause mortality (hazard ratio [HR], 1.081; P < .05) and vascular mortality (HR, 1.247; P < .01).
• The genome-wide association study identified 38 genetic variants associated with IPFD. The PRS derived from these variants explained only a small percentage (2.31%) of pancreatic fat variability but was associated with all-cause mortality (odds ratio [OR], 1.007), vascular mortality (OR, 1.004), and nonvascular noncancer mortality (OR, 1.004; P < .05 for all).
• In the independent MRI-naive cohort, the PRS remained associated with all-cause mortality (OR, 1.001) and vascular mortality (OR, 1.001; P < .05 for both), supporting the observed association between genetically predicted IPFD and mortality.
• IPFD was also associated with higher risk for incident exocrine pancreatic diseases overall (HR, 1.381), including acute pancreatitis (HR, 1.534) and pancreatic cancer (HR, 1.344; P < .05 for all).

IN PRACTICE

“The PRS explained only 2.31% of the variance in IPFD, indicating that common genetic variants account for only a modest proportion of interindividual variability in pancreatic fat. This suggests that a substantial part of IPFD is likely influenced by nongenetic factors, such as dietary patterns, physical activity, and broader metabolic status. From a clinical perspective, this is important because it implies that IPFD may not be a fixed trait and may remain amenable to modification through lifestyle or metabolic interventions. At the same time, the relatively low explained variance also indicates that the current PRS has limited utility for individual risk prediction, and its value may lie more in supporting disease etiology than in immediate clinical stratification,” the authors of the study wrote.

SOURCE

The study was led by Xiaowu Dong, MD, Yangzhou Key Laboratory of Pancreatic Disease, Pancreatic Center, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China. It was published online in the American Journal of Gastroenterology.

LIMITATIONS

The study predominantly included middle-aged and older White participants, which may have limited the generalizability of the findings. Despite genetic analyses supporting the findings, the study established associations rather than a definitive causal relationship between IPFD and mortality. Residual confounding could not be fully excluded.

DISCLOSURES

The study received financial support from the National Natural Science Foundation of China and the Natural Science Foundation of Jiangsu Province. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.