Genome-wide association study identifies FUT2 rs601338 polymorphism linking intra-pancreatic fat deposition to chronic pancreatitis.

BACKGROUND

Pancreas fat deposition, measured by pancreatic proton density fat fraction (PDFF) in the MRI, has emerged as a critical area of research within the metabolic field. However, its genetic basis and how genetic predisposition impacts the pancreatic disorders remain poorly understood.

METHODS

We conducted a genome-wide association study (GWAS) in 20,040 European individuals (excluding those with acute/chronic pancreatitis and pancreatic cancer) from the UK Biobank. Subsequent post-GWAS analyses including colocalization, transcriptome-wide association studies (TWAS) and integrative analysis with single-cell transcriptomics were employed to identify genetic loci and prioritize genes enriched in pancreatic tissue. Regression models and interaction analyses were used to assess the impact of candidate genetic variant on the risk of pancreatic disorders.

RESULTS

Our analyses identified 44 independent significant genetic variants near 14 protein-coding genes, including FUT2, CBFA2T2, FAF1, MAMSTR, SGMS1, CSNK2A1, CEBPB, and CEBPG. Genetic colocalization and transcriptome-wide association studies (TWAS) confirmed the essential roles of FUT2 and CBFA2T3 in the pancreas. Single-cell transcriptomics showed high FUT2 expression specifically in the exocrine pancreas (acinar and ductal cells). Notably, the polymorphism rs601338 in the FUT2 exon region can cause a stop gain mutation in protein translation. Regression analysis revealed that the rs601338 AA genotype was significantly associated with an increased risk of chronic pancreatitis (CP) across all populations in full adjustment model (OR 1.26 [95 % CI 1.07-1.48], p < 0.001; HR 1.24 [95 % CI 1.03-1.50], p < 0.001). Subgroup analyses revealed population-specific patterns: in Europeans, the AA genotype showed significant associations in logistic regression, while in non-Europeans, both GA and AA genotypes exhibited positive trends, with AA achieving statistical significance (OR 1.20 [95 % CI 1.01-1.41], p = 0.034). Sex-stratified analyses showed significant associations in elevated risk of CP in males (OR 1.33 [95 % CI 1.08-1.62], p = 0.006; HR 1.31 [95 % CI 1.04-1.67], p = 0.025) but not females with full adjustment. Interaction analysis indicated a synergistic effect of current smoking and the rs6031218 AA genotype on CP risk, while COX-2 inhibitor treatment might reduce CP risk in rs6031218 AA individuals.

CONCLUSION

This study identified novel genetic variants for pancreatic PDFF and confirmed related genes functions in the pancreas. These findings emphasize the need for regular surveillance of pancreatic fat deposition in the population with a high genetic risk based on FUT2 polymorphism, which could facilitate risk stratification and tailored therapeutic approaches for the primary prevention of CP.