Thyroid hormone signaling causally influences pancreatic disease risk: Evidence from Mendelian randomization and...

The relationship between thyroid function and pancreatic disease has been observed clinically, yet causality remains unestablished. We applied bidirectional Mendelian randomization using genetic instruments from genome-wide association studies encompassing over 500,000 individuals to determine causal relationships. We demonstrate that genetic liability to hypothyroidism substantially protects against acute pancreatitis (odds ratio 0.37, 95 % CI 0.17-0.80). Genetically elevated basal metabolic rate increases acute pancreatitis risk (OR 1.16) while decreasing chronic pancreatitis risk (OR 0.77), revealing divergent pathophysiological mechanisms. No causal relationship exists between thyroid function and pancreatic cancer. To elucidate underlying mechanisms, we performed multi-omics analysis including bulk RNA sequencing from 172 pancreatic adenocarcinomas, single-cell RNA sequencing from acute pancreatitis (32,830 cells), chronic pancreatitis (30,426 cells), and pancreatic cancer (95,751 cells), and GeoMx spatial transcriptomics (253 regions). High metabolic gene expression predicts favorable cancer survival (hazard ratio 0.52, P = 0.0015). Single-cell analysis reveals myeloid-specific metabolic gene downregulation in chronic pancreatitis and 31-fold upregulation of the thyroid hormone-inactivating enzyme DIO3 in tumor epithelial cells. Spatial transcriptomics demonstrates that PPARGC1A downregulation occurs in preneoplastic lesions before malignant transformation. These findings establish thyroid function as a causal determinant of pancreatitis susceptibility, identify cell type-specific mechanisms including local thyroid hormone inactivation and metabolic reprogramming, and demonstrate that patient-derived organoids better preserve prognostically favorable metabolic phenotypes than cell lines. Thyroid function represents a potentially modifiable risk factor for inflammatory pancreatic disease.