Background & aims: Chronic pancreatitis and pancreatic adenocarcinoma are associated with alcohol abuse, consumption of tobacco smoke, and environmental aromatic hydrocarbon exposure. The role of genetic factors is incompletely defined. Uridine 5'-diphosphate glucuronosyltransferases are phase II detoxifying enzymes capable of tobacco-borne toxicant inactivation and cellular protection. This study analyzes UGT1A7 gene polymorphisms in pancreatic diseases.
Methods: Genomic DNA from northern German white patients with pancreatic adenocarcinoma (n = 52) and chronic pancreatitis (n = 146), as well as healthy blood donors (n = 235) was analyzed by UGT1A7-specific PCR, sequencing analysis, and temperature gradient gel electrophoresis. Pancreatic expression of UGT1A genes was identified by duplex reverse-transcription PCR.
Results: Predominant expression of the UGT1A7 gene was identified in human pancreatic tissue. Pancreatic adenocarcinoma was associated with the low detoxification activity UGT1A7*3 allele, which combines the W208R, N129K, and R131K mutations (odds ratio [OR], 1.98; 95% confidence interval [CI ], 1.24-3.14; P = 0.003). The association of UGT1A7*3 was especially strong in smokers with pancreatic carcinoma who were younger than 55 years (OR, 4.7; 95% CI, 1.9-11.8; P = 0.0009). Chronic pancreatitis was also associated with UGT1A7*3 (OR, 1.76; 95% CI, 1.26-2.46; P = 0.0009). UGT1A7*3 was specifically associated with the subgroup of patients with alcoholic pancreatitis, of whom 89% were smokers (OR, 2.24; 95% CI, 1.46-3.43; P = 0.0001) but was not associated with the nonalcoholic pancreatitis subgroup.
Conclusions: The UGT1A7 gene is predominantly expressed in human pancreas. The low detoxification activity UGT1A7*3 allele is identified as a novel risk factor of pancreatic diseases defining the interaction of genetic predisposition and environmentally induced oxidative injury.