UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer.
OBJECTIVE
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.
Ockenga
Johann
J
Department of Gastroenterology, Hepatology and Oncology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Vogel
Arndt
A
Teich
Niels
N
Keim
Volker
V
Manns
Michael P
MP
Strassburg
Christian P
CP
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D002908:Chronic Disease; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity; D010179:Pancreas / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000235:genetics*; D010195:Pancreatitis / Q000209:etiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D012306:Risk
D014453:Glucuronosyltransferase