UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer.

Abstract

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.

• Authors: Johann Ockenga, Arndt Vogel, Niels Teich, Volker Keim, Michael P Manns, Christian P Strassburg
• Journal: Gastroenterology (Gastroenterology) Vol. 124 Issue 7 Pg. 1802-8 (Jun 2003) ISSN: 0016-5085 [Print] United States
• PMID: 12806614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucuronosyltransferase

Topics

• Adenocarcinoma (etiology, genetics)
• Adult
• Aged
• Chronic Disease
• Female
• Glucuronosyltransferase (genetics)
• Humans
• Male
• Middle Aged
• Organ Specificity
• Pancreas (enzymology)
• Pancreatic Neoplasms (etiology, genetics)
• Pancreatitis (etiology, genetics)
• Polymorphism, Genetic
• Risk