Genetic Variants in Cyclooxygenase-2: Expression and Risk of Gastric Cancer and Its Precursors in a Chinese Population

Abstract

To screen the genetic variants in cyclooxygenase-2 (COX-2), and evaluate their effects on COX-2 expression and risk of gastric cancer (GC) and its precursors, a population-based study was conducted in Linqu County, Shangdong Province, an area of China, a high-risk area of GC. Genotypes were determined by polymerase chain reaction (PCR)-based denaturing high-performance liquid chromatography analysis in 248 GC cases and 1523 subjects with precancerous gastric lesions. COX-2 expression was detected by immunohistochemical analysis of biopsy specimens of 593 subjects selected at random from 1523 subjects. COX-2 transcriptional activity was examined by luciferase reporter gene assay. We found an increased risk of GC in subjects with -1195 AA genotype (adjusted odds ratio [OR], 2.33; 95% confidence interval [CI]: 1.45-3.75). Stratified analysis indicated that an elevated risk of GC was observed in subjects carrying the AA genotype and Helicobacter pylori infection (OR, 3.88; 95% CI: 1.46-10.34) or smoking (OR, 7.02; 95% CI: 2.19-22.48), and a high expression of COX-2 was found in subjects with AA genotype (OR, 1.84; 95% CI: 1.09-3.10) compared with GG genotype. The prevalence of COX-2 expression positivity varied markedly by histologic status, and the OR (OR, 5.35; 95% CI: 2.64-10.8) was significantly increased for dysplasia compared with superficial gastritis/chronic atrophic gastritis. Furthermore, tissue homogenate with H pylori infection could significantly stimulate COX-2 promoter activity driven by -1195A compared with the -1195G containing counterparts. These findings suggest that COX-2 polymorphisms may play an important role, at least in part, in developing GC in this high-risk population.