Abstract
BackgroundOver-expression and increased activity of cyclooxygenase (COX)-2 induced by smoking has been implicated in the development of cancer. This study aimed to explore the interaction between smoking and functional polymorphisms of COX-2 in modulation of gastric cardia adenocarcinoma (GCA) risk.Methods and FindingsThree COX-2 polymorphisms, including –1195G>A (rs689466), –765G>C (rs20417), and 587Gly>Arg (rs3218625), were genotyped in 357 GCA patients and 985 controls. In the multivariate logistic regression analysis, we found that the –1195AA, –765GC, and 587Arg/Arg genotypes were associated with increased risk of GCA (OR = 1.50, 95% CI = 1.05–2.13; OR = 2.06, 95% CI = 1.29–3.29 and OR = 1.67, 95% CI = 1.04–2.66, respectively). Haplotype association analysis showed that compared with G−1195-G−765- GGly587Arg, the A−1195-C−765-AGly587Arg conferred an increased risk of GCA (OR = 2.49, 95% CI = 1.54–4.01). Moreover, significant multiplicative interactions were observed between smoking and these three polymorphisms of –1195G>A, –765G>C, and 587Gly>Arg, even after correction by false discovery rate (FDR) method for multiple comparisons (FDR-P interaction = 0.006, 5.239×10−4 and 0.017, respectively). Similarly, haplotypes incorporating these three polymorphisms also showed significant interaction with smoking in the development of GCA (P for multiplicative interaction = 2.65×10−6).ConclusionThese findings indicated that the functional polymorphisms of COX-2, in interaction with smoking, may play a substantial role in the development of GCA.
Highlights
Gastric cardia adenocarcinoma (GCA) is the second leading cause of cancer-related mortality in the world, with more than 700,000 deaths annually [1,2,3]
These findings indicated that the functional polymorphisms of COX-2, in interaction with smoking, may play a substantial role in the development of gastric cardia adenocarcinoma (GCA)
Subjects characteristics The demographic characteristics of all subjects are presented in COX-2 genotypes and GCA risk The genotype distributions of the COX-2 –1195G.A
Summary
Gastric cardia adenocarcinoma (GCA) is the second leading cause of cancer-related mortality in the world, with more than 700,000 deaths annually [1,2,3]. During the past two decades, epidemiological studies have shown a steady decline in incidence of non-cardia gastric cancer but a continuously increased trend in incidence and mortality of GCA, emphasizing the importance of prevention strategy to GCA [4,5]. Extensive studies have revealed several environmental factors involved in the development of GCA, including cigarette smoking, alcohol consumption, inflammation, and diet. Most significantly, smoking has been established by considerable studies as a causal factor for GCA [6], which was supported by a recent meta-analysis including 33 studies that smokers had 1.8 fold increased risk of GCA than never-smokers [7]. This study aimed to explore the interaction between smoking and functional polymorphisms of COX-2 in modulation of gastric cardia adenocarcinoma (GCA) risk
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