A case-control study of the association between polymorphisms of the endothelial nitric oxide synthase and glycoprotein IIIa genes and upper gastrointestinal bleeding in users of low-dose aspirin

Abstract

Background: Previous studies have reported a potential genetic predisposition to NSAID-related upper gastrointestinal (GI) bleeding. Objective: This study evaluated whether there was an association between 2 polymorphisms-the platelet glycoprotein (GP) IIIa PlA1/A2 polymorphism and the 27-bp VNTR (variable number of tandem repeats) polymorphism in intron 4 of the endothelial nitric oxide synthase ( eNOS) gene-and a risk for nonvariceal upper GI bleeding in Spanish patients taking low-dose aspirin for secondary prophylaxis of vascular occlusive diseases. Methods: Genotyping for the 2 polymorphisms was performed in patients hospitalized for upper GI bleeding associated with the use of low-dose aspirin between September 1998 and October 2000, and race-, age-, and sex-matched controls who were taking low-dose aspirin but had no history of upper GI bleeding. To ascertain allele frequencies in a healthy population, genotyping was also performed in an unmatched group of blood donors. Results: The study included 88 white patients (65 men, 23 women; mean age, 67.5 years) with an episode of upper GI bleeding, 108 matched controls with no history of upper GI bleeding (79 men, 29 women; mean age, 65.9 years), and 158 blood-donor controls (109 men, 49 women; mean age, 53.4 years). No significant differences were found between cases and controls in terms of genotype, carriage, or allele frequency of the GPIIIa PlA1/A2 polymorphism. However, after adjustment for confounding variables, logistic regression analysis indicated an association between carriage of the eNOS “a” allele and a reduced risk of upper GI bleeding (odds ratio [OR] ＝ 0.39; 95％ CI, 0.18-0.85; P ＝ 0.018). In this model, treatment with ni-trovasodilators (OR ＝ 0.28; 95％ CI, 0.12-0.66; P ＝ 0.004) and use of antisecretory drugs (OR ＝ 0.15; 95％ CI, 0.05-0.47; P ＝ 0.001) were also identified as protective factors. Helicobacter pylori infection (OR ＝ 3.07; 95％ CI, 1.23-7.70; P ＝ 0.017), alcohol consumption (OR ＝ 5.04; 95％ CI, 1.86-13.70; P ＝ 0.001), and a history of peptic ulcer (OR ＝ 13.41; 95％ CI, 3.78-47.64; P ＜ 0.001) were identified as risk factors for upper GI bleeding. Conclusion: In this small, selected population of individuals taking low-dose aspirin for secondary prevention, carriage of the “a” allele of the eNOS gene was associated with a decreased risk for upper GI bleeding.