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.
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 nitrovasodilators (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.


CONCLUSIONS
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.
Piazuelo
Elena
E
Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain. epiazor@unizar.es
Fuentes
Javier
J
García-González
María Asunción
MA
Jiménez
Pilar
P
Lanas
Angel
A
D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects*; D016022:Case-Control Studies; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016481:Helicobacter Infections / Q000150:complications; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics*; D007438:Introns; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010437:Peptic Ulcer / Q000150:complications; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014665:Vasodilator Agents / Q000627:therapeutic use
D039661:Integrin beta3; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III; D001241:Aspirin