eNOS and ACE genes influence peripheral arterial disease predisposition in smokers.
OBJECTIVE
Several biologic mediators and genetic predisposing factors may contribute to the development of peripheral arterial disease (PAD). The eNOS gene, encoding for endothelial nitric oxide synthase, has been proposed as a candidate gene in the predisposition to the disease. In this study, we evaluated the role of eNOS-786T>C, -894G>T and 4a/4b polymorphisms as markers of PAD per se and in the presence of the ACE D allele in patients previously investigated.


METHODS
We analyzed 281 consecutive patients (220 men, 61 women; median age, 72 years) with PAD and 562 healthy controls, comparable for sex and age.


RESULTS
eNOS-786C, but not -894T and 4a, allele frequency was significantly higher in PAD patients than in controls (P = .03). An association with the predisposition to PAD was found for the eNOS-786C allele (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.11-2.09; P = .009) and the eNOS -786C/4a haplotype (OR, 1.41; 95% CI, 1.02-1.94, P = .04) at univariate analysis but not after adjustment for traditional risk factors. When smoking habit was considered, we observed that eNOS-786C/4a haplotype, but not the eNOS-786C allele, influenced PAD predisposition after adjustment for traditional risk factors in smokers (OR, 2.71; 95% CI, 1.38-5.30; P = .004). The eNOS-786C and eNOS-786C/4a haplotype did not modify the susceptibility to PAD in patients carrying the ACE D allele. Nevertheless, the presence of the eNOS-786C/4a haplotype increased PAD predisposition in smokers also carrying ACE D allele (OR, 2.71 to 3.79; P > .05 for interaction).


CONCLUSIONS
This study demonstrated an association between eNOS and ACE genes in increasing PAD susceptibility in smokers, thus providing evidence for a gene-environment interaction in modulating predisposition to the disease.
Sticchi
Elena
E
Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
Sofi
Francesco
F
Romagnuolo
Ilaria
I
Pratesi
Giovanni
G
Pulli
Raffaele
R
Pratesi
Carlo
C
Abbate
Rosanna
R
Fatini
Cinzia
C
D000368:Aged; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D016017:Odds Ratio; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D016491:Peripheral Vascular Diseases / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*
C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A