The Promoter Polymorphism rs3918226 of the Endothelial Nitric Oxide Synthase Gene as a Novel Susceptibility Marker for Peripheral Artery Disease.

Background: This pilot study aimed to investigate the association between the single nucleotide polymorphism (SNP) rs3918226 in the promoter of the nitric oxide synthase (NOS3) gene and the risk of peripheral artery disease (PAD).
Methods: DNA samples from 1,263 unrelated subjects of Slavic origin, including 620 patients with PAD and 643 controls, were genotyped for the SNP rs3918226 using the MassArray-4 system.
Results: The rs3918226 polymorphism was found to be strongly associated with an increased risk of PAD regardless of coronary artery disease, hypertension, or cigarette smoking (odds ratio [OR] = 2.86; 95% confidence interval [CI] 1.89-4.32; P _perm < 0.0001). The SNP-PAD association was almost 3 times stronger in females (OR = 8.31; 95% CI 3.07-22.48) than in males (OR = 1.79; 95% CI 1.10-2.93). SNP rs3918226 was correlated with ankle-brachial index and total plasma cholesterol in patients with PAD (Р _perm < 0.05). The NOS3 polymorphism was closely associated with SNPs rs7692387 and rs13139571 in guanylate cyclase soluble subunit alpha-3 (GUCY1A3) to determine the risk of PAD, suggesting that the rs3918226 polymorphism may disrupt signaling in the NO-soluble guanylyl cyclase pathway. Diplotypes with wild-type alleles, such as NOS3 rs3918226-C/C×GUCY1A1 rs7692387G/G and NOS3 rs3918226-C/C×GUCY1A1 rs13139571C/C, showed strong protection against disease risk (false discovery rate ≤ 0.001). Functional SNP annotation revealed that the allele rs3918226-T was associated with decreased expression of NOS3, most strongly in the tibial arteries than in the coronary artery or aorta.
Conclusions: The present study is the first to show that the rs3918226 polymorphism of NOS3 is a novel susceptibility marker for PAD. Further research in independent populations is necessary to reproduce the association between polymorphism rs3918226 and disease risk.
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