The rs2682826 Polymorphism of the NOS1 Gene Is Associated with the Degree of Disability of Erectile Dysfunction.

Erectile dysfunction (ED) is a common male disorder, often associated with cardiovascular disease and ageing. The Sildenafil, a PDE5 inhibitor, can improve the erectile function by prolonging the nitric oxide (NO) downstream effect. NO is a molecule of pivotal importance in erection physiology and is mainly produced by neuronal nitric oxide synthase (nNOS) and endothelial NO synthase (eNOS). While it has been shown that eNOS and nNOS genetic polymorphisms could be associated with Sildenafil responsiveness in ED, no study so far has assessed whether nNOS polymorphisms and PDE5A polymorphism could be associated with increased risk to ED or with intensity of symptoms. A total of 119 ED patients and 114 controls were studied, with evaluation of the clinical disability by the International Index for Erectile Function instrument, plasma assessment of nitrite levels and genomic DNA analysis regarding the rs41279104 and rs2682826 polymorphisms of the NOS1 gene and the rs2389866, rs3733526 and rs13124532 polymorphisms of the PDE5A gene. We have found a significant association of the rs2682826 with lower IIEF scores in the clinical ED group. While this result should be confirmed in other populations, it may be helpful in establishing a genetic panel to better assess disease risk and prognosis on ED therapy.

Clinically relevant endothelial nitric oxide synthase polymorphisms and their impact on drug response.

INTRODUCTION: Nitric oxide (NO) is a molecule with multiple functions. Several drugs involve the modulation of NO levels in their mechanism of action. NO is mainly produced in vessels by endothelial NO synthase, which is encoded by NOS3 gene. This gene shows genetic polymorphisms associated with hypertension and other cardiovascular diseases, inflammation, psychiatric disorders, cancer, and others. AREAS COVERED: Four functional polymorphisms of NOS3 were selected: rs2070744, rs3918226, rs61722009, and rs1799983 and their association with differential drug responses was explored. This review explores beyond the cardiovascular area, including drugs regardless of their clinical indications. EXPERT OPINION: While there is good evidence of the clinical importance of NOS3 single nucleotide polymorphisms, the current knowledge is superficial in most clinical settings and further studies are needed. Basic science advances are also needed to help to interpret genetic association data. While there are controversies, most data from chronic treatment studies show a trend for loss-of-function alleles, that predispose to higher risk for disease, associating with better clinical response across different drug classes and clinical settings. Acute pharmacological responses were poorly explored, although there seem to be a trend where gain-of-function alleles associate with better clinical responses when observed in the scale of minutes to hours.