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

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.

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.

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.