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

ABSTRACT

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.

KEYWORDS:

• Nitric Oxide
• eNOS
• NOS3
• pharmacogenetics
• pharmacogenomics
• drug response
• polymorphism

Article highlights

• Nitric oxide has a bell-shaped-curve in most settings, and increased NO may not always lead to better phenotypes

• The advance in physiology, pathology, and pharmacology of NO is of pivotal importance to better understand genetic associations

• There is good evidence of NOS3 polymorphisms affecting different drug responses across different clinical settings and drug classes that involve NO in their mechanism of action

• There seem to be a trend of better responsiveness to chronic treatments when subjects carry loss-of-function NOS3 alleles

• Few studies on acute drug responses seem to show the opposite trend, where gain-of-function alleles associated with better acute responses

Acknowledgments

The authors are thankful for the financial support as scholarships from Fundação de Amparo à Pesquisa do Estado de São Paulo FAPESP (Grant # 2019/10748-9), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico CNPq (Grant # 302241/2017-5), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported with scholarships from CNPq, CAPES, and FAPESP.