Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction

Abstract

Erectile dysfunction (ED) is usually treated with sildenafil. Although genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may impair endogenous NO formation, there is little information about how eNOS polymorphisms and haplotypes affect the responses to sildenafil. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. eNOS genotypes for three eNOS polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and eNOS haplotypes were estimated using PHASE 2.1. The clinical responses to sildenafil were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. No other significant differences were found. Our findings show evidence that eNOS polymorphisms affect the responses of PED and clinical ED patients to sildenafil.

Pharmacologic Treatments for Pulmonary Hypertension: Exploring Pharmacogenomics

“…A key effector in the NO–cGMP pathway is endothelial NO synthase (eNOS). In two separate studies, the 4a variable number tandem repeat in intron 4 of NOS3 (the gene that encodes eNOS) was associated with better ED response to sildenafil [121,122]. A separate group replicated this variable number tandem repeat association and also found an association between C allele in T-786C and good response to sildenafil [122].…”

“…In two separate studies, the 4a variable number tandem repeat in intron 4 of NOS3 (the gene that encodes eNOS) was associated with better ED response to sildenafil [121,122]. A separate group replicated this variable number tandem repeat association and also found an association between C allele in T-786C and good response to sildenafil [122]. A retrospective study suggests that variation in GNB3 , a gene that encodes a key component of intracellular signal transduction in G-protein-coupled receptors, affects sildenafil response in ED [123].…”

CYP3A4 Genotype is Associated with Sildenafil Concentrations in Patients with Heart Failure with Preserved Ejection Fraction

“…Limited and inconsistent data from small to moderate size studies have suggested that genetic variants related to a variety of biological pathways could influence sildenafil's hemodynamic effects in patients with pulmonary hypertension or its efficacy in treating erectile dysfunction. [4][5][6][7][8][9] Considering that a majority of the markers judged to be clinically useful by the National Institutes of Health's Clinical PGx Implementation Consortium are absorption, distribution, metabolism and elimination (ADME) genes, 10 it is surprising that few studies have focused on variants of genes which could modulate sildenafil concentrations and dosing requirements. In particular, given that sildenafil is extensively metabolized in the liver by the cytochrome P450 3A (CYP3A) isoenzymes (major metabolizing route; 79%) and CYP2C9 (20%), [11][12][13] genetic variants coding for these isoenzymes would biologically appear to be likely genetic modulators of the effects of sildenafil.…”

Pharmacogenetic Implications of eNOS Polymorphisms (Glu298Asp, T786C, 4b/4a) in Cardiovascular Drug Therapy

“…Various eNOS gene polymorphisms have been described (10), such as insertions/deletions, microsatellites, single nucleotide polymorphisms (SNPs), and variable number of tandem repeats (VNTRs). NO signaling can be modulated by different drugs, and their effect may be influenced by eNOS gene polymorphism (12)(13)(14)(15)(16)(17)(18). Despite being constitutively expressed, eNOS is regulated by many stimuli at transcriptional, posttranscriptional and posttranslational level (19).…”