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The Association Between Intron 4 VNTR, E298A and IVF 23+10 G/T

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The Association Between Intron 4 VNTR, E298A and IVF 23+10 G/T International Journal of Impotence Research (2007) 19, 149–153 & 2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00 www.nature.com/ijir ORIGINAL ARTICLE The association between intron 4 VNTR, E298A and IVF 23 þ 10 G/T polymorphisms of ecNOS gene and sildenafil responsiveness in patients with erectile dysfunction L Peskircioglu1, FB Atac2, SR Erdem3, S Deveci1, H Verdi2,HO¨ zkardes¸1 1Department of Urology, Baskent University, School of Medicine, Bahc¸elievler, Ankara, Turkey; 2Department of Medical Biology and Genetics, Baskent University, School of Medicine, Bahc¸elievler, Ankara, Turkey and 3Department of Pharmacology, Baskent University, School of Medicine, Bahc¸elievler, Ankara, Turkey The objective of the study was to determine the association between intron 4 variable number of tandem repeats (VNTR), E298A and IVF 23 þ 10 G/T polymorphisms of ec-NOS gene and sildenafil responsiveness in patients with erectile dysfunction (ED). Ninety-six patients who were evaluated for ED between November 2003 and June 2004 and 167 healthy individuals representing the normal population as controls were included in the present study. The patients were evaluated by medical history, five-item version of International Index of Erectile Function, serum glucose, testosterone levels and lipid profiles. Sixty-seven patients received four consecutive doses of sildenafil from 25 to 100 mg according to the response. The ec-NOS gene intron 4 VNTR, E298A and IVF 23 þ 10 G/T polymorphisms were evaluated in the isolated DNA blood samples obtained from the patient group with ED (n ¼ 96), from the group received sildenafil (n ¼ 67) and from the healthy group (n ¼ 167). Genotype distributions of ec-NOS gene intron 4, E298A and IVF 23 þ 10 G/T polymorphisms in the patient group were similar to those in the healthy group. The frequency of the ec-NOS gene intron 4 genotype were found as bb ¼ 41.7%, ab ¼ 50% and aa ¼ 8.3% in the sildenafil responders and bb ¼ 93.5% and ba ¼ 6.5% in the sildenafil non-responders. This finding was statistically significant. Statistical analysis of ec-NOS gene E298A and IVF 23 þ 10 G/T polymorphisms did not reveal any significant difference between sildenafil responders and non-responders. These findings may indicate that ‘a’ allele of ec-NOS gene intron 4 VNTR polymorphism associates with a better sildenafil response. International Journal of Impotence Research (2007) 19, 149–153. doi:10.1038/sj.ijir.3901501; published online 27 July 2006 Keywords: erectile dysfunction; oral treatment; sildenafil; genetics; gene polymorphism; molecular biology Introduction cavernosal smooth muscle during sexual stimula- tion.2 Penile erection has been shown to be mainly The Massachusetts Male Aging Study noted that mediated by nitric oxide (NO).3 NO is released from erectile dysfunction (ED) is a common disorder penile non-adrenergic, non-cholinergic nerve end- in men between 40 and 70 years of age with a ings and endothelial cells of corpus cavernosum and prevalence of 52%.1 Penile erection and detumes- penile blood vessels and additionally from the cence are regulated by corporeal smooth muscle smooth muscle.4–6 NO diffuses into the smooth relaxation and contraction. ED mainly results from muscle cell, and activates soluble guanylyl cyclase, the inadequate relaxation of the penile corpora which in turn gives rise to the production of cyclic guanosine monophosphate (cGMP). NO-induced increase in intracellular cGMP levels results in the relaxation of the cavernous smooth muscle by Correspondence: Dr L Peskircioglu, Department of Urol- 2 þ ogy, Baskent University, School of Medicine, 5.Sok.No:48, reducing intracellular Ca . The above-mentioned Bahc¸elievler, Ankara 06490, Turkey. pathway appears to be of major importance to E-mail: [email protected] modulate erectile function. Factors disrupting this Received 7 March 2006; revised 16 May 2006; accepted 19 pathway may impair the relaxation of corporeal June 2006; published online 27 July 2006 smooth muscle and may lead to ED.7 Association between intron 4 VNTR, E298A and IVF 23 þ 10 G/T polymorphisms L Peskircioglu et al 150 Sildenafil citrate is the first phosphodiesterase Materials and methods type 5 (PDE-5) inhibitor approved by Food and Drug Administration (1998). PDE-5 inhibition Ninety-six male patients suffering from ED and 167 causes an elevation in intracellular cGMP level healthy individuals representing normal population as cGMP is degraded intracellularly by PDE.8 in our country were included in the study. Patients Therefore, PDE-5 inhibition augments the normal were evaluated by a detailed medical history, erectile response. Sildenafil has been shown to physical examination followed by laboratory tests, be beneficial in men with ED owing to organic, including serum glucose, lipid profile, testosterone, psychogenic and mixed etiological factors. Gold- prolactine and combined intracavernous injection, stein et al.9 have reported an overall beneficial effect and stimulation test. Penile Doppler ultrasonogra- of sildenafil in 70% of patients compared with that phy was performed when indicated. Following of placebo (20–30%). As sildenafil acts through the this initial evaluation, the etiology (vasculogenic, inhibition of intracellular cGMP degradation, it is neurologic, endocrinologic, mixed and psychogenic) obvious that the physiological production of this and contributing risk factors (atherosclerosis, dia- PDE substrate in response to NO is an essential step betes mellitus, hyperlipidemia, medications, smok- in sildenafil action. Therefore, any impairment in ing and cardiovascular comorbidities) were defined. this process might result in irresponsiveness to Patient profile with regard to the risk factors is given sildenafil treatment. However, to the best of our in Table 1. Sexual function before and after treat- knowledge, there has not been any satisfactory ment were determined by the five-item version of explanation of sildenafil irresponsiveness in the International Index of Erectile Function (IIEF-5). literature. The degree of the severity of ED of the patients was NO is synthesized as a by-product during classified into five categories according to their IIEF- L-citrulline production from L-arginine, a reaction 5 scores. Success with treatment was defined catalyzed by the enzyme NO synthase (NOS).8 according to IIEF-5 categories as 4 (mild ED) and 5 Three isoforms of NOS, namely neuronal (nNOS, (no ED). Out of 96 patients, sildenafil was given to NOS 1), inducible (iNOS, NOS 2) and endo- 67 men with no contraindication for sildenafil use. thelial (eNOS, NOS 3) NOSs have been deter- The dosage ranged from 25 to a maximum 100 mg. mined.10 All three isoforms of NOS have been Those who did not respond to 100 mg were regarded shown to play a role within the penile tissues. as non-responders (Tables 2–4). eNOS is mainly expressed in endothelial cells and is involved in several important cardiovascular functions. Therefore, regulation of the expression of NOS isoforms including any polymorphism of Genotyping the gene encoding for NOS enzyme might be of All of the participant patients were requested to sign clinical importance. the written informed consent form regarding the Several previous studies have supported this protocol of the present study, including the blood suggestion by pointing out the association of sample collection for DNA analysis. The Ethics intron 4 variable number of tandem repeats (VNTR), E298A and IVF 23 þ 10 G/T polymorphisms of Table 2 Distribution of ecNOS intron 4 genotype frequency eNOS gene with diabetes-related and cardio- vascular disorders.11,12 Thus, we aimed to investi- N bb (%) ab (%) aa (%) gate the possible association of eNOS gene intron 4 VNTR, E298A and IVF 23 þ 10 G/T poly- Healthy group 167 morphisms in particular, with the responsive- Patients with ED 96 80 16.7 3.1 Patients receiving sildenafil 67 65.7 29.9 3 ness to sildenafil treatment in patients with Sildenafil responders 31 41.7 50 8.3 ED. We hypothesized that ED patients with Sildenafil non-responders 36 93.5 6.5 0 eNOS gene polymorphisms respond less to sildenafil. Abbreviation: ED, erectile dysfunction. Table 1 Etiology of ED in the patient group N Vasculogenic Neurologic Psychogenic Endocrinologic Mixed Patients with ED 96 50 5 20 3 18 Patients receiving sildenafil 67 42 4 6 2 13 Sildenafil responders 31 20 2 3 — 6 Sildenafil non-responders 36 22 2 3 2 7 Abbreviation: ED, erectile dysfunction. International Journal of Impotence Research Association between intron 4 VNTR, E298A and IVF 23 þ 10 G/T polymorphisms L Peskircioglu et al 151 Table 3 Distribution of ecNOS intron 23 genotype frequency Results N gg (%) gt (%) The mean age was 52715.2 years in the patient group. The etiological factors determined to be Healthy group 167 80.4 16.9 Patients with ED 96 90.3 9.7 responsible for ED in the patient group were as Patients receiving sildenafil 67 90.5 9.5 follows: vasculogenic (50 patients, 52.1%), endo- Sildenafil responders 31 90.9 9.1 crinologic (three patients, 3.1%), psychogenic (20 Sildenafil non-responders 36 90.2 9.8 patients, 3.1%), mixed (18 patients, 18.8%) and neurologic (five patients, 5.2%). Thirty-one of 67 Abbreviation: ED, erectile dysfunction. patients who received sildenafil responded posi- tively to the treatment. The mean age was 48.5 years (range 35–70 years) in sildenafil responders and Table 4 Distribution of ecNOS exon 7 genotype frequency 52.3 years (range 39–66 years) in non-responders. The etiological evaluation of ED in sildenafil N gg (%) gt (%) tt (%) responders was as follows: vasculogenic (20 pa- tients, 64.5%), neurologic (two patients, 6.5%) Healthy group 167 32.5 50.8 16.7 Patients with ED 96 17.3 52 30.7 mixed (six patients, 19.4%) and psychogenic (three Patients receiving sildenafil 67 20.3 59.5 20.3 patients, 9.7%).
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