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Original article
Single nucleotide polymorphisms in 5-HT receptors in the etiology of premature ejaculation
Polimorfismos de nucleótido único en receptores 5-HT en la etiología de la eyaculación precoz
Melis Danışman Sonkurta, Gülcan Güleçb, Didem Turgut Coşanc, İbrahim Uğur Çalışc, Fezan Mutlud, İyimser Üree, Harun Olcay Sonkurta,
Corresponding author
hosonkurt@gmail.com

Corresponding author.
a Ağrı State Hospital, Department of Psychiatry, Merkez District, Ağri, Turkey
b Eskişehir Osmangazi University, Department of Psychiatry, Odunpazari, Eskişehir, Turkey
c Eskişehir Osmangazi University, Department of Medical Biology, Odunpazari, Eskişehir, Turkey
d Eskişehir Osmangazi University, Department of Biostatistics, Odunpazari, Eskişehir, Turkey
e Eskişehir Osmangazi University, Department of Urology, Odunpazari, Eskişehir, Turkey
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Premature ejaculation &#40;PE&#41; has been reported to be the most common male sexual dysfunction&#44; with an estimated global prevalence of approximately 30&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a> PE is characterized by shorter intravaginal ejaculation latency time &#40;IELT&#41; than it is acceptable for the patient or partner&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">While the psychological&#44; environmental&#44; and situational risk factors for the etiology of PE are still important&#44; recent research has focused on the neurobiological and genetic explanatory frameworks of PE&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a> Bernard Schapiro first investigated the genetic component of the etiology of PE in his familial prevalence study in 1943&#44; and it was found that PE was common in male family members of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a> Waldinger et al&#46; confirmed this study by finding 88&#37; of first-degree relatives of men with PE&#39;s IELT was less than 1<span class="elsevierStyleHsp" style=""></span>min&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Serotonin or 5-hydroxytryptamine &#40;5-HT&#41; is the most widely studied neurotransmitter associated with mediating ejaculation in men&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a> Waldinger et al&#46; described PE as a neurobiological dysfunction with a genetic susceptibility to short IELT associated with reduced central 5-HT neurotransmission and&#47;or 5-HT receptor dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">5&#44;7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In the first deoxyribonucleic acid &#40;DNA&#41; based study on the genetic etiology of lifelong PE&#44; it was aimed to determine the effect of serotonin transporter promoter region &#40;5-HTTLPR&#41; polymorphism&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> Later&#44; the same gene polymorphisms were researched in Turkey&#44; Iran&#44; China&#44; Italy&#44; Finland&#44; and in Egyptian populations&#59; conflicting results were obtained&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9&#8211;15</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the literature&#44; there are a limited number of studies investigating serotonin receptor polymorphisms in lifelong PE&#46; In 2010&#44; Luo et al&#46; investigated 5-HT2C receptor polymorphisms&#59; and found that men with the &#8722;759T or &#8722;697C genotype had an increased lifelong PE&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> In the study of Jern et al&#46;&#44; the effects of a total of 6 single gene nucleotide polymorphisms on 5-HT1A&#44; 1B and 2C receptor genes on IELT were investigated in 1399 men&#44; and only 5-HT1B related polymorphisms were found to be significant&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> Janssen et al&#46;&#44; who investigated the effect of 5-HT1A receptor C &#40;1019&#41; G polymorphism on IELT in PE patients&#44; showed that individuals with CC genotypes shorter ejaculation times&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> The same single nucleotide polymorphism &#40;SNP&#41; was studied in the Egyptian patient group&#44; and the authors stated that GG genotype and G allele were found to be significantly higher in the control group&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">18</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Considering the insufficient data on the genetics of lifelong PE&#44; it is essential to determine which genetic polymorphisms contribute to the etiology of PE&#46; For this purpose&#44; in this study&#44; 5-HT2C receptor gene rs3813929&#44; rs518147&#44; 5-HT1A receptor gene rs6295&#44; 5-HT1B receptor gene rs11568817 in the patients of lifelong PE is planned to be compared to the healthy control group in terms of single nucleotide polymorphisms&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">The study was approved by Eski&#351;ehir Osmangazi University Clinical Research Ethics Committee on 21&#46;06&#46;2018 with a decision number 45425468-25 and supported by Eski&#351;ehir Osmangazi University Scientific Research Project Unit with the project code 2018-2223&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study group</span><p id="par0040" class="elsevierStylePara elsevierViewall">The study group included patients who applied to Eski&#351;ehir Osmangazi University Faculty of Medicine psychiatry and urology outpatient clinics with premature ejaculation&#44; met the inclusion criteria&#44; and agreed to participate in the study&#46; For the healthy control group&#44; couples who applied to urology and infertility clinics were evaluated&#44; males with no urological or psychiatric disorders detected&#44; and who are willing to participate included&#46; The participants were evaluated according to DSM-5 lifelong premature ejaculation diagnostic criteria&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The inclusion criteria for the patient group were being male between the ages of 18 and 65&#44; being literate&#44; having a regular sexual partner for at least six months&#44; willing to participate in the study&#44; in all or almost all &#40;75&#8211;100&#37;&#41; sexual activity&#44; having the experience of a pattern of ejaculation occurring during partnered sexual activity within 1<span class="elsevierStyleHsp" style=""></span>minute after vaginal penetration&#44; occurring from first sexual activity&#59; not occurring situational&#46; Inclusion criteria for the control group were being male between the ages of 18&#8211;65 and being literate&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The exclusion criteria were&#44; currently having a psychiatric diagnosis&#44; use of antidepressants or antipsychotics&#44; history of a head trauma&#44; having any neurological disorder&#44; having diagnosed with diabetes&#44; cardiovascular disease&#44; and having a urological disease other than premature ejaculation for the patient group&#44; having a urological disease for the control group&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The selection of the participants was made between 22&#46;06&#46;2018 and 04&#46;08&#46;2019&#46; In determining the study sample for the power analysis&#44; the PASS-II program was used&#46; Using one-way analysis of variance&#44; 0&#46;85 power and type 1 error was calculated as 0&#46;05&#46; Summary values used in power analysis were obtained from the study titled &#8220;Association between polymorphisms in the serotonin 2C receptor gene and premature ejaculation in Han Chinese subjects&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> As the result of the power analysis&#44; a total of 200 people&#44; 100 people per group was considered appropriate&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">All candidates were informed about the study&#44; and their written consent was obtained&#46; A psychiatrist evaluated the participants&#46; Sociodemographic Data Form was applied to the participants&#59; age&#44; education level&#44; working status&#44; marital status&#44; and ejaculation times were questioned&#46; In order to evaluate IELT&#44; we asked the participants&#44; &#8220;In the most of the sexual activities &#40;75&#8211;100&#37; of sexual activities&#41;&#44; after entering the vagina&#44; when does the ejaculation occur&#63;&#8221;&#46; 10 cc venous blood samples were collected from the participants&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">DNA extraction and analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Venous blood sample taken from the participants was sent to the laboratory for a short period to obtain DNA in tubes containing EDTA&#46; DNA has extracted from the blood in accordance with the kit &#40;Thermo Scientific GeneJET Genomic DNA Purification&#44; USA&#41; procedure&#46; For the PCR amplification mixture&#44; 10<span class="elsevierStyleHsp" style=""></span>&#956;l Master Mix TaqProb 2&#215; &#40;Abmgood&#44; Canada&#41;&#44; 1<span class="elsevierStyleHsp" style=""></span>&#956;l probe &#40;Applied Biosystems&#44; Thermo Fisher Scientific&#44; USA&#41;&#44; 5<span class="elsevierStyleHsp" style=""></span>&#956;l d H<span class="elsevierStyleInf">2</span>O and 4<span class="elsevierStyleHsp" style=""></span>&#956;l DNA samples were completed&#44; and the total volume was completed by 20<span class="elsevierStyleHsp" style=""></span>&#956;l&#46; PCR was performed by setting the PCR mixture&#44; the amplification program automatic heat cycle device &#40;Step One Plus&#44; Applied biosystems&#44; Thermo Fisher Scientific&#44; USA&#41; to the specified program&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Appropriate procedures were applied to the probes &#40;rs3813929&#44; rs518147&#44; rs6295&#44; rs11568817&#41; suitable for the DNA studied&#46; After completion of DNA amplification in PCR&#44; the temperature was raised very slowly&#44; creating a melting curve for each sample&#46; During the elevation of the temperature&#44; single nucleotide polymorphisms were determined by separating the typical sequence and the sequence containing polymorphism&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0075" class="elsevierStylePara elsevierViewall">The continuous data were given as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation&#46; Categorical data were given as a percentage &#40;&#37;&#41;&#46; We used Pearson Chi-Square analysis for the analysis of the cross tables&#46; Odds ratio &#40;OR&#41; was used as the disease risk ratio&#46; Logistic regression analysis was performed&#46; The power of the study was 0&#46;80&#46; IBM SPSS Statistics 21&#46;0 &#40;IBM Corp&#46; Released 2012&#46; IBM SPSS Statistics for Windows&#44; Version 21&#46;0&#46; Armonk&#44; NY&#58; IBM Corp&#46;&#41; was used for the analyses&#46; A <span class="elsevierStyleItalic">p</span>-value of &#60;0&#46;05 was considered as statistically significant&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0080" class="elsevierStylePara elsevierViewall">In the patient group&#44; 23 of the patients had elementary school education&#44; 19 had a middle school education&#44; 31 had a high school education and 27 had a university education&#46; Whereas in the healthy control group&#44; these numbers were 7&#44; 12&#44; 38 and 43 respectively&#46; There was a statistically significant difference in the patient and healthy control groups in terms of educational level &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#44; <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#46;49&#41;&#46; As for employment status&#44; 87 were employed in the patient group&#44; while 97 were employed in the healthy control group&#46; There was a statistically signifcant difference between the groups in terms of employment status &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#44; <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;79&#41;&#46; Lastly&#44; 89 patients were living together or married&#44; while 80 healthy controls were livng together or married&#44; and there was no statistically significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;079&#44; <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;09&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The ejaculation time of all participants in the control group was over 60<span class="elsevierStyleHsp" style=""></span>s after vaginal intercourse&#46; Of 100 patients with PE&#44; 2 of them reported ejaculation before contact&#44; 8 reported ejaculation within 15<span class="elsevierStyleHsp" style=""></span>s after contact&#44; 17 were within 15&#8211;30<span class="elsevierStyleHsp" style=""></span>s&#44; and 73 reported ejaculation in between 30 and 60<span class="elsevierStyleHsp" style=""></span>s&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">5-HT2C receptor gene rs518147 polymorphism</span><p id="par0090" class="elsevierStylePara elsevierViewall">In order to investigate the rs518147 polymorphism&#44; sufficient DNA could not have been obtained in 19 participants&#46; rs518147 polymorphism was analyzed in a total of 181 participants&#44; 87 in the patient group&#44; and 94 in the control group&#46; As a result of statistical analysis&#44; it was found that lifelong PE was 2&#46;15 times higher in individuals carrying C allele than those carrying G allele &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;152&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;149&#44; 4&#46;029&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">5-HT2C receptor gene rs3813929 polymorphism</span><p id="par0095" class="elsevierStylePara elsevierViewall">In order to investigate the polymorphism of rs3813929&#44; sufficient DNA could not have been obtained in 16 participants&#46; The rs3813929 polymorphism was analyzed in a total of 186 participants&#44; 91 from the patient group&#44; and 93 from the control group&#46; There was no statistically significant difference between the two groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;092&#41;&#46; Since the 5HT2C receptor gene is located on the X chromosome&#44; males carry only one allele for this gene&#46; Therefore&#44; no Hardy-Weinberg Equilibrium &#40;HWE&#41; calculation was made for rs518147 and rs3813929&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">5-HT1B receptor gene rs11568817 polymorphism</span><p id="par0100" class="elsevierStylePara elsevierViewall">In order to investigate the polymorphism of rs11568817&#44; sufficient DNA could not have been obtained in 14 participants&#46; The rs11568817 polymorphism was analyzed in a total of 186 participants&#44; 92 in the patient group&#44; and 94 in the control group&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The most common genotype in both groups was GT genotype&#44; which was 42&#37; in the patient group and 46&#37; in the control group&#46; There was a 2&#46;55-fold increase in the likelihood of lifelong PE in individuals with TT genotype compared to individuals with GG genotype &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;557&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;160&#8211;5&#46;636&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;019&#41;&#46; Genotype distributions for 5-HT1B receptor gene rs11568817 polymorphism are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">In terms of rs11568817 polymorphism&#44; the genotyping results of the participants were distributed within HWE &#40;<span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#44; degree of freedom<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;995&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Allele frequencies for rs11568817 polymorphism were also analyzed&#46; It was found that the lifetime probability of PE in individuals with T allele was 1&#46;68 times higher than those with G allele &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;68&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;116&#8211;2&#46;533&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">5-HT1A receptor gene rs6295 polymorphism</span><p id="par0120" class="elsevierStylePara elsevierViewall">In order to investigate the rs6295 polymorphism&#44; sufficient DNA could not have been obtained in 12 participants&#46; The rs6295 polymorphism was analyzed in a total of 188 participants&#44; 93 from the patient group and 95 from the control group&#46; The most common genotype was GC &#40;43&#37; and 40&#37;&#41; in the patient and control groups&#46; There was no statistically significant difference between the two groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Genotype distributions of 5-HT1A receptor gene rs6295 polymorphism of the participants are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">In terms of rs6295 polymorphism&#44; the genotyping results of the participants were distributed in HWE &#40;<span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#44; degree of freedom<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;985&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Allele frequencies for rs6295 polymorphism were also evaluated in patient and control groups&#46; C and G alleles were 52&#46;7&#37; and 47&#46;3&#37;&#44; respectively&#44; in the patient group&#44; and 52&#46;6&#37; and 47&#46;4&#37; were in the control group&#46; There was no statistically significant difference between the groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;991&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Allele distributions for 5-HT2C receptor gene rs518147&#44; 5-HT2C receptor gene rs3813929&#44; 5-HT1B receptor gene rs11568817&#44; 5-HT1A receptor gene rs6295 polymorphisms are shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">When two SNPs&#44; which were found to be statistically significantly correlated with lifelong PE&#44; added to logistic regression analysis as an independent variable&#44; it was found that in the rs518147 &#40;C&#47;G reference&#41; polymorphism&#44; individuals with C allele had a probability of lifelong PE 1&#46;99 times higher than those with G allele&#46; &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;990&#44; 95&#37; CI OR&#58; 1&#46;049&#8211;3&#46;776&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#46; For the rs11568817 &#40;TT&#47;GG reference&#41; polymorphism&#44; the probability of disease was found to be 2603 times higher in individuals with TT genotype than GG genotype &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;603&#44; 95&#37; CI OR&#58; 1&#46;139&#8211;5&#46;946&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;023&#41;&#46; Logistic regression analysis is shown in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0145" class="elsevierStylePara elsevierViewall">This study aimed to investigate the role of SNPs in serotonergic receptor protein genes in the etiology of lifelong PE&#46; As a result of our study&#44; we found a relationship between rs3813929 and rs11568817 polymorphisms and lifelong PE&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In our study&#44; the education level of the control group was higher than the patient group&#46; Several authors state that as the level of education in PE increases&#44; concerns about satisfaction of the partner increase&#44; so the admittance to the doctor may increase&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> In our study which is investigating the genetic etiology in lifelong PE&#44; we believe that the environmental factors have a low role and thus the results are not affected by the educational and occupational status&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The rs11568817 polymorphism&#44; which is one of the polymorphisms in which we found a significant difference in genotype and allele distributions between the patient group and healthy control group&#44; is located on the 5-HT1B receptor gene&#46; It was found that the probability of lifelong PE was 2&#46;56 times higher in individuals with TT genotype than those with GG genotype &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;557&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;160&#8211;5&#46;636&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;019&#41;&#46; When allele frequencies were analyzed&#44; it was found that individuals with T allele had 1&#46;68 times higher risk of PE than individuals with G allele &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;68&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;116&#8211;2&#46;533&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;019&#41;&#46; This SNP occurs in the promoter region of the 5-HT1B receptor gene and affects the expression of the gene&#46; G allele transport has been shown to cause a 2&#46;3-fold increase in gene expression when compared with the T allele&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">19</span></a> It is difficult to fully understand the role of the 5-HT1B receptor in the physiology of ejaculation&#44; as this is a 5-HT receptor subtype&#46; This G protein-bound receptor inhibits adenylate cyclase&#44; it can be both a presynaptic autoreceptor and postsynaptic heteroreceptor&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a> Studies in rats and mice have shown that systemic or local injection of selective 5-HT1B receptor agonists delays ejaculation&#44; and this effect can be reversed by 5-HT1B receptor antagonists&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">21&#8211;23</span></a> The mechanism by which 5-HT1B receptors inhibit ejaculation has not yet been demonstrated&#44; but the role of 5-HT1B autoreceptors does not seem to be possible&#44; as these receptors cause a reduction in the serotonin release&#44; which is expected to reduce the ejaculation threshold&#46; The effect of 5-HT1B on ejaculation physiology is not only through serotonin release&#46; 5-HT1B heteroreceptor activation may also inhibits the release several chemicals&#44; which are thought to facilitate the ejaculation&#44; e&#46;g&#46; acetylcholine&#44; glutamate and galanin&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">In the light of these data&#44; having T allele may decrease the expression of 5-HT1B receptor gene and thus receptor activity&#59; theoretically&#44; it may result in shortening of IELT&#46; The increased risk of PE in individuals with TT genotype or T allele supports this hypothesis&#46; In the literature&#44; the relationship between rs11568817 polymorphism and PE was previously examined in a Finnish community-based study&#44; and it was found that GG genotype was associated with shorter IELT&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> In the study&#44; 33 &#40;2&#46;4&#37;&#41; of 1399 participants reported IELT in less than 1<span class="elsevierStyleHsp" style=""></span>minute&#46; However&#44; in this community-based study&#44; participants were grouped according to their IELT time&#59; it is not specified whether those who have short IELT have this complaint since the first sexual activity &#40;lifelong PE&#41; or not&#46; This may be the reason why our findings are not in the same direction&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The 5-HT2C receptor protein gene rs518147&#44; rs3813929 SNPs are both located in the promoter region of the gene&#44; close to the significant transcription starting site&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a> Their proximity to the transcription starting site makes these SNPs good candidates for regulating gene expression&#46; Regarding promoter activity&#44; there have been studies suggesting that the T allele of rs3813929 polymorphism increases the transcription rates&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;26</span></a> but there are also studies contradicting these results&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a> There are also studies suggesting having T or C alleles does not alter gene expression&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a> The C allele of the rs518147 polymorphism is thought to increase gene transcription&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;27</span></a> Systemic injection of the non-selective agonist of the 5-HT2 receptor increased ejaculation latency in rats&#44; and this effect was shown to be reversed with the 5-HT2 receptor antagonist&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">29&#44;30</span></a> Systemic administration of 5-HT2C agonist meta-chlorophenylpiperazine dose-dependently reduced the number of those capable of ejaculation in rats and rhesus monkeys&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a> In our study&#44; there was no relationship between rs3813929 polymorphism and lifelong PE&#46; Among the variants of rs518147 polymorphism&#44; the risk of PE was found to be 2&#46;15 times higher in individuals carrying the C allele than in individuals carrying the G allele &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;152&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;149&#44; 4&#46;029&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#41;&#46; This finding does not support the hypothetical 5-HT2C receptor hypofunction that is thought to be in PE&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a> but it is consistent with the results of Luo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> The mechanism of how 5-HT2C receptor activation increases the ejaculation threshold has not yet been established&#46; One of the reasons why the hypothesis are not parallel with the findings may be that polymorphisms cause changes in receptor expression as well as changes in agonist binding activity&#44; down regulation&#44; and desensitization&#46; To our knowledge&#44; there is no study that clearly demonstrates the functional consequences of the SNPs we investigated&#44; and this interpretation can be made on the basis of some other in vivo receptor gene polymorphism studies&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Another serotonin receptor that plays a role in the pathophysiology of PE is 5-HT1A&#46; The most studied polymorphism of the 5-HT1A receptor gene is the C&#40;-1019&#41; G polymorphism&#44; which is designated as rs6295&#46; The G allele variant of this SNP is associated with higher 5-HT1A receptor activity and decreased 5-HT release via autoreceptors&#46; In our study&#44; no statistically significant difference was found between the groups in terms of genotype and allele distributions of rs6295 polymorphism &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Janssen et al&#46; investigated the relationship between GG genotype and IELT&#44; and contradictory to their hypothesis&#44; they found that individuals with CC genotypes had significantly shorter IELTs&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">17&#44;18</span></a> In another study&#44; no significant difference was found between the groups&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">The polymorphisms rs11568817 and rs 3813929 that we found to be associated with lifetime PE&#44; were previously found to be also associated with suicidal ideation&#44; alcohol and drug dependence&#44; obesity and attention deficit hyperactivity disorder&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">33&#8211;37</span></a> PE&#44; which is thought to be multifactorial&#44; cannot be wholly associated with a single nucleotide polymorphism&#44; and a single nucleotide polymorphism can play a role in the etiology of more than one clinical condition&#46; In individuals with rs11568817 and rs 3813929 polymorphisms&#44; lifelong PE and other mental illnesses may coexist&#44; or a clinical situation may begin first and cause or contribute to other diseases later on&#46; Identifying and distinguishing other diseases in individuals with these polymorphisms in a structured interview will shed more light on the effect of genetic polymorphisms on psychopathologies&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">In our work&#44; the diagnostic evaluation was made by a face-to-face interview&#46; In the field of sexuality&#44; which can be seen as a taboo in Turkish society&#44; obtaining reliable information from participants before the opportunity to develop a reliable patient-physician relationship has difficulties in clinical practice&#46; However&#44; there is no study validating the reliability of the lifelong diagnosis of PE in Turkish&#46; Scales such as Premature Ejaculation Profile&#44; Index of Premature Ejaculation&#44; Premature Ejaculation Diagnostic Tool developed for PE are available in the international literature&#59; however&#44; it is emphasized that these scales may be insufficient to diagnose the PE subtypes and that the scales should not replace the face-to-face patient-physician evaluation when working on PE&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">IELT was determined based on the self-report of the participants&#46; IELT&#44; which defines the period between vaginal entry and ejaculation in sexual intercourse&#44; can be measured by two methods&#44; based on self-report or with a stopwatch&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">39</span></a> IELT data were obtained based on self-report since it was difficult for the participants to use a stopwatch in clinical practice&#44; and our study was a cross-sectional design with a one-time interview&#46; Although authors are stating that using stopwatches is necessary&#44; there are also studies reporting that IELT values measured by self-report and stopwatch show interrelated levels&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">To our knowledge&#44; our study is the first to have the quality of work being done in this field in Turkey&#46; As a result of our study&#44; which was carried out on four polymorphisms that were previously made in various countries and found to be associated with lifelong PE&#44; the relationship of rs3813929 and rs11568817 polymorphisms to lifelong PE was confirmed&#46; Repeating the study in larger sample groups in other populations could be useful in determining the genetic etiology of PE&#46; As with the similar studies in the field&#44; our study&#39;s patient group consisted of individuals with lifelong PE because it is reported that the role of genetics are higher in the etiology of PE&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a> However&#44; non-genetic factors may play a role in the etiology of PE in this group&#46; Accordingly&#44; future studies should include lifelong PE participants with a familial history of PE&#44; in order to evaluate the role of the genetics more clearly&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The presence of patients who have been diagnosed with lifelong PE and have not benefited from the current treatments suggests that there may be unclear points in the etiology&#46; As in our study&#44; the data obtained from research in this field may shed light on the development of new screening&#44; diagnostic tools&#44; or pharmacological treatment methods in the future&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusions</span><p id="par0200" class="elsevierStylePara elsevierViewall">In conclusion&#44; a statistically significant relationship was found between lifelong PE and the rs11568817 polymorphism &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;019&#41; in the 5-HT1B receptor gene and the rs518147 polymorphism &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#41; in the 5-HT2C receptor gene&#46; Also&#44; no statistically significant relationship was found between 5-HT1A receptor gene rs6295 polymorphism and 5-HT2C receptor gene rs3813929 polymorphism and lifelong PE&#46; As a result&#44; the relationship between rs3813929 and rs11568817 polymorphisms with lifelong PE was confirmed&#46; Repeating the study in larger sample groups could be useful in determining the genetic etiology of PE&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Ethical disclosures</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Protection of human and animal subjects</span><p id="par0205" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Confidentiality of data</span><p id="par0210" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Right to privacy and informed consent</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Funding</span><p id="par0220" class="elsevierStylePara elsevierViewall">This study was supported by <span class="elsevierStyleGrantSponsor" id="gs1">Eski&#351;ehir Osmangazi University Scientific Research Project Unit</span> with the project code 2018-2223&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflict of interest</span><p id="par0225" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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              "titulo" => "5-HT2C receptor gene rs518147 polymorphism"
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              "titulo" => "5-HT2C receptor gene rs3813929 polymorphism"
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          "identificador" => "sec0065"
          "titulo" => "Ethical disclosures"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Protection of human and animal subjects"
            ]
            1 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Confidentiality of data"
            ]
            2 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Right to privacy and informed consent"
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        10 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Funding"
        ]
        11 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Conflict of interest"
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        12 => array:2 [
          "identificador" => "xack628758"
          "titulo" => "Acknowledgments"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2020-05-18"
    "fechaAceptado" => "2021-02-14"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1562047"
          "palabras" => array:4 [
            0 => "Premature ejaculation"
            1 => "Serotonin"
            2 => "Genetics"
            3 => "Polymorphism"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1562048"
          "palabras" => array:4 [
            0 => "Eyaculaci&#243;n precoz"
            1 => "Serotonina"
            2 => "Gen&#233;tica"
            3 => "Polimorfismo"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Premature ejaculation &#40;PE&#41; is characterized by shorter intravaginal ejaculation latency time than it is acceptable for the patient or partner&#46; It is thought that lifelong PE is a neurobiological dysfunction associated with genetic predisposition and with central serotonin neurotransmission dysfunction in receptors&#46; To contribute to the understanding the genetic etiology of lifelong PE&#44; it was planned to compare the 5-HT2C receptor gene rs3813929&#44; rs518147&#44; 5-HT1A receptor gene rs6295&#44; 5-HT1B receptor gene rs11568817 of lifelong PE patients to healthy controls&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">For this purpose&#44; 100 patients with premature ejaculation and 100 healthy controls were included in the study&#46; Blood samples for DNA extraction were obtained&#46; Appropriate procedures were applied to the probes &#40;rs3813929&#44; rs518147&#44; rs6295&#44; rs11568817&#41; suitable for the DNA studied&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A statistically significant relationship was found between the rs11568817 polymorphism &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;019&#41; in the 5-HT1B receptor gene and the rs518147 polymorphism &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#41; in the 5-HT2C receptor gene&#46; Also&#44; no statistically significant relationship was found between 5-HT1A receptor gene rs6295 polymorphism and 5-HT2C receptor gene rs3813929 polymorphism and lifelong PE&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The relationship between rs3813929 and rs11568817 polymorphisms with lifelong PE was confirmed&#46; Repeating the study in larger sample groups could be useful in determining the genetic etiology of PE&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction and objectives"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Materials and methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La eyaculaci&#243;n precoz &#40;EP&#41; se caracteriza por un tiempo de latencia de eyaculaci&#243;n intravaginal m&#225;s corto de lo que es aceptable para el paciente o para la pareja&#46; Se cree que la EP de por vida es una disfunci&#243;n neurobiol&#243;gica asociada con la predisposici&#243;n gen&#233;tica y con la disfunci&#243;n central de la neurotransmisi&#243;n de serotonina en los receptores&#46; Para contribuir a la comprensi&#243;n de la etiolog&#237;a gen&#233;tica de la EP de por vida&#44; se planific&#243; comparar el gen del receptor 5-HT2C rs3813929&#44; rs518147&#44; el gen del receptor 5-HT1A rs6295 y el gen del receptor 5-HT1B rs11568817 de pacientes con EP de por vida con controles sanos&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materiales y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Para este prop&#243;sito&#44; se incluyeron en el estudio 100 pacientes con eyaculaci&#243;n precoz y 100 controles sanos&#46; Se obtuvieron muestras de sangre para extracci&#243;n de ADN&#46; Se aplicaron procedimientos apropiados a las sondas &#40;rs3813929&#44; rs518147&#44; rs6295&#44; rs11568817&#41; adecuadas para el ADN estudiado&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se encontr&#243; una relaci&#243;n estad&#237;sticamente significativa entre el polimorfismo rs11568817 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;019&#41; en el gen del receptor 5-HT1B y el polimorfismo rs518147 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;016&#41; en el gen del receptor 5-HT2C&#46; Adem&#225;s&#44; no se encontr&#243; una relaci&#243;n estad&#237;sticamente significativa entre el polimorfismo del gen del receptor 5-HT1A rs6295 y el polimorfismo del gen del receptor 5-HT2C rs3813929 y la EP de por vida&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se confirm&#243; la relaci&#243;n entre los polimorfismos rs3813929 y rs11568817 con EP de por vida&#46; Repetir el estudio en grupos de muestra m&#225;s grandes podr&#237;a ser &#250;til para determinar la etiolog&#237;a gen&#233;tica de la EP&#46;</p></span>"
        "secciones" => array:4 [
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                  \t\t\t\t"><span class="elsevierStyleBold">2&#46;557</span></td><td class="td" title="\n
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ISSN: 1698031X
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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