Association Between 5-HTTLPR and STin2 VNTR Polymorphisms in the Serotonin Transporter Gene and Clinical Response to Dapoxetine in Lifelong Premature Ejaculation
Premature ejaculation (PE) is a prevalent male sexual dysfunction affecting approximately 30% of men globally. Lifelong premature ejaculation (LPE), a subtype of PE, is characterized by persistent early ejaculation from the first sexual experiences. Emerging evidence suggests genetic factors contribute to LPE pathogenesis, particularly polymorphisms in the serotonin transporter gene (SLC6A4), which regulates synaptic serotonin levels. Two key polymorphisms—5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) and serotonin transporter gene intron 2 variable number tandem repeat (STin2 VNTR)—have been implicated in modulating serotonin reuptake efficiency. However, prior studies report conflicting associations between these polymorphisms and LPE susceptibility or treatment outcomes. This study investigates the relationship between 5-HTTLPR/STin2 genotypes and clinical response to dapoxetine, a short-acting selective serotonin reuptake inhibitor (SSRI), in LPE patients.
Study Design and Participant Characteristics
The study enrolled 95 LPE patients and 102 age-matched healthy controls from the Urology Department of The First Affiliated Hospital of Xi’an Jiaotong University. Participants were aged 21–50 years, sexually active in stable heterosexual relationships for >6 months, and free of comorbidities such as erectile dysfunction, psychiatric disorders, diabetes, or cardiovascular diseases. Exclusion criteria included a history of sexual abuse, prostatitis, or chronic medical conditions. Diagnosis of LPE was confirmed using validated tools: the Premature Ejaculation Diagnostic Tool (PEDT) score >9 and International Index of Erectile Function (IIEF) score >20 for patients, while controls had PEDT 20. Intravaginal ejaculatory latency time (IELT), measured via stopwatch, served as an objective endpoint.
Genetic Analysis and Treatment Protocol
Genomic DNA was extracted from venous blood samples. Polymerase chain reaction (PCR) amplified 5-HTTLPR and STin2 VNTR regions for genotyping. The 5-HTTLPR polymorphism was classified into L (long) and S (short) alleles, yielding LL, LS, and SS genotypes. STin2 VNTR alleles included 10- and 12-repeat variants, categorized as 10/10, 12/10, and 12/12 genotypes. Patients received 30 mg dapoxetine on-demand for two weeks. Treatment efficacy was evaluated using the Clinician Global Impression of Change (CGIC) scale, with responders defined as those showing improvement in CGIC scores.
Key Findings: Genetic Associations with LPE Susceptibility
5-HTTLPR Polymorphism
The distribution of 5-HTTLPR genotypes differed significantly between LPE patients and controls. The SS genotype frequency was higher in patients (44.2% vs. 25.5% in controls; P = 0.017), while the LL genotype was less frequent (12.6% vs. 24.5%; P = 0.017). The S allele frequency was markedly elevated in patients (64.2% vs. 48.0%; P = 0.003), establishing the S allele as a risk factor for LPE. LS genotype distribution did not differ between groups (P = 0.531).
STin2 VNTR Polymorphism
STin2 12/12 genotype frequency was significantly higher in LPE patients (42.1% vs. 24.5%; P < 0.05), with the 12-repeat allele overrepresented (62.1% vs. 48.0%; P < 0.05). The 10/10 and 12/10 genotypes showed no intergroup differences. The rare STin2.9 allele was excluded from analysis due to low frequency (detected in two patients and one control).
Treatment Response and Genetic Predictors
Dapoxetine improved ejaculatory control in 66.3% (63/95) of patients. Genetic stratification revealed distinct response patterns:
5-HTTLPR and Dapoxetine Efficacy
Non-responders exhibited higher SS genotype prevalence (75.0% vs. 44.5% in responders; P = 0.018; OR = 0.354, 95% CI: 0.130–0.769). The S allele frequency was elevated in non-responders (84.3% vs. 64.2%; P = 0.028; OR = 0.460, 95% CI: 0.226–0.798), indicating reduced dapoxetine efficacy in S allele carriers. LL genotype frequency was marginally higher in responders (15.8% vs. 6.3%), though not statistically significant.
STin2 VNTR and Dapoxetine Efficacy
STin2 12/12 genotype frequency was significantly higher in non-responders (67.8% vs. 37.1%; P = 0.018; OR = 0.409, 95% CI: 0.215–0.986). Similarly, the 12-repeat allele was overrepresented in non-responders (70.9% vs. 62.1%; P = 0.026; OR = 0.438, 95% CI: 0.247–0.963). No associations were observed for 10/10 or 12/10 genotypes.
Clinical and Demographic Correlates
Demographic factors such as age, BMI, marital status, and substance use showed no association with LPE. Occupational differences emerged, with mental workers overrepresented among patients. Earlier age at first sexual encounter, lower monthly sexual frequency, and higher PEDT scores correlated with LPE (P < 0.05).
Discussion
This study provides robust evidence linking 5-HTTLPR and STin2 polymorphisms to LPE susceptibility and SSRI treatment outcomes. The S allele of 5-HTTLPR is associated with reduced transcriptional efficiency of the serotonin transporter, potentially lowering synaptic serotonin levels and predisposing individuals to rapid ejaculation. Similarly, the STin2 12-repeat allele may alter gene expression patterns, exacerbating serotonergic dysregulation.
The observed resistance to dapoxetine in S allele and STin2 12/12 carriers aligns with prior studies suggesting that genetic variants affecting serotonin transporter function may diminish SSRI efficacy. For instance, Janssen et al. (2009) reported shorter IELT in LL genotype carriers, while Huang et al. (2016) linked STin2 12/12 genotypes to reduced IELT. However, Safarinejad (2009) found no 5-HTTLPR association with PE, highlighting ethnic and methodological variability across studies.
Limitations and Future Directions
This study’s focus on Han Chinese limits generalizability to other populations. The modest sample size and absence of long-term follow-up further constrain conclusions. Future multicenter studies with diverse cohorts and extended observation periods are needed to validate these findings. Additionally, exploring epigenetic modifications and gene-environment interactions could elucidate mechanisms underlying serotonergic dysregulation in LPE.
Conclusion
The 5-HTTLPR S allele and STin2 12-repeat allele are genetic risk factors for LPE and predictors of poor dapoxetine response. These findings underscore the potential of genetic screening to personalize PE treatment, optimizing therapeutic outcomes.
doi.org/10.1097/CM9.0000000000001843
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