Association between 5-HTTLPR and STin2 VNTR Polymorphisms in the Serotonin Transporter Gene and Clinical Response of Dapoxetine in Lifelong Premature Ejaculation
Premature ejaculation (PE) affects approximately 30% of men worldwide, making it one of the most common male sexual dysfunctions. For many, PE is a lifelong condition—starting with their first sexual experience—and its causes are complex, blending psychological, environmental, and genetic factors. A 2022 study from researchers at Xi’an Jiaotong University in China sheds new light on how specific genetic variants in the serotonin transporter gene (SLC6A4) might influence both the risk of lifelong PE and how well patients respond to dapoxetine, a first-line treatment for the condition.
What the Study Examined
The research, led by Junping Xing and colleagues from the Department of Urology and Research Centre of Reproduction Medicine at The First Affiliated Hospital, Xi’an Jiaotong University, focused on two key SLC6A4 variants:
- 5-HTTLPR: A polymorphism in the gene’s promoter region that comes in “short” (S) or “long” (L) forms.
- STin2 VNTR: A variable number tandem repeat (VNTR) in intron 2 of the gene, with common variants including 10- and 12-repeat alleles.
Both variants affect serotonin transporter function—a critical factor in regulating serotonin levels in the brain, which plays a key role in sexual arousal and ejaculation.
How the Study Was Conducted
The team recruited 95 men with lifelong PE (defined as consistent early ejaculation since first intercourse) and 102 healthy controls. All participants were between 21 and 50 years old, in stable relationships, and free of conditions that could impact sexual function (e.g., erectile dysfunction, diabetes, psychiatric disorders).
For the PE group:
- Intra-vaginal ejaculation latency time (IELT) was measured with stopwatches.
- Genomic DNA was extracted from blood samples to test for 5-HTTLPR and STin2 VNTR variants.
- Patients took 30 mg of dapoxetine daily for two weeks. Response was assessed using the Clinician Global Impression of Change (CGIC) score and changes in premature ejaculation profile (PEP) scores.
Key Findings: Genetics, PE Risk, and Dapoxetine Response
The study revealed strong associations between SLC6A4 variants and both lifelong PE risk and treatment outcomes:
1. Genetic Variants Linked to Lifelong PE
- 5-HTTLPR: Men with the SS genotype (two copies of the S allele) were significantly more likely to have PE than those with the LL genotype (two L alleles). The S allele itself was also more common in PE patients.
- STin2 VNTR: The STin2.12/12 genotype (two copies of the 12-repeat allele) and the STin2.12 allele were both overrepresented in PE patients, suggesting these variants increase risk.
2. Genetic Variants and Dapoxetine Response
Approximately 66% of PE patients (63 out of 95) responded positively to dapoxetine. However:
- 5-HTTLPR: Patients with the SS genotype were less likely to respond to treatment than those with other genotypes. The S allele was a clear risk factor for poor response.
- STin2 VNTR: The STin2.12/12 genotype and STin2.12 allele were more frequent in non-responders, meaning men with these variants had a lower chance of benefiting from dapoxetine.
How This Fits with Previous Research
The findings build on mixed results from earlier studies:
- A 2009 Dutch study by Janssen et al. found that the LL genotype of 5-HTTLPR was linked to shorter IELT in men with lifelong PE.
- A 2009 Turkish study by Ozbek et al. reported higher S allele frequency in PE patients.
- A 2016 Chinese study by Huang et al. linked the STin2.12/12 genotype to shorter IELT in lifelong PE.
However, some research has found no association between SLC6A4 variants and PE. This study clarifies that specific variants (SS in 5-HTTLPR, STin2.12/12) may play a role—at least in Han Chinese men from northwest China.
Limitations and Future Directions
The study had important limitations:
- All participants were Han Chinese from northwest China, so results may not apply to other ethnic groups.
- The sample size was small (95 PE patients), and the rare STin2.9 variant was excluded due to low frequency.
The researchers emphasize the need for larger, more diverse studies to confirm these findings and explore how genetics interact with other factors (e.g., psychology, environment) in PE.
What This Means for PE Treatment
For men with lifelong PE, these results suggest that genetic testing could one day help personalize treatment. If a patient has the SS genotype (5-HTTLPR) or STin2.12/12 genotype, dapoxetine may be less effective—a valuable clue for doctors when choosing therapies.
PE is a complex condition, but this study adds a key piece to the puzzle of its genetic basis. As research expands, we may move closer to more targeted, effective treatments for millions of men.
The study was published in the Chinese Medical Journal in 2022 by Abdullah, Yang Yang, Shang-Shu Ding, Ping Sun, Huoyong-Wei, Tian Hong, and Junping Xing.
doi:10.1097/CM9.0000000000001843
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