STin2 Polymorphism Research Articles

Genetic predictors of cultural values variation between societies

Associations between the STin2 and 5-HTTLPR polymorphisms within the serotonin transporter gene, SLC6A4, and culture across societies were examined. Based on an analysis of 75 primary studies (28,726 individuals), STin2 allelic frequencies were found to vary widely across countries, ranging from 26% in Germany to 85% in Singapore. Across 53 countries, and after controlling for all major environmental influences of culture, STin2 and 5-HTTLPR were found to explain 23.6% unique variance in monumentalism but none in individualism. Our findings evidence a significant role of genetics in predicting cross-societal cultural values variation, and potentially speak to the need for and importance of incorporating both nature and nurture in theories of cultural values variation across societies.

Research Progress on the Relationship Between the Regulation of SLC6A4 Gene and Anxiety Disorders

Anxiety disorder is one of the most common mental disorders. Numerous studies have demonstrated the critical role played by genetic variables in the etiology of anxiety disorders. SLC6A4, which encodes serotonin transporter, is considered to be an important gene associated with anxiety susceptibility. The SLC6A4 gene's upstream promoter has a polymorphism region that has an impact on the transcriptional activity of the gene. Research has shown that this promoter polymorphism has a certain relationship with the occurrence of anxiety disorders and drug treatment. Anxiety disorders are also linked to SLC6A4 gene methylation and intron 2 (Stin2) polymorphism. Stin2 point and SLC6A4 gene methylation are all related to gene expression. This review summarizes the current research on the relationship between SLC6A4 gene promoter polymorphism, Stin2 polymorphism, and SLC6A4 gene methylation in the pathogenesis and drug treatment of anxiety disorder, to understand the current research progress of SLC6A4 gene expression in anxiety disorder.

Unraveling the Contribution of Serotonergic Polymorphisms, Prefrontal Alpha Asymmetry, and Individual Alpha Peak Frequency to the Emotion-Related Impulsivity Endophenotype

The unique contribution of the serotonin transporter-linked polymorphic region (5-HTTLPR), intronic region 2 (STin2), and monoamine oxidase A (MAO-A) genes to individual differences in personality traits has been widely explored, and research has shown that certain forms of these polymorphisms relate to impulsivity and impulsivity-related disorders. Humans showing these traits are also described as having an asymmetrical prefrontal cortical activity when compared to others. In this explorative study, we examine the relationship between serotonergic neurotransmission polymorphisms, cortical activity features (prefrontal alpha asymmetry, individual alpha peak frequency [iAPF]), emotion-related and non-emotion-related impulsivity in humans. 5-HTTLPR, MAO-A, and STin2 polymorphisms were assessed in blood taken from 91 participants with high emotion-related impulsivity levels. Sixty-seven participants completed resting electroencephalography and a more comprehensive impulsivity index. In univariate analyses, iAPF correlated with both forms of emotion-related impulsivity. In multiple linear regression models, 5-HTTLPR polymorphism (model 1, adj. R2 = 15.2%) and iAPF were significant interacting predictors of emotion-related impulsivity, explaining a large share of the results’ variance (model 2, adj. R2 = 21.2%). Carriers of the low transcriptional activity 5-HTTPLR and MAO-A phenotypes obtained higher emotion-related impulsivity scores than others did. No significant results were detected for non-emotion-related impulsivity or for a form of emotion-related impulsivity involving cognitive/motivational reactivity to emotion. Our findings support an endophenotypic approach to impulsivity, showing that tri-allelic 5-HTTLPR polymorphism, iAPF, and their interaction are relevant predictors of one form of emotion-related impulsivity.

Serotonin transporter functional polymorphisms potentially increase risk of schizophrenia separately and as a haplotype

Schizophrenia is a severe, disabling psychiatric disorder with unclear etiology. Family-based, twins, and adoption studies have shown that genetic factors have major contributions in schizophrenia occurrence. Until now, many studies have discovered the association of schizophrenia and its comorbid symptoms with functional polymorphisms that lie within serotonin reuptake pathway genes. Here, we aimed to investigate the association of three variable number tandem repeats (VNTR) functional polymorphisms in MAOA and SLC6A4 with schizophrenia in the Iranian population. Two hundred and forty-one subjects with schizophrenia and three hundred and seventy age and sex-matched healthy controls were genotyped for MAOA promoter uVNTR, 5-HTTLPR, and STin2 polymorphisms. Genotyping was performed by polymerase chain reaction (PCR) with locus-specific primers and running the PCR product on agarose 2.5% gel electrophoresis. Finally, the statistical inference was performed using R programming language and Haploview software. MAOA promoter uVNTR analysis of allele frequency showed no differences between schizophrenia subjects and healthy controls in both males and females and no significant differences were observed between female cases and female controls in MAOA promoter uVNTR 4 repeat frequency. Also, there were no differences between Schizophrenia and healthy control groups in 5-HTTLPR allele and genotype frequency but, 5-HTTLPR S allele carriers are significantly more frequent among cases. In addition, STin2.12 repeats were significantly more frequent among schizophrenia patients. Genotype comparison suggested that 5-HTTLPR S allele and STin2.12 repeat carriers were significantly more frequent among schizophrenia cases and being STin2.12 repeat carrier significantly increase the risk of schizophrenia occurrence. Besides, analysis of haplotype showed stronger linkage disequilibrium between 5-HTTLPR and STin2 haplotype block in cases than controls. These results suggest that SLC6A4 functional polymorphisms potentially could play a possible role as risk factors for the incidence of schizophrenia.

Role of serotonin transporter and receptor gene polymorphisms in treatment response to selective serotonin reuptake inhibitors in major depressive disorder.

Significant challenges in the management of major depressive disorder include the lag period from treatment initiation to an evident response, low response rates and unpredictable disparities in outcome between patients. As a large part of these has been linked to genetic mechanisms, we tried to establish a relationship between genes associated with serotonin neurotransmission and outcome to selective serotonin reuptake inhibitor (SSRI) treatment. One hundred and twenty-five patients with moderate to severe depression [at least 15 on the Hamilton Depression (HAM-D) Rating Scale] being started on SSRI were recruited. Those with a reduction of at least 50% from baseline or an absolute score of 7 or less after 8weeks of treatment were considered as responders. The serotonin transporter linked polymorphic region 5HTTLPR, serotonin transporter intron 2 (STin2) polymorphism and the 5-HT receptor 1A rs6295 polymorphisms were studied in association with outcome. The l/l genotype of the 5HTTLPR was associated with greater likelihood of response (OR: 4.65, CI: 1.74-12.38, p=0.003). Patients with the 12/12 repeat variant of the STin2 VNTR polymorphism showed a greater reduction in HAM-D score, compared to patients with the 10/10 genotype (OR: 0.12, CI: 0.03-0.44, p=0.001). We found no association of the 5HTR1Ars6295 polymorphism with response. The 5HTTLPR polymorphism and the SLC6A4 intron 2 polymorphism were associated with treatment response, with the l/l genotype and 12-copy allele showing a tendency towards better outcomes, respectively.

Association between 5-HTTLPR and STin2 VNTR polymorphisms in the serotonin transporter gene and clinical response of a selective serotonin reuptake inhibitor (dapoxetine) in lifelong premature ejaculation

Association between 5-HTTLPR and STin2 VNTR polymorphisms in the serotonin transporter gene and clinical response of a selective serotonin reuptake inhibitor (dapoxetine) in lifelong premature ejaculation

Association analysis of SLC6A4 and HTR2A genes with obsessive-compulsive disorder: Influence of the STin2 polymorphism

BackgroundObsessive-Compulsive Disorder (OCD) is a complex and chronic disorder characterized by recurrent thoughts and/or repetitive behaviors. Given the potent anti-obsessional effects of the so-called serotonin reuptake inhibitors, genes related to serotonergic system may be well implicated in the etiopathogenesis of OCD. The gene encoding the serotonin transporter (SLC6A4), which shows a variable number of tandem repeat (VNTR) polymorphism in intron 2 (STin2), have been previously associated with OCD. Additionally, the serotonin 2A receptor gene (HTR2A) has two polymorphisms (A-1438G - rs6311, and T102C - rs6313), which have also been overrepresented among OCD patients. Therefore, the aim of this study is to evaluate the association of these three polymorphisms with OCD, through the examination of potential sources of heterogeneity in previous studies including age of onset, sex and symptom dimensions. MethodsPolymorphisms were genotyped by Polymerase Chain Reaction (PCR) in a sample of 203 OCD patients and 205 healthy controls from Brazil. ResultsAlthough we did not observe any statistically significant association between the HTR2A gene polymorphisms and OCD or its clinical features, SLC6A4 STin2 polymorphism was significantly more common among OCD patients as compared to health controls. Further, a significant association between the STin2.12 allele and OCD, as well as a dominant effect of the STin2.12 allele in OCD was seen. Of note, late-onset (>18years) OCD was significantly more often seen in association with homozygosis for STin2.12 allele. No significant associations were observed with different OCD symptom dimensions. ConclusionOur results indicate an important influence of the STin2 polymorphism in OCD, but more studies are warranted to confirm these results.

Serotonin transporter gene polymorphisms may be associated with poststroke neurological recovery after escitalopram use

ObjectiveSelective serotonin reuptake inhibitors (SSRIs) putatively improve neurological recovery after stroke. We aimed to investigate whether serotonin transporter (SERT) gene polymorphisms are related to the responsiveness to SSRIs in the...

Association between serotonin transporter gene polymorphisms and heroin dependence: a meta-analytic study.

BackgroundStudies have examined the association between heroin dependence and serotonin transporter gene polymorphisms but yielded inconsistent results. The purpose of current study is to determine the overall effect of these polymorphisms on the risk for heroin dependence through a meta-analytic method.MethodsA meta-analysis was conducted to examine the association of heroin dependence with two common polymorphisms of serotonin transporter gene, in the promoter (5-hydroxytryptamine transporter-linked promotor region [5-httlpr]) and intron 2 (a various number tandem repeat in serotonin transporter intron 2 [STin2]). Data from studies with 5-httlpr (6 studies) and STin2 (8 studies) were synthesized by random effects model.ResultsIn the analysis, heroin dependence was found to be significantly associated with the S allele of 5-httlpr (odds ratio [OR] =1.22, 95% confidence interval [CI] =1.08–1.41, P=0.002). The association between the S allele of 5-httlpr and heroin dependence was significant in Caucasian subjects (OR =1.37, 95% CI =1.12–1.68, P=0.003), but not in non-Caucasian subjects. On the other hand, no association with STin2 polymorphism was found (OR =1.14, 95% CI =0.91–1.42, P=0.242).ConclusionThe results suggest an ethnic-specific effect of the 5-httlpr polymorphism on the risk for heroin dependence, but the influence of the genetic variance in the patients with comorbidities or intermediate phenotypes of heroin dependence needs to be further examined.

The 5-HTT gene polymorphisms correlated with the clinical manifestations of depression

Objective To determine the potential correlation of 5-HTT gene polymorphisms (5-HTTLPR and STin2) with clinical manifestations in depression. Methods A total of 401 depressed patients, all of Chinese Han region, were collected and genotyped by polymerase chain reactions (PCR). All patients were evaluated using a 17-item Hamilton depression rating scale (HAMD-17) and Hamilton anxiety rating scale (HAMA), and then associated analysis was applied. Results (1) The age of onset in patients with L/S genotype of 5-HTLPR polymorphism were much younger than that of patients with L/L and S/S genotype (F=3.281, P=0.039). Besides, there was also a significant difference of HAMA1 (anxious mood) scores among patients with different genotypes for 5-HTTLPR polymorphism, where the scores of those with L/S genotype were the highest (2.34±0.80, P=0.010). (2) The scores of HAMD10 (mental anxiety), HAMA1 (anxious mood), HAMA3 (fear) and mental anxiety factor were higher in patients with 12/10 genotype than patients with 12/12 and 10/10 genotype for STin2 polymorphism (2.40±0.83, 2.38±0.90, 1.42±1.04, 14.60±4.26 respectively; P value: 0.014, 0.044, 0.03 and 0.006 respectively). The scores of HAMD10(mental anxiety) and mental anxiety factor were (2.11±0.77), ( 12.96±3.78) in the 12/12 genotype patients, and significantly lower than that in the 12/10 genotype patients (adjusted P value: 0.018, 0.006). Conclusions A positive association of the 5-HTT polymorphisms with anxious symptoms in depressed patients is revealed. These findings might provide some evidences for the clinical phenotype and optimization of depression treatment. Key words: 5-HTT; Gen polymorphism; Depression

Retraction statement: Analysis of association between the 5-HTTLPR and STin2 polymorphisms in the serotonin-transporter gene and clinical response to a selective serotonin reuptake inhibitor (sertraline) in patients with premature ejaculation.

Study Type – Therapy (cohort) Level of Evidence 2b OBJECTIVE To test the hypothesis that polymorphism within the gene-linked polymorphic region (5-HTTLPR) and second intron of SLC6A4 gene (STin2) is associated with selective serotonin-reuptake inhibitors (SSRIs) response in subjects with premature ejaculation (PE). PATIENTS AND METHODS In all, 246 men with PE were recruited in this study. They were asked to take sertraline 50 mg daily for 2 weeks, and thereafter 100 mg daily, for a 12-week treatment period. Pretreatment evaluation included history and physical examination, intravaginal ejaculatory latency time (IELT), and International Index of Erectile Function (IIEF). The efficacy of treatment was assessed using responses to IIEF, and geometric mean IELT evaluation. 5-HTTLPR was genotyped using polymerase chain reaction techniques. A repeated-measures analysis of variance of geometric mean IELT was done to test a genotype effect on treatment outcome with SSRI (sertraline). RESULTS Of 227 participants who completed the study, 175 (77.1%) responded to sertraline (IELT >1 min). Overall the patients had a 3.7-fold (95% confidence interval, CI, 1.72–5.46) increase of the geometric mean IELT (P = 0.001). The results showed that responses were significantly better for the LA/LA genotype of the 5-HTTLPR polymorphism than for S-allele carriers (P = 0.001). The STin2 12/12 genotype was found more often in those responding to sertraline than in those not responding (P = 0.001). The probability of patients responding sufficiently to sertraline with an LA/LA genotype was highest (odds ratio 4.66, 95% CI, 2.48–6.14). CONCLUSIONS These findings indicate that the genotype of 5-HTT contributes in unique ways to the variation in the outcome of PE treatment with SSRIs.

Study of the association of serotonin transporter triallelic 5-HTTLPR and STin2 VNTR polymorphisms with lithium prophylaxis response in bipolar disorder

The 5-hydroxy tryptamine transporter (5-HTT) gene has been previously implicated in lithium response, but the roles of the triallelic 5-HTT linked promoter region (5-HTTLPR) and variable number tandem repeats in the second intron [serotonin transporter intron 2 (STin2)] have not been reported. We examined these polymorphisms in 122 patients with bipolar I disorder, among which 49 patients were classified as good responders, 49 as nonresponders, and 24 as partial responders to lithium prophylaxis. We observed significant variation in the genotype frequencies of STin2 polymorphism among the response groups (P=0.02). There was also a significant association of haplotype consisting of the S allele of 5-HTTLPR and 10 repeat allele of STin2 with lithium response (P=0.01) and no such relationship was found with 5-HTTLPR variants. Our data support preliminary information of a possible association of STin2 and its combined effect with 5-HTTLPR variants with lithium response and also suggest that lithium is likely to be more effective for patients carrying 5-HTT polymorphisms associated with reduced transcriptional activity.

Multi-cultural association of the serotonin transporter gene (SLC6A4) with substance use disorder.

A number of studies have reported associations between the serotonin transporter gene (SLC6A4) and alcohol, heroin, cocaine, or methamphetamine abuse. Other studies have yielded contrary results. There are a number of reasons for non-replication, including inadequate statistical power, population stratification, and poor phenotype definition. This study was to test the association using a meta-analytic approach across a variety of racial and ethnic populations. Using the genotype data of 55 studies (7999 cases, 8264 controls, and 676 families or parent-offspring trios) published in the past 15 years, we have conducted comprehensive meta-analyses to examine the associations of the 5-HTTLPR and STin2 polymorphisms with substance use disorder. The meta-analyses support the associations of 5-HTTLPR with alcohol, heroin, cocaine, and methamphetamine dependence and abuse (eg, the smallest P-values were 0.0058 with odds ratio (OR)=0.54 (0.35, 0.84); 0.0024 with OR=0.77 (0.66, 0.91); 0.018 with OR=1.38 (1.06, 1.81); and 0.028 with OR=0.46 (0.23, 0.92) for alcohol, heroin, cocaine, and methamphetamine dependence/abuse, respectively). When all the phenotypes are combined, the P-value was 0.0006 with OR=0.86 (0.78, 0.94) in the combined European, Asian, and Mexican populations and P-value was 0.0028 with OR=1.41 (1.13, 1.78) in the African populations. Evidence of significant associations was also identified in other subgroup analyses regarding differently combined substance and populations. The effect sizes of 5-HTTLPR were comparable among the European, Asian, and Mexican populations, however, the risk allele was more frequent in Asians than in Europeans and Mexicans. The opposite directions of risk allele in African population might be driven by the opposite directions of risk allele in cocaine dependence. This meta-analysis supports that the association of the SLC6A4 gene with substance use disorder varies depending on substances with different risk allele frequencies in the multi-cultural populations. Further studies using larger sample size are warranted.

AVPR1A and SLC6A4 Polymorphisms in Choral Singers and Non-Musicians: A Gene Association Study

Amateur choral singing is a common pastime and worthy of study, possibly conferring benefits to health and social behaviour. Participants might be expected to possess musical ability and share some behavioural characteristics. Polymorphisms in genes concerned with serotonergic neurotransmission are associated with both behaviour and musical aptitude. Those investigated previously include the variable number tandem repeats RS1, RS3 and AVR in the AVPR1A (arginine vasopressin receptor 1a) gene and STin2 in the SLC6A4 (solute carrier family 6 [neurotransmitter transporter, serotonin], member 4) gene, as well as the SLC6A4 promoter region polymorphism, 5-HTTLPR. We conducted a genetic association study on 523 participants to establish whether alleles at these polymorphisms occur more commonly in choral singers than in those not regularly participating in organised musical activity (non-musicians). We also analysed tagging single nucleotide polymorphisms (SNPs) for AVPR1A and SLC6A4 to determine whether other variants in these genes were associated with singer/non-musician status. At the STin2 polymorphism, overall association with singer/non-musician status was evident at P = 0.006. The 9-repeat (P = 0.04) and 12-repeat (P = 0.04) alleles were more common in singers and the 10-repeat allele less so (P = 0.009). Odds ratios were 0.73 (95% CI 0.57–0.94) for the 10-repeat allele and 2.47 (95% CI 0.88–6.94) for the rarer 9-repeat allele. No overall association was detected at P<0.05 between any other polymorphism and singer/non-musician status. Our null findings with respect to RS3, RS1 and AVR, polymorphisms associated with musical ability by other authors, suggest that choir membership may depend partly on factors other than musical ability. In a related musical project involving one participating choir, a new 40-part unaccompanied choral work, “Allele”, was composed and broadcast on national radio. In the piece, each singer's part incorporated their personal RS3 genotype.

Interactions between serotonin transporter gene haplotypes and quality of mothers' parenting predict the development of children's noncompliance.

The LPR and STin2 polymorphisms of the serotonin transporter gene (SLC6A4) were combined into haplotypes that, together with quality of maternal parenting, were used to predict initial levels and linear change in children's (N = 138) noncompliance and aggression from age 18-54 months. Quality of mothers' parenting behavior was observed when children were 18 months old, and nonparental caregivers' reports of noncompliance and aggression were collected annually from 18 to 54 months of age. Quality of early parenting was negatively related to the slope of noncompliance only for children with the LPR-S/STin2-10 haplotype and to 18-month noncompliance only for children with haplotypes that did not include LPR-S. The findings support the notion that SLC6A4 haplotypes index differential susceptibility to variability in parenting quality, with certain haplotypes showing greater reactivity to both supportive and unsupportive environments. These different genetic backgrounds likely reflect an evolutionary response to variation in the parenting environment.

Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment

In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of the serotonin receptor 1D beta (HTR1B), the T102C (rs6113) and C516T (rs6305) polymorphisms of the serotonin receptor gene subtype 2A (HTR2A), the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3), the Val-158-Met (rs4680) polymorphism of the COMT and the silent mutation G1287A (rs5569) in the norepinephrine transporter gene (SLC6A2). We genotyped 41 obsessive-compulsive disorder (OCD) outpatients, classified as good-responders (n=27) and poor-responders (n=14) to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS). Patients who achieved a reduction in symptoms of 40% or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.

Serotonin transporter gene polymorphism and psychiatric disorders: Is there a link?

Though still in infancy, the field of psychiatric genetics holds great potential to contribute to the development of new diagnostic and therapeutic options to treat these disorders. Among a large number of existing neurotransmitter systems, the serotonin system dysfunction has been implicated in many psychiatric disorders and therapeutic efficacy of many drugs is also thought to be based on modulation of serotonin. Serotonin transporter gene polymorphism is one of the most extensively studied polymorphisms in psychiatric behavioral genetics. In this article, we review the status of evidence for association between the serotonin gene polymorphism and some common mental disorders like affective disorders, post-traumatic stress disorder, obsessive-compulsive disorder, suicide, autism, and other anxiety and personality disorders. Going beyond traditional association studies, gene-environment interaction, currently gaining momentum, is also discussed in the review. While the existing information of psychiatric genetics is inadequate for putting into practice genetic testing in the diagnostic work-up of the psychiatric patient, if consistent in future research attempts, such results can be of great help to improve the clinical care of a vast majority of patients suffering from such disorders.

5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene and irritable bowel syndrome: effect of bowel habit and sex

Conflicting data exist on the association between functional polymorphisms in the serotonin reuptake transporter (SERT) gene (SLC6A4) and irritable bowel syndrome (IBS). This may be partly because of small participant numbers and varying ethnic origin and sex within the cohorts studied. To reassess the potential association between the SERT polymorphisms 5-HTTLPR and STin2 in both male and female IBS patients with diarrhoea (IBS-D) and constipation (IBS-C) compared with healthy volunteers. In this case-control study, 196 Caucasian Rome II IBS patients [97 IBS-D (aged 18-66 years; 67 female) and 99 IBS-C (aged 18-65 years; 95 female)] and 92 Caucasian healthy volunteers (aged 18-63 years; 60 female) from the UK had genomic DNA extracted from peripheral blood and the 5-HTTLPR and STin2 polymorphisms genotyped. The frequency of the 5-HTTLPR (ss) genotype was slightly lower in both IBS-D (16.5%) and IBS-C (14.3%) patients compared with controls (23.9%), although not significantly (P<or=0.191). This seemed to be related to a reduction in the frequency of the 5-HTTLPR (ss) genotype in male patients, particularly those with IBS-D [IBS-D 10%, IBS-C 25%, controls 37.5%; P=0.01 for IBS-D vs. controls; odds ratio (95% confidence interval) for 5-HTTLPR (ss) vs. 5-HTTLPR (non-ss)=0.185 (0.046-0.744)] than in female patients (IBS-D 19.4%, IBS-C 13.8%, controls 16.7%). There were no differences in the frequencies of either the 5-HTTLPR (ll) or (ls), or STin2 genotypes between any of the three groups. Our finding that male IBS-D patients have a reduced frequency of the 5-HTTLPR (ss) genotype contradicts three earlier studies of a similar size, which did not take sex into account. Therefore, replication studies in even larger cohorts, stratifying for sex and endophenotypes, after assessing physiological and psychological traits, are required to unravel the contribution of SERT polymorphisms to the IBS phenotype.

Association analysis between gene variants of the tyrosine hydroxylase and the serotonin transporter in borderline personality disorder

objectives. For patients with borderline personality disorder (BPD), we previously reported an independent effect of the catechol-o-methyl-transferase (COMT) low-activity (Met158) allele and an interaction with the low-expression allele of the deletion/insertion (short/long or S/L, resp.) polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR). The purpose of the present study was to extend these findings to the tyrosine hydroxylase (TH) Val81Met single nucleotide polymorphism (SNP), the 5-HTTLPR S/L polymorphism incorporating the recently described functional A/G SNP within the long allele of the 5-HTTLPR (rs25531) as well as the variable number of tandem repeat (VNTR) polymorphism within intron 2 of the serotonin transporter gene (STin2). Methods. In 156 Caucasian BPD patients and 152 healthy controls, we tested for association between BPD and the TH Val81Met SNP, the 5-HTTLPR/rs25531 polymorphism, the STin2, the interaction of the TH Val81Met SNP with the tri-allelic 5-HTTLPR/rs25531, the interaction of the TH Val81Met SNP with STin2. Results. Between BPD patients and controls, we observed a slight over-representation of the TH Met81Met genotype in BPD patients compared to controls, but no statistically significant differences in genotype distribution of the individual markers after adjusting for multiple testing. Logistic regression analysis showed a lack of interaction between the TH Val81Met and the 5-HTTLPR/rs25531 as well as between the TH Val81Met and the STin2 polymorphism. Conclusions. These data do not suggest independent or interactive effects of the TH Val81Met, the 5-HTTLPR/rs25531, or the STin2 polymorphisms in BPD.

Analysis of association between the 5‐HTTLPR and STin2 polymorphisms in the serotonin‐transporter gene and clinical response to a selective serotonin reuptake inhibitor (sertraline) in patients with premature ejaculation

To test the hypothesis that polymorphism within the gene-linked polymorphic region (5-HTTLPR) and second intron of SLC6A4 gene (STin2) is associated with selective serotonin-reuptake inhibitors (SSRIs) response in subjects with premature ejaculation (PE). In all, 246 men with PE were recruited in this study. They were asked to take sertraline 50 mg daily for 2 weeks, and thereafter 100 mg daily, for a 12-week treatment period. Pretreatment evaluation included history and physical examination, intravaginal ejaculatory latency time (IELT), and International Index of Erectile Function (IIEF). The efficacy of treatment was assessed using responses to IIEF, and geometric mean IELT evaluation. 5-HTTLPR was genotyped using polymerase chain reaction techniques. A repeated-measures analysis of variance of geometric mean IELT was done to test a genotype effect on treatment outcome with SSRI (sertraline). Of 227 participants who completed the study, 175 (77.1%) responded to sertraline (IELT >1 min). Overall the patients had a 3.7-fold (95% confidence interval, CI, 1.72-5.46) increase of the geometric mean IELT (P = 0.001). The results showed that responses were significantly better for the L(A)/L(A) genotype of the 5-HTTLPR polymorphism than for S-allele carriers (P = 0.001). The STin2 12/12 genotype was found more often in those responding to sertraline than in those not responding (P = 0.001). The probability of patients responding sufficiently to sertraline with an L(A)/L(A) genotype was highest (odds ratio 4.66, 95% CI, 2.48-6.14). These findings indicate that the genotype of 5-HTT contributes in unique ways to the variation in the outcome of PE treatment with SSRIs.