Tri-allelic 5-HTTLPR Genotype Research Articles

Association of Serotonin Transporter Gene (5-HTTLPR/rs25531) Polymorphism with Comorbidities of Panic Disorder

Introduction: Panic disorder (PD) has many comorbidities such as depression, bipolar disorder (BPD), and agoraphobia (AG). PD is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Recently, a tri-allelic serotonin transporter (5-HTTLPR/rs25531) polymorphism was reported to be more sensitive to personality traits compared to the bi-allelic 5-HTTLPR polymorphism. We hypothesized that the 5-HTTLPR/rs25531 polymorphism may lead to a pathological anxious state depending on the presence or absence of a comorbidity in PD. Methods: In this study, we investigated the relationship between comorbidities in PD and tri-allelic 5-HTTLPR polymorphisms. A total of 515 patients with PD (148 males, 367 females) were genotyped, and the Revised NEO Personality Inventory as well as anxiety-related psychological tests were administered. Depression, BPD, and AG were diagnosed as comorbidities. Results: For the tri-allele 5-HTTLPR genotype, a significant interaction effect was found between openness to experience and comorbid depression. Examination of the interaction between AG and the tri-allelic 5-HTTLPR genotype revealed that L’ allele carriers are associated with higher trait anxiety than the S’S’ genotype group in PD without AG. Conclusion: Some anxiety and personality traits can be characterized by the tri-allelic gene effect of 5-HTTLPR. These results suggest that tri-allelic 5-HTTLPR genotypes have genetic effects on the presence of comorbidities of PD.

Population differences in associations of serotonin transporter promoter polymorphism (5HTTLPR) di- and triallelic genotypes with blood pressure and hypertension prevalence

Logistic regression and linear models tested associations between triallelic (L'S', based on rs25531) 5HTTLPR genotypes and hypertension severity and mean systolic and diastolic blood pressure (SBP and DBP) collected during the Wave IV survey of the National Longitudinal Study of Adolescent to Adult Health (Add Health, N=11,815) in 2008-09 and during 2004-07 in 4196 Singaporeans. In US Whites, L' allele carriers had higher SBP (0.9 mm Hg, 95% CI=0.26-1.56) and greater odds (OR=1.23, 95% CI=1.10-1.38) of more severe hypertension than those with S'S' genotypes. In African Americans, L' carriers had lower mean SBP (-1.27mm Hg, 95% CI=-2.53 to -0.01) and lower odds (OR = 0.78, 95% CI=0.65-0.94) of more severe hypertension than those with the S'S' genotype. In African Americans, those with L'L' genotypes had lower DBP (-1.13mm Hg, 95% CI=-2.09 to -0.16) than S' carriers. In Native Americans, L' carriers had lower SBP (-6.05mm Hg, 95% CI=-9.59 to -2.51) and lower odds of hypertension (OR = 0.34, 95% CI=0.13-0.89) than those with the S'S' genotype. In Asian/Pacific Islanders those carrying the L' allele had lower DBP (-1.77mm Hg, 95% CI=-3.16 to -0.38) and lower odds of hypertension (OR = 0.68, 95% CI=0.48-0.96) than those with S'S'. In the Singapore sample S' carriers had higher SBP (3.02mm Hg, 95% CI=0.54-5.51) and DBP (1.90mm Hg, 95% CI=0.49-3.31) than those with the L'L' genotype. These findings suggest that Whites carrying the L' allele, African Americans and Native Americans with the S'S' genotype, and Asians carrying the S' allele will be found to be at higher risk of developing cardiovascular disease and may benefit from preventive measures.

Alcohol Dependence and Genetic Variability in the Serotonin Pathway among Currently and Formerly Alcohol-Dependent Males

Background: Genes involved in the serotonin pathway may determine the susceptibility to alcohol dependence and its severity. The present study explored whether specific polymorphisms in the serotonin pathway could be associated with alcohol dependence or alcohol-related psychopathological symptoms. Methods: The cohort comprised 101 currently and 100 formerly alcohol-dependent males, as well as 97 male healthy blood donors. The following questionnaires were employed: the Alcohol Use Disorders Identification Test, the Zung Depression and Anxiety Scale, the Brief Social Phobia Scale, the Yale-Brown Obsessive Compulsive Scale and Obsessive Compulsive Drinking Scale, and the Buss-Durkee Hostility Inventory. Subjects were genotyped for bi- and triallelic SLC6A4 5-HTTLPR,HTR1A rs6295, and HTR1B rs13212041. Results: Statistical differences in bi- and triallelic SLC6A4 5-HTTLPR genotype distribution were observed between the 3 groups investigated (p = 0.008 and p = 0.023, respectively); however, no gene-dose effect was observed. The severity of the alcohol problems was higher in currently alcohol-dependent subjects with the 5-HTTLPR LL (p = 0.039) and L′L′ genotypes (p = 0.027). Formerly dependent subjects with the 5-HTTLPR S′S′ genotype showed more social anxiety, depressive, and anxiety traits (p = 0.009, p = 0.006, and p = 0.036, respectively). Healthy controls with the 5-HTTLPR SS genotype showed more traits of social anxiety (p = 0.020). Conclusions: Our findings suggest that bi- and triallelic SLC6A4 5-HTTLPR has some effects on the severity of alcohol dependence. Triallelic 5-HTTLPR was associated with social anxiety, anxiety, and depressive traits in alcohol-dependent subjects.

Interaction effects between the 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype and family conflict on adolescent alcohol use and misuse.

To investigate whether the effects of family conflict on adolescent drinking differed as a function of 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype cross-sectionally and prospectively in two independent samples of adolescents. Path analysis and multi-group analysis of two prospective datasets were conducted. United States and United Kingdom. Sample 1 was 175 adolescents in the United States (mean age = 15 at times 1 and 2 with a 6-month interval); Sample 2 was 4916 adolescents in the United Kingdon (mean age = 12 at time 1 and 15 at time 2). In both samples, demographics, tri-allelic 5-HTTLPR genotype and perceived family conflict were assessed at time 1. Alcohol use (frequency of drinking) and alcohol misuse (frequency of intoxication, frequency of drinking three or more drinks, maximum number of drinks) were assessed at times 1 and 2. A significant gene-environment interaction on alcohol misuse at time 1 was found in both sample 1 (β = 0.57, P = 0.001) and sample 2 (β = 0.19, P = 0.01), indicating that the 5-HTTLPR low-activity allele carriers exposed to higher levels of family conflict were more likely to engage in alcohol misuse than non-carriers. A significant gene-environment interaction effect on change in alcohol misuse over time was found only in sample 1 (β = 0.48, P = 0.04) but not in sample 2. Compared with non-carriers, adolescents carrying the 5-HTTLPR low-activity allele are more susceptible to the effects of family conflict on alcohol misuse.

Difference in perception of heat and the thermal grill illusion (TGI) in relation to the expression of the serotonin transporter and the effect of cutaneous capsaicin sensitization on the TGI

Abstract Aims The aims of this study are to investigate the differences in (1) heat pain threshold, (2) pain and temperature perception of the TGI and (3) the sensation of capsaicin between subjects with high and low expression of the serotonin transporter (5-HTT). In addition the effects of capsaicin sensitization on the thermal grill illusion are studied. Methods A total of 80 healthy subjects are selected on the basis of their tri-allelic 5-HTTLPR genotype. Threshold for heat pain is examined and pain and unpleasantness of cutaneous capsaicin application are rated on visual analog scales (VAS). The sensory dimensions of the TGI (before and after capsaicin) is determined i.e. description of temperature (burning hot, hot, neutral, cold or freezing cold) and potential pain and intensity of cold and warmth are rated on respective VAS-scales. Results The study is ongoing. We expect that the low expression group has a higher heat pain threshold and rates the TGI and capsaicin less painful. The capsaicin sensitization lowers the heat pain threshold and increases the cold pain threshold. Therefore we hypothesize a lower rating of the TGI, determined as a lower heat VAS-score. Conclusions No conclusions yet. Preliminary results from the study will be presented at the SASP14.

Afraid to help: Social anxiety partially mediates the association between 5-HTTLPR triallelic genotype and prosocial behavior

There is growing evidence that the serotonin system influences prosocial behavior. We examined whether anxiety mediated the association between variation in the serotonin transporter gene regulatory region (5-HTTLPR) and prosocial behavior. We collected self-reported tendencies to avoid certain situations and history of helping others using standard instruments and buccal cells for standard 5-HTTLPR genotyping from 398 undergraduate students. Triallelic 5-HTTLPR genotype was significantly associated with prosocial behavior and the effect was partially mediated by social anxiety, such that those carrying the S′ allele reported higher levels of social avoidance and lower rates of helping others. These results are consistent with accounts of the role of serotonin on anxiety and prosocial behavior and suggest that targeted efforts to reduce social anxiety in S′ allele carriers may enhance prosocial behavior.

Respiratory sinus arrhythmia and serotonin transporter promoter gene polymorphisms: Taking a triallelic approach makes a difference

It has been recently reported in Psychophysiology that carriers of the short allele of an insertion/deletion (ins/del) functional polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter gene may display decreased resting respiratory sinus arrhythmia (RSA). However, this region hosts another functionally connected single-nucleotide polymorphism (rs25531), which should also be genotyped in order to correctly categorize the low- and high-expressing alleles of 5-HTTLPR. The present study investigated resting RSA in an ethnically homogenous sample (N = 143) of participants genotyped for both the ins/del and rs25531 polymorphisms in 5-HTTLPR. In contrast with the biallelic genotypes, based only on the ins/del alleles, the triallelic 5-HTTLPR genotypes (i.e., including rs25531) showed no association with resting RSA. Taking a triallelic approach to 5-HTTLPR is thus necessary in order to avoid false positive results.

Post‐Treatment Outcomes in a Double‐Blind, Randomized Trial of Sertraline for Alcohol Dependence

Pharmacotherapy studies in alcohol dependence (AD) are generally of short duration and do not include post-treatment follow-up. We examined the durability of treatment effects in a placebo-controlled trial of sertraline for AD. As previously reported, patients received 12 weeks of treatment with sertraline (n = 63) or placebo (n = 71), followed by assessments at 3 and 6 months post-treatment (Kranzler et al., 2011, J Clin Psychopharmacol 31:22-30). We examined the main and interaction effects with time of 3 between-subject factors (medication group, age of onset of AD [late-onset alcoholics, LOAs, vs. early-onset alcoholics, EOAs], and the tri-allelic 5-HTTLPR genotype) on drinking days (DDs) and heavy drinking days (HDDs). The medication group effect, which was significant during treatment, remained significant during the 3-month follow-up period for L'/L' LOAs, with the sertraline group having fewer DDs than the placebo group (p = 0.027). However, the medication group effect seen in L'/L' EOAs during treatment was no longer significant (p = 0.48). There were no significant effects in S' carriers at the 3-month follow-up visit, or in either genotype group at the 6-month follow-up. The beneficial effects of sertraline observed in LOAs during treatment persisted during the 3-month post-treatment period. Additional studies are needed to validate these pharmacogenetic findings, which together with the effects seen during active treatment support the use of sertraline only in LOAs.

Social constraints, genetic vulnerability, and mental health following collective stress

A repeat-length polymorphism of the serotonin promoter gene (5-HTTLPR) has been associated with depression and posttraumatic stress disorder (PTSD) in trauma-exposed individuals reporting unsupportive social environments. We examine the contributions of the triallelic 5-HTTLPR genotype and social constraints to posttraumatic stress (PTS) symptoms in a national sample following the September 11, 2001 (9/11) terrorist attacks. Saliva was collected by mail from 711 respondents (European American subsample n = 463) of a large national probability sample of 2,729 adults. Respondents completed web-based assessments of pre-9/11 mental and physical health, acute stress 9 to 23 days post-9/11, PTS symptoms, and social constraints on disclosure regarding fears of future terrorist attacks 2-3 years post-9/11. Social constraints were positively associated with PTS symptoms 2-3 years post-9/11. The triallelic 5-HTTLPR genotype was not directly associated with PTS symptoms, but it interacted with social constraints to predict PTS symptoms 2-3 years post-9/11: Social constraints were more strongly associated with PTS symptoms for individuals with any s/lg allele than for homozygous la/la individuals. Constraints on disclosing fears about future terrorism moderate the 5-HTTLPR genotype-PTS symptom association even when indirectly exposed to collective stress.

Conditioned Pain Modulation Is Associated with Common Polymorphisms in the Serotonin Transporter Gene

BackgroundVariation in the serotonin transporter (5-HTT) gene (SLC6A4) has been shown to influence a wide range of affective processes. Low 5-HTT gene-expression has also been suggested to increase the risk of chronic pain. Conditioned pain modulation (CPM) - i.e. ‘pain inhibits pain’ - is impaired in chronic pain states and, reciprocally, aberrations of CPM may predict the development of chronic pain. Therefore we hypothesized that a common variation in the SLC6A4 is associated with inter-individual variation in CPM. Forty-five healthy subjects recruited on the basis of tri-allelic 5-HTTLPR genotype, with inferred high or low 5-HTT-expression, were included in a double-blind study. A submaximal-effort tourniquet test was used to provide a standardized degree of conditioning ischemic pain. Individualized noxious heat and pressure pain thresholds (PPTs) were used as subjective test-modalities and the nociceptive flexion reflex (NFR) was used to provide an objective neurophysiological window into spinal processing.ResultsThe low, as compared to the high, 5-HTT-expressing group exhibited significantly reduced CPM-mediated pain inhibition for PPTs (p = 0.02) and heat-pain (p = 0.02). The CPM-mediated inhibition of the NFR, gauged by increases in NFR-threshold, did not differ significantly between groups (p = 0.75). Inhibition of PPTs and heat-pain were correlated (Spearman’s rho = 0.35, p = 0.02), whereas the NFR-threshold increase was not significantly correlated with degree of inhibition of these subjectively reported modalities.ConclusionsOur results demonstrate the involvement of the tri-allelic 5-HTTLPR genotype in explaining clinically relevant inter-individual differences in pain perception and regulation. Our results also illustrate that shifts in NFR-thresholds do not necessarily correlate to the modulation of experienced pain. We discuss various possible mechanisms underlying these findings and suggest a role of regulation of 5-HT receptors along the neuraxis as a function of differential 5-HTT-expression.

Genetic moderation of CO2-induced fear by 5-HTTLPR genotype

Inhalation of an increased concentration of carbon dioxide (CO(2)) has been shown to induce a state of negative affect in healthy subjects that is closely related to the clinical phenomenon of panic. It has been suggested that the vulnerability to CO(2) is moderated by differences in serotonin (5-HT) activity, caused by a functional polymorphism in the promoter region of the 5-HT transporter (5-HTTLPR) gene. Our aim was to examine the relationship between bi- and tri-allelic 5-HTTLPR genotype and the affective response to different dosages of inhaled CO(2) in healthy volunteers. Ninety-six subjects performed a double inhalation of four mixtures containing, respectively, 0%, 9%, 17.5% and 35% CO(2), following a double-blind, cross-over, randomized design. Affective responses were measured with a visual analogue scale for fear and the Panic Symptom List. 5-HTTLPR genotype was expressed as LL, SL and SS. Subjects with the SL and SS genotype reported less fear than LL subjects. A significant interaction effect was found between genotype and CO(2) dosage: the SS genotype showed lower fear scores than the LL genotype, particularly in the 17.5% CO(2) dose condition. The present study suggests that the dose-dependent fear reaction to CO(2) is moderated by a polymorphism in the 5-HT transporter gene, particularly at intermediate CO(2) dosages. It also underscores the usefulness of the introduction of an intermediate phenotype related to panic to reveal an underlying genetic vulnerability otherwise staying elusive. These results are in line with current theories on the role of 5-HT in both panic and respiration.

Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults

Previous research examining gene-environment interaction (GxE) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate GxE between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This GxE replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for GxE was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.

Genetic Variation in the Serotonin Transporter Gene (5-HTTLPR, Rs25531) Influences the Analgesic Response to the Short Acting Opioid Remifentanil in Humans

BackgroundThere is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on μ-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders.ResultsAt baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression(LA/LA), p < 0.02. The analgesic effect for the three different genotype groups was linear to degree of 5-HTT expression.ConclusionThis is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.