Working conditions,serotonin transporter gene polymorphism (5-HTTLPR) and anxiety disorders: A prospective cohort study

Background

The etiology and pathology of anxiety disorders involve both genetic and environmental influences. Adverse working conditions may contribute to the development of anxiety. The serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in stress sensitivity. Therefore, we investigated the potential interplay between 5-HTTLPR and job-related risk factors in the prediction of the occurrence of anxiety.

Methods

We conducted a prospective study using the first two waves of a Swedish population-based cohort. At Wave I, 1585 individuals without anxiety, depression or dysthymia who were active in the labor market during both waves were included. Information on job demands, skill discretion, decision authority and social climate was collected at Wave I. After a three year interval, the presence of anxiety disorders was determined at Wave II. All 1585 participants were genotyped for 5-HTTLPR. Both additive and multiplicative models were considered in examining the potential interaction between 5-HTTLPR and adverse working conditions on the development of anxiety.

Results

Anxiety was associated with high job demands but not with 5-HTTLPR. An interaction was observed between 5-HTTLPR and high job demands among females. Individuals with 5-HTTLPR high expression genotype (LL) developed anxiety disorders more frequently when exposed to high job demands compared to ‘LS/SS’ carriers.

Limitations

A limited number of participants developed anxiety.

Conclusions

High job demands predict the development of anxiety. The 5-HTT polymorphism has a moderating effect on the relationship between high job demands and anxiety among females.     

Polymorphism C in the serotonin transporter gene (SLC6A4) in questionable dementia and Alzheimer's disease

The promoter region of the serotonin transporter gene (SLC6A4) shows a 22-bp tandem repeat polymorphism, indicated as polymorphism C, that has been associated to depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding its association with Alzheimer's disease (AD). No data were reported regarding its association with questionable dementia (QD). In this study we investigate for polymorphism C in the SLC6A4 gene 302 elderly subjects with a clinical diagnosis of AD (n = 105), QD (n = 88) and no cognitive impairment (n = 114) attending a geriatric ward. A community-dwelling sample of 390 healthy subjects was also included in the analysis. A significant higher prevalence of the C16/C16 genotype in AD than in QD was observed (37.14% vs. 3%; p = 0.041, OR 2.001, 95%CI 1.018–4.024), while no differences in the C16/C14 and C14/C14 genotypes as well as in the estimated allele frequencies were found. No further differences among the three groups of subjects were found, also when they were compared with the community-dwelling sample. These findings suggest that SLC6A4 gene variation may have only a minor role, if any, in AD or QD.     

Psychological distress following marital separation interacts with a polymorphism in the serotonin transporter gene to predict cardiac vagal control in the laboratory

Marital separation is linked to negative mental and physical health; however, the strength of this link may vary across people. This study examined changes in respiratory sinus arrhythmia (RSA), used to assess cardiac vagal control, in recently separated adults (N = 79; M time since separation = 3.5 months). When reflecting on the separation, self‐reported psychological distress following the separation interacted with a polymorphism in the serotonin transporter gene (5‐HTTLPR) and a relevant single nucleotide polymorphism (SNP), rs25531, to predict RSA. Among people reporting emotional difficulties after the separation, those who were homozygous for the short allele had lower RSA levels while reflecting on their relationship than other genotypes. The findings, although limited by the relatively small sample size, are discussed in terms of how higher‐sensitivity genotypes may interact with psychological responses to stress to alter physiology.     

Novel allelic variants in the human serotonin transporter gene linked polymorphism (5-HTTLPR) among depressed patients with suicide attempt

A polymorphism in the serotonin transporter gene (5-HTTLPR) is being extensively studied for association with suicidal behavior. A new allelic variant within the 5-HTTLPR polymorphism was described but it has not been thoroughly analyzed in the recent literature. The SNP functional analysis demonstrated that the A variant of the L allele (L_A) produces high levels of mRNA and that the G variant (L_G) is equivalent to the S allele. Our aims were to compare the frequency of 5-HTTLPR alleles in 94 depressed patients who attempted suicide compared to 94 controls free of psychiatric disorder, including the embedded SNP rs25531. Using the biallelic classification, our sample contained 62 (33%) LL, 76 (40.4%) LS, and 50 (26.6%) SS individuals. Using the functional classification system, our sample contained 43 (22.5%) L’L’, 84 (44.7%) L'S’, and 61 (32.4%) S'S’ individuals, with no significant differences between cases and controls in genotypic tests in either biallelic (χ² = 2.543; df = 2; p = 0.280) and functional models (χ² = 2.995; df = 2; p = 0.228). The minor allele frequency (MAF) – the S allele – did not show any distributional difference between cases and controls using biallelic classification system 0.51 vs. 0.43, (OR = 1.41; CI95% 0.94 to 2.12; p = 0.121). Also the S’ allele of the functional classification system did not show any distributional difference between the two groups 0.59. vs. 0.51 (OR = 1.35; CI95% 0.90 to 2.03; p = 0.178). This study provided the possibility of a re-analysis of novell 5-HTTLPR functional variants identified within L allele that alters its mRNA production and thus changes its functionality. We could not find any association between both biallelic and functional 5-HTTLPR in depressed patients with suicide attempt, being the small sample size an important limitation for these results. In conclusion, we can suggest that despite the several studies in this issue, the exact effect and role of 5-HTTLPR in genetics of suicide is still unclear and should be better investigated for future studies.     

Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia in the Han Chinese population

Serotonin transmission has long been suspected as being involved in the pathogenesis of schizophrenia. 5-HTT is a promising candidate gene for schizophrenia due to its critical role in regulating serotonin transmission and role in the mechanism of the atypical antipsychotic drugs. A common polymorphism STin2 VNTR in the 5-HTT gene has been extensively investigated in the genetic association studies, but the results are conflicting. Meanwhile, the SNPs of the 5-HTT gene have been much less explored. We therefore conducted a case-control study of the association between STin2 VNTR and three tagging SNPs in 5-HTT and schizophrenia in the Han Chinese population based on a cohort of 329 schizophrenic patients and 288 control subjects. No association was found in the single locus, but haplotype-based analyses revealed significant association between two haplotypes with schizophrenia even after Bonferroni correction (P = 0.00000538 and 0.011).     

Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and personality traits in asymptomatic patients with panic disorder

The serotonin transporter promoter polymorphism (5-HTTLPR) has been investigated regarding its association with neuroticism, which, in its turn, is a personality dimension often found in patients with panic disorder (PD). It has been recently evidenced that the long 5-HTTLPR polymorphism has a genetic variation (Lg), which is related to its lower expression. The objective of this study was to assess the association between the 5-HTTLPR polymorphism in the triallelic system and the neurotic personality traits in patients in PD remission. Sixty-seven Caucasian patients with PD diagnosis according to the DSM-IV-TR assessed with the MINI (mini international neuropsychiatric interview) were included. The MMPI (Minnesota multiphasic personality inventory) was used to assess the personality. The remission of PD symptoms was defined as CGI (clinical global impression) 相似文献   

Inconsistent relationship between body weight/body mass index prior to total knee arthroplasty and the 12-year survival

BackgroundThe primary hypothesis was that body weight (BW) and body mass index (BMI) significantly impact the long-term survival rate after implantation of a mobile bearing total knee arthroplasty (TKA).MethodsA national, multicentric, retrospective study was performed in France. A total of 1604 TKAs were included. The 10-year follow-up was documented, and the influence of BW and BMI on the survival rate was assessed.ResultsThere was a significant influence of the BW on the 12-year survival rate for any reason and for infection; but this influence was not proportional to the BW or BMI. There was no significant influence of the BMI on the 12-year survival rate for any reason, for any mechanical reason or for infection.ConclusionOur results suggest that a higher BMI should not be considered as a risk factor for revision for mechanical purpose if a mobile bearing TKA with confirming design is implanted.     

Exclusion of linkage between schizophrenia and the gene encoding a neutral amino acid glutamate/aspartate transporter,SLC1A5

An abnormality in glutamatergic function has been hypothesized as being of etiological importance in schizophrenia. Twenty-three multiplex English and Icelandic schizophrenia families were genotyped with a polymorphic dinucleotide repeat sequence in the 3′-untranslated region of the glutamate/aspartate transporter gene called SLC1A5. Using the lod and a model-free method of linkage analysis (MFLINK), no evidence of linkage between SLC1A5 and schizophrenia was found. Our results do not support the hypothesis that SLC1A5 gene mutations or allelic variants provide a major gene contribution to the etiology of schizophrenia. However, because of the likelihood of heterogeneity of linkage in schizophrenia, there is a case for testing other pedigrees for linkage to the SLC1A5 locus. The SLC1A5 locus is one of a complex family of genes encoding neutral amino acid transporter proteins and the genetic relation between these other loci and schizophrenia has not yet been established. Am. J. Med. Genet. 74:50–52, 1997. © 1997 Wiley-Liss, Inc.     

Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits.

Anxiety-related personality traits, such as NEO neuroticism and TCI/TPQ harm avoidance, have been shown to have significant genetic components. To date, however, no specific genetic variants that contribute to these traits have been conclusively identified. At least 26 studies have investigated a putative association between a functional serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. The results of these studies have been inconsistent with some studies finding evidence for an association, and others not. We performed a meta-analysis of all applicable studies investigating this association. In the overall analysis (N = 5,629 subjects), we found suggestive evidence for an association between the 5-HTTLPR short allele (s) and increased anxiety-related personality trait scores (P = 0.087). However, we also found strong evidence for heterogeneity. This heterogeneity is largely explained by substantial variation between the studies in the inventory used. When the analysis was stratified by inventory type, there was a significant association between 5-HTTLPR and NEO neuroticism (P = 0.000016), a non-significant association between 5-HTTLPR and TCI/TPQ harm avoidance (P = 0.166), and no association between 5-HTTLPR and other anxiety-related personality traits (P = 0.944). There was no evidence that these results were either due to publication bias or accounted for by any one single study. We conclude that there is a strong association between the serotonin transporter promoter variant and neuroticism as measured in the NEO personality inventory and that non-replications are largely due to small sample size and the use of different inventories.     

Sex differences in the association between sleep duration, diet and body mass index: a birth cohort study

Sex differences in the effects of sleep duration on dietary intake and eating behaviours were examined prospectively in relation to overweight/obesity at ages 6 and 7. Using data from a representative sample (QLSCD 1998-2010) of children born in the province of Québec (Canada), 1106 children were followed to age 6 and 1015 to 7years. Average nocturnal sleep duration was surveyed annually from 2.5-6years, food-frequency and eating behaviour questionnaires were administered at age 6, and body weight and height were measured at 6 and 7years. Associations were examined longitudinally and mediation examined with adjustments for potential confounders. In boys and girls, shorter sleep duration patterns were associated significantly with less favourable dietary intakes at 6years: boys consumed vegetables and fruits less frequently and meats/alternatives more frequently than boys with longer sleep patterns; and girls consumed vegetables, fruits and milk products less frequently and soft-drinks more frequently than girls with longer sleep patterns. However, boys with shorter sleep patterns were also more likely to eat at irregular hours or to eat too much/fast at 6years. These behaviours, and not dietary intake, mediated an inverse association between sleep duration and overweight/obesity in boys. Sleep duration did not associate with any problem eating behaviours or overweight/obesity in girls. Shorter sleep in early childhood appears to associate with problematic eating behaviours in boys and diet quality in both sexes, regardless of an association with overweight/obesity. This is important for public health and should be considered in relation to other diet-related diseases.     

他莫昔芬诱发的脂肪肝病人肝/脾CT值与BMI及P3/P2的相关性

目的：探讨他莫昔芬诱发的脂肪肝病人的肝/脾CT值与体重指数（BMI）及孕三醇（P₃）/孕二醇（P₂）的相关性。方法：56名乳腺癌采用保守疗法的病人给予他莫昔芬前后每年测肝/脾CT值及终止服药后她们尿中孕三醇/孕二醇的水平。结果：（Fisher）精确测试结果显示体重指数>23.6 kg/sqm与肝/脾CT<0.9密切相关；孕三醇/孕二醇<1与肝/脾CT<0.9密切相关。结论：服用他莫昔芬的病人BMI超过23.6 kg/sqm及尿中孕三醇/孕二醇比值小于1是脂肪肝发展的危险信号。     

The novel p.Ser263Phe mutation in the human high‐affinity choline transporter 1 (CHT1/SLC5A7) causes a lethal form of fetal akinesia syndrome

A subset of a larger and heterogeneous class of disorders, the congenital myasthenic syndromes (CMS) are caused by pathogenic variants in genes encoding proteins that support the integrity and function of the neuromuscular junction (NMJ). A central component of the NMJ is the sodium‐dependent high‐affinity choline transporter 1 (CHT1), a solute carrier protein (gene symbol SLC5A7), responsible for the reuptake of choline into nerve termini has recently been implicated as one of several autosomal recessive causes of CMS. We report the identification and functional characterization of a novel pathogenic variant in SLC5A7, c.788C>T (p.Ser263Phe) in an El Salvadorian family with a lethal form of a congenital myasthenic syndrome characterized by fetal akinesia. This study expands the clinical phenotype and insight into a form of fetal akinesia related to CHT1 defects and proposes a genotype‐phenotype correlation for the lethal form of SLC5A7‐related disorder with potential implications for genetic counseling.     

The short (S) allele of the serotonin transporter polymorphism and acute tryptophan depletion both increase impulsivity in men

Reduced serotonergic neurotransmission is implicated in impulsive behavior. We studied the triallelic system of the serotonin transporter gene linked polymorphic region (5-HTTLPR) and acute manipulation of serotonin together to further delineate the mechanisms by which serotonergic neurotransmission affects impulsivity. Fifty-two healthy participants (38 men and 14 women) underwent acute tryptophan depletion (ATD) or placebo in a randomized, double-blind, parallel group experiment. Impulsive response style was measured on two versions of the Continuous Performance Task (CPT), and calculated using signal detection theory. We observed a dose-dependent effect for the short (S′) allele of the 5-HTTLPR on impulsive response style. Individuals who had the S′/S′ genotype were more impulsive than individuals with the L/S′ genotype. Participants with the L/S′ genotype were more impulsive than those with the L/L genotype. ATD increased impulsivity in men, and decreased impulsivity in women. These data demonstrate for the first time that reduced serotonergic tone as a result of either 5-HTTLPR genotype, or experimental ATD, are both independently and additively, associated with elevated impulsive response style in Caucasian men.     

No association between 5-HTTLPR and harm avoidance in Korean college students

There have been numerous studies on the association between 5-HTTLPR (polymorphisms in the promoter region of the serotonin transporter gene) and anxiety-related personality traits, with conflicting results. In this study, we administered Korean version of the Temperament and Character Inventory (K-TCI) to a sample of 158 Korean college students and genotyped for the 5-HTTLPR in order to compare the TCI dimensional scores including harm avoidance according to the 5-HTTLPR genotype and sex. We could not find the association between 5-HTTLPR and harm avoidance and other TCI measures. Considering known allele frequencies differences of 5-HTTLPR among different ethnic groups, further cross-cultural studies with a larger sample would be needed.     

Haplotype variation at the IBD5/SLC22A4 locus (5q31) in coeliac disease in the Irish population

In addition to the well-established association of coeliac disease (CD) with HLA-DQ (6p21) and possibly CTLA4 (2q33), there is considerable evidence for a susceptibility locus on chromosome 5q, which contains many potential candidates for inflammatory disease, including a cluster of cytokine genes in 5q31. CD cases and controls were genotyped for four single-nucleotide polymorphism (SNP) markers that together characterize >90% of the haplotype variation at the IBD5 locus encoding, among others, the SLC22A4 gene. IBD5 and SLC22A4 map to 5q31 and have recently been associated with Crohn's disease and rheumatoid arthritis. Haplotype frequencies do not differ significantly between CD cases and controls in the Irish population, and therefore the chromosome 5 CD susceptibility locus most likely lies elsewhere on 5q.     

No causal role for the G482T and G689T polymorphisms in translation regulation of serotonin transporter (SLC6A4) or association with attention-deficit-hyperactivity disorder (ADHD)

Purpose of the study: The G482T and G689T polymorphisms in the 3′-UTR of serotonin transporter (SLC6A4) are implicated in translational regulation and allelic variants may mediate susceptibility to attention-deficit-hyperactivity disorder (ADHD). Accordingly, we examined influence of allelic variation on stable secondary structure formation and on seed sequences necessary for microRNA-binding. Furthermore, 90 ADHD cases from India were genotyped for these markers and tested for association with ADHD. Methods: The Mfold software was used for secondary structure predictions and miRNA-binding sequences were obtained from the PicTar database. Using a family-based study design we assessed genetic association by means of the haplotype-based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) statistics. With respect to G689T, previously published TDT data were included in pooled analysis. Result: Secondary structure analysis reveals that G482, U482, G689 and U689 conformers are energetically similar. Unlike G482, the U482 change maps within a loop and this conformer differs in free energy by ∼4.4 kcal/mol. While G482T is proximal to various miRNA-binding sequences, it is not part of the seed sequence for any of them. Thus, G482T and G689T polymorphisms do not regulate SLC6A4 translation in cis. From the HHRR (χ² = 0.860, p = 0.353; R.R. = 1.11; 95% C.I. = 0.89–1.65 for G482T; χ² = 0.902, p = 0.342; R.R. = 1.17; 95% C.I. = 0.83–1.32 for G689T), TDT (χ² = 1.33, p = 0.25; O.R. = 1.35; 95% C.I. = 0.94–1.94 for G482T; χ² = 1.45, p = 0.23; O.R. = 1.44; 95% C.I. = 0.94–2.22 for G689T) and pooled TDT (χ² = 0.52, p = 0.47; O.R. = 1.05; 95% C.I. = 0.96–1.15) statistics we infer that these polymorphisms are not associated with risk of ADHD.     

The serotonin transporter gene polymorphism (5HTTLPR) moderates the effect of adolescent environmental conditions on self-esteem in young adulthood: a structural equation modeling approach

Here we examine the effects of both self-reported and independent observer-reported environmental risk indices, the serotonin transporter gene promoter (5HTTLPR) polymorphism, and their interaction on self-esteem. This trait was assessed during early and mid adolescence (mean age=14 and 16.5, respectively) and young adulthood (mean age=21.8) in a prospective cohort of 1214 unrelated participants in the Longitudinal Study of Adolescent Health (Add Health). Using structural equation modeling we identified a gene-environment (G×E) interaction using observer-report but not self-report measures of environmental stress exposure during adolescence: 5HTTLPR genotype and observer-reports of home and neighborhood quality (HNQ) during adolescence interacted to predict self-esteem levels in young adulthood (p<.004). Carriers of the s allele who lived in poor HNQ conditions during adolescence reported lower self-esteem in young adulthood than those with a good HNQ during adolescence. In contrast, among individuals with the l/l genotype, adolescent HNQ did not predict adulthood self-esteem. Genes may moderate the effect of adolescent environmental conditions on adulthood self-esteem.