Short Allele Research Articles

“Diminished” association between the serotonin transporter linked polymorphism (5HTTLPR) and body mass index in a large psychiatric sample

BackgroundThe role of the promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) in psychiatric illnesses has been studied extensively. Serotonergic function also regulates many central nervous system, including appetite and feeding behaviors. The 5HTTLPR short allele was found to be associated with increased body mass index and obesity risk among the general population. No data is available to support generalizability of such association among psychiatric population. MethodsWe examined the relationship between BMI and the 5HTTLPR genotype in a large sample of 1831 psychiatric patients at Mayo Clinic, Rochester, Minnesota, using a retrospective chart review. ResultsAverage BMI among groups with the short/short (28.29±7.27kg/m2), the short/long (28.07±6.45kg/m2) and the long/long (28.15±7.51kg/m2) genotypes of 5HTTLPR were not statistically different. This negative association persisted even with the sub-analysis of the Caucasians. However, we observed an increased rate of obesity among our psychiatric patient sample compared to the general population of Minnesota (36.6% versus 27.6%, p=0.0001 for males, 30.3% versus 24.4%, p=0.0001 for females). Also, sub-analysis showed female inpatients to have a significantly higher average BMI than outpatients (28.64±8.08kg/m2 versus 27.13±6.92kg/m2, p=0.026). This confirmed a significant association between mental health disorder and BMI. LimitationsRetrospective study design with limited control for potential confounders. ConclusionsIn this large sample of psychiatric patients we found no significant association between 5HTTLPR genotype and BMI, which is different from the case with general population reported in the literature.

Live long and prosper: “Germline stem cell maintenance revisited” (retrospective on DOI: 10.1002/bies.201000085)

In many animals there is an apparent trade-off between reproduction and lifespan. Reproductive capacity is often determined by germ line stem cell (GLSC) function. These cells undergo self-renewing divisions to give rise to a gametogenic daughter cell that differentiates into one or more gametes, and a stem cell daughter that remains in the stem cell niche. If GLSC aging is slow or their mitoses are biased towards self-renewing conditions, then theymay last longer and enable animals to undergo late-life reproduction, associated with increased longevity. In contrast, if GLSC aging is rapid or their divisions tend to produce gametogenic daughters, then they may limit animals with such cells to early-life reproduction and shortened lifespan. Kazmarczyk and Kopp recently suggested that variation in GLSC maintenance may mediate this trade-off. Their hypothesis predicts that allelic variation in GLSC genes in short-lived strains would show bias towards “short term alleles” driving high, early-life expression of GLSC maintenance genes; in long-lived strains, “long term alleles” driving high, late-life expression of stem cell maintenance genes would predominate [1]. However, female flies from a longlived lineage show little change over their lifespan in expression levels of genes associated with oogenesis and stem cell division: they do not downregulate these genes with age, in contrast to shorterlived control females [2]. Moreover, there was no clear overlap between the results of this next generation sequencing study and an independent microarray-based

Meta-analysis confirms a functional polymorphism (5-HTTLPR) in the serotonin transporter gene conferring risk of bipolar disorder in European populations

The serotonin transporter (5-HTT) is a candidate risk gene for bipolar disorder, and a functional polymorphism of 44-bp insertion/deletion (5-HTTLPR) located in the promoter region of this gene has been investigated for the association with the illness extensively among worldwide populations, but overall results were inconsistent and its role in the disorder remains unclear. The present study attempts to find its potential association with bipolar disorder using meta-analyzes that maximize the statistical power. We applied meta-analysis techniques by combining all available case–control studies of 5-HTTLPR and bipolar disorder in samples of European ancestry (with a total of 3778 cases and 4997 controls), and we assessed the evidence for allelic associations, heterogeneity among different studies, influence of each single study, and potential publication bias. The short allele (S allele) of 5-HTTLPR showed a significant association with bipolar disorder in our meta-analysis (odds ratio=1.10, p-value=0.005), suggesting it is likely a risk polymorphism for the illness, and the observed OR is consistent with other susceptibility loci identified through recent large-scale genetic association studies on bipolar disorder, which could be regarded simply as a small but detectable effects.

Personality Traits of Schizophrenic Patients in Remission and Their First-Degree Relatives: A Dopaminergic and Glutamatergic Gene Polymorphism Study

Objective: The dopaminergic and glutamatergic systems are of major interest in the etiology of schizophrenia and supposed endophenotypes such as personality traits. In the present study, we investigated the association between the catechol-O-methyltransferase (COMT) gene P2 promoter rs2075507, Val/ Met (rs4680), the dopamine transporter gene (DAT1) VNTR and the glutamate transporter gene (SLC1A2) promoter -181A/C polymorphisms, and personality traits as well as symptomatic features in schizophrenia.Methods: There were 112 healthy subjects, 51 schizophrenic patients in remission for at least six months and 45 first-degree relatives of the patients enrolled in the study. The samples were genotyped for the COMT P2 promoter rs2075507, Val/Met, DAT1 VNTR and SLC1A2 promoter -181A/C polymorphisms and assessed with the Temperament and Character Inventory (TCI). Schizophrenia patients were also evaluated using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression) and The Positive and Negative Symptom Scale.Results: Our findings demonstrate that schizophrenic patients, even after remission, had a different personality pattern from controls, showing higher scores in harm avoidance and self-transcendence and lower scores in novelty seeking, persistence, self-directedness and cooperativeness. First-degree relatives of patients also had profiles distinguishable from those of the patients only by intermediate levels of harm-avoidance and higher levels of cooperativeness. In the association of genotypes and personality, COMT Val/Met polymorphism was not associated with personality in patients or in healthy subjects. Another functional polymorphism in the COMT gene the P2 promoter rs2075507 G allele was associated with significantly higher novelty seeking scores in patients than was the A allele. DAT1 VNTR long alleles (10 or 11 repeats) were demonstrated to show a non-significant trend to association with higher self-transcendence scores than in those with the short alleles (3, 7, 8 or 9 repeats) in control samples and patients. In SLC1A2 promoter -181A/C polymorphism, the C allele was significantly associated with higher self-transcendence scores than in those with the A allele in healthy subjects. We did not find any associations between the psychotic symptom dimensions of patients and DAT1 VNTR, SLC1A2 promoter -181A/C and COMT Val/Met polymorphism; however, COMT P2 promoter rs2075507 polymorphism showed an association with the delusion and mania factor scores.Conclusions: Schizophrenia may be associated with different personality patterns from controls and some personality dimensions may be associated with the appearance of psychotic symptoms. The same genes may be responsible for the development of the disease, with personality patterns seen in at least one group of patients.

DRD4 and TH gene polymorphisms are associated with activity, impulsivity and inattention in Siberian Husky dogs

Both dopamine receptor D4 (DRD4) exon 3 and tyrosine hydroxylase (TH) intron 4 repeat polymorphisms have been linked to activity and impulsivity in German Shepherd dogs (GSDs). However, the results in GSDs may not be generalisable to other breeds, as allelic frequencies vary markedly among breeds. We selected the Siberian Husky for further study, because it is highly divergent from most dog breeds, including the GSD. The study sample consisted of 145 racing Siberian Huskies from Europe and North America. We found that this breed possesses seven DRD4 length variants, two to five more variants than found in other breeds. Among them was the longest known allele, previously described only in wolves. Short alleles of the DRD4 and TH repeat polymorphisms were associated with higher levels of activity, impulsivity and inattention. Siberian Huskies possessing at least one short allele of the DRD4 polymorphism displayed greater activity in a behavioural test battery than did those with two long alleles. However, the behavioural test was brief and may not have registered variation in behaviour across time and situations. Owners also completed the Dog-Attention Deficit Hyperactivity Disorder Rating Scale (Dog-ADHD RS), a more general measure of activity and attention. Siberian Huskies from Europe with two short alleles of the TH polymorphism received higher ratings of inattention on the Dog-ADHD RS than did those with the long allele. Investigation of the joint effect of DRD4 and TH showed that dogs possessing long alleles at both sites were scored as less active-impulsive than were others. Our results are aligned with previous studies showing that DRD4 and TH polymorphisms are associated with activity-impulsivity related traits in dogs. However, the prevalence of variants of these genes differs across breeds, and the functional role of specific variants is unclear.

Psychophysiological responses to pain identify reproducible human clusters

Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at 1year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P⩽0.01); greater sympathetic tone (P<0.05); and higher cortisol levels (P⩽0.001). During pain, less stimulus was tolerated (P⩽0.01), and there was an increase in parasympathetic tone (P⩽0.05). The 5-HTTLPR short allele was over-represented (P⩽0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P⩽0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies.

Human Fear Acquisition Deficits in Relation to Genetic Variants of the Corticotropin Releasing Hormone Receptor 1 and the Serotonin Transporter

The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS) was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886) and the serotonin transporter (5HTTLPR). These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886) showed no acquisition of fear conditioned responses (FPS) to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele) and 5HTTLPR (short allele) was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.

Relationship between EGFR Intron-1 CA SSR 1 polymorphism and skin rash in patients treated with cetuximab.

e22087 Background: EGFR inhibiting drugs do not work equally effectively in cancer patients. We were looking for potential genetic factors which could help to select patients who benefit from treatment with cetuximab. One of established clinical factors is skin rash, which correlate with clinical response to EGFR inhibitors. Our hypothesis was that rash intensity depends on genetic polymorphisms of gene encoding EGFR, especially on Intron-1 CA SSR 1 polymorphism. The number of CA repeats in Intron-1 may affect the level of preRNA synthesis. Methods: The prospective study included 62 patients (colon cancer, head and neck, non-small cell lung cancer and gastric cancer) who were treated with cetuximab together with chemotherapy. 4 weeks after the start of treatment with cetuximab, rash intensity was assessed according to NCI CTAEv.3.0. criteria. DNA for analysis was isolated from 5 ml of peripheral blood. Using the PCR reaction with specific primers (polymorphic DNA segment was amplified. The obtained DNA fragments were analysed by GenScan to determine their lengths. Results: Patients with 15-18 “CA” repetitions were classified as having a short allele “S”, while patients with 19-22 “CA” repetitions have been marked as having a long allele “L”. The relationship between the rash intensity and the CA-polymorphism was assessed (Table). The analysis showed that there is tendency to more intensive rash in patients with pair of “short” alleles (SS), than in patients with “short-long” (SL) and “long” (LL) allelles (p&lt;0,1 chi-square test). Conclusions: There is a relationship between the EGFR Intron-1 CA-polymorphism and the rash intensity in patients treated with cetuximab which warrants further prospective clinical investigation. [Table: see text]

No interaction between serotonin transporter gene (5-HTTLPR) polymorphism and adversity on depression among Japanese children and adolescents

BackgroundIdentification of gene × environment interactions (G × E) for depression is a crucial step in ascertaining the mechanisms underpinning the disorder. Earlier studies have indicated strong genetic influences and numerous environmental risk factors. In relation to childhood and adolescent depression, evidence is accumulating that the quality of the parental environment is associated with serotonin biology in children. We hypothesized that maternal depression is a crucial environmental risk factor associated with serotonin-regulating genes.MethodsThis study was designed to ascertain the G × E interaction for diagnosis of depression in a Japanese pediatric sample. DNA samples from 55 pediatric patients with depression and 58 healthy schoolchildren were genotyped for the 5-HTT (2 short (S) alleles at the 5-HTT locus) promoter serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We examined whether an adverse parental environment, operationalized as the mother’s history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict patients’ depression symptoms.ResultsBinary logistic regression analyses revealed that maternal depression (adversity), gender, and FSIQ significantly affect the diagnosis of depression among children and adolescents. However, no main effect was found for adversity or genotype. Results of multivariable logistic regression analyses using stepwise procedure have elicited some models with a good fit index, which also suggests no interaction between 5-HTTLPR and adversity on depression.ConclusionsTo assess G × E interaction, data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression. Despite an equivocal interaction effect, adversity and gender showed significant main effects.

The (TTTA) n polymorphism in intron 4 of CYP19 and the polycystic ovary syndrome risk in a Chinese population

Polycystic ovary syndrome (PCOS) is a heterogeneous disease with a strong genetic origin, but the specific determinants are still unknown. The aim of this study was to investigate the association between the (TTTA) n polymorphism in intron 4 of CYP19 and the PCOS risk in a Chinese population. We performed a case-control study which involved 222 PCOS patients and 281 controls. The fluorescent-labeled target DNA fragments containing the (TTTA)n short tandem repeats were obtained by PCR, thereafter genotyped via capillary electrophoresis. Representative alleles were directly sequenced to confirm their repeat numbers. Genotype analysis revealed seven different alleles including 7-3(∆)-, 7-, 8-, 10-, 11-, 12- and 13-TTTA-repeats. The most common allele in a Chinese population is (TTTA) 11 in our study (0.354 for PCOS and 0.390 for controls). PCOS patients showed a higher frequency of short alleles compared with controls (0.47 vs. 0.41, OR=1.245, 95% CI 0.97-1.60). The overall allelic distributions of this polymorphism did not show any significant differences between PCOS patients and the control group. No statistical differences were found in the clinical parameters or serum steroid hormone levels among PCOS patients with different genotypes. In conclusion, PCOS patients had a higher frequency of short alleles, albeit this might not strongly affect the risk of PCOS.

Abstract 507: Genetic Correlates of Cognitive Change in Patients Undergoing Carotid Interventions

OBJECTIVES Carotid interventions have been shown to decrease stroke risk and improve cerebral perfusion. However, nearly 40% of patients who undergo carotid revascularization procedures experience cognitive deterioration. We have demonstrated that subclinical microembolization is associated with memory decline, but whether genetic factors plays a role in post-procedural cognitive change is unclear. We herein seek to assess genetic determinants as potential risk factors for these procedures. METHODS Over one year period, patients undergoing carotid interventions at a single academic institution were recruited to participate. Patients underwent neuropsychological testing two weeks prior to and at one month following their procedure and MRI prior to and within 48 hours following their procedure. Saliva samples were collected for genetic testing and demographics were recorded. Logistic regressions were used to search for associations. RESULTS 34 patients were included (18 CAS, 16 CEA); all were male with a mean age of 68. The majority of patients exhibit hypertension (94%) and have a history of smoking (76%). Other co-morbidities included diabetes (47%), obesity (35%), and CAD (44%). Consistent with previous findings, CAS was associated with higher incidence of microemboli (p=.0005) and with susceptibility to memory decline (p=.0085). Negative univariate associations were found for 5-HTT (serotonin transporter) short alleles with memory decline (p=.016) and brain-derived neurotrophic factor (BDNF) polymorphism with incidence of microemboli (p=.018). After adjusting for apolipoprotein E (ApoE) risk alleles, incidence of microemboli trended with memory decline (p=.099). CONCLUSIONS Despite a small number of patients, our study showed that genetic polymorphisms such as 5-HTT, BDNF, and ApoE may provide additional insight on post-operative changes in cognition. Further investigation of these polymorphisms is warranted to understand and potentially prevent cognitive deterioration following carotid revascularization procedures.

Triple Therapy with Darbepoetin Alfa, Idebenone, and Riboflavin in Friedreich’s Ataxia: an Open-Label Trial

Minimal objective evidence exists regarding management of Friedreich's ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy-darbepoetin alfa, idebenone, and riboflavin-in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45years of age (average 28 ± 8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat ≥400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7 ± 8.3) on the scale for the assessment and rating of ataxia and 94.3 ± 27.2g/m(2) in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150μg darbepoetin alfa every 2 or 3weeks, 10-20mg/kg/day idebenone, and 10-15mg/kg/day riboflavin for 32 ± 19.4months (range of 8-56months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA.

Association of the CAG repeat polymorphisms in androgen receptor gene with polycystic ovary syndrome: A systemic review and meta-analysis

BackgroundMany studies have reported the associations of polymorphic CAG repeats in androgen receptor (AR) gene with PCOS risk, but with inconsistent results. So, the aim of present meta-analysis was to clarify such inconsistence, so as to provide more conclusive results. MethodsPubMed was searched for the eligible reports published until February 2012 without language limitation. The studies reporting the relationship between CAG repeat length and PCOS were selected for the meta-analysis according to the inclusion criteria. Two reviewers independently extracted the data and evaluated the study quality. Principal findingsAs for the relationship between CAG repeat length and PCOS risk, the pooled results showed that the biallelic mean was not significantly different between PCOS and controls (SMD −0.03, 95% CI −0.16–0.10, P=0.603), and that the ORs of PCOS were not demonstrated for the individuals with the biallelic mean less than median (OR 0.96, 95% CI 0.68–1.35, P=0.794), with the short CAG allele (OR 0.94, 95% CI 0.80–1.10, P=0.424), or with the X-weighted biallelic mean (OR 0.81, 95% CI 0.46–1.41, P=0.447). Further, as for the relationship between CAG repeat length and T levels in PCOS patients, the biallelic mean was not significantly different between PCOS patients with high T and those with low T (SMD 0.79, 95% CI −0.12–1.70, P=0.088), while the summary correlation r indicated that the CAG biallelic mean appeared to be positively associated with T levels in PCOS (r 0.20, 95% CI 0.11–0.30, p=0.000). ConclusionsThis meta-analysis demonstrates no evident association between the CAG length variations in AR gene and PCOS risk, while the CAG length appears to be positively associated with T levels in PCOS patients.

Predictors of 30-Day Readmission and Postdischarge Mortality Following Carotid Endarterectomy in the ACS-NSQIP

of smoking (76%). Other co-morbidities included diabetes (47%), obesity (35%), and CAD (44%). Consistent with previous findings, CAS was associated with higher incidence of microemboli (P 1⁄4 .0005) and with susceptibility to memory decline (P 1⁄4 .0085). Negative univariate associations were found for 5-HTT (serotonin transporter) short alleles with memory decline (P 1⁄4 .016) and brainderived neurotrophic factor (BDNF) polymorphism with incidence of microemboli (P 1⁄4 .018). After adjusting for ApoE risk alleles, incidence of microemboli trended with memory decline (P 1⁄4 .099). Conclusions: Despite a small number of patients, our study showed that genetic polymorphisms such as 5-HTT, BDNF, and ApoE may provide additional insight on postoperative changes in cognition. Further investigation of these polymorphisms is warranted to understand and potentially prevent cognitive deterioration following carotid revascularization procedures.

Symptom Status and Degree of Ipsilateral Stenosis Determine Whether Contralateral Stenosis Increases the Risk for Carotid Revascularization

of smoking (76%). Other co-morbidities included diabetes (47%), obesity (35%), and CAD (44%). Consistent with previous findings, CAS was associated with higher incidence of microemboli (P 1⁄4 .0005) and with susceptibility to memory decline (P 1⁄4 .0085). Negative univariate associations were found for 5-HTT (serotonin transporter) short alleles with memory decline (P 1⁄4 .016) and brainderived neurotrophic factor (BDNF) polymorphism with incidence of microemboli (P 1⁄4 .018). After adjusting for ApoE risk alleles, incidence of microemboli trended with memory decline (P 1⁄4 .099). Conclusions: Despite a small number of patients, our study showed that genetic polymorphisms such as 5-HTT, BDNF, and ApoE may provide additional insight on postoperative changes in cognition. Further investigation of these polymorphisms is warranted to understand and potentially prevent cognitive deterioration following carotid revascularization procedures.

Auditory event-related potentials (P3a, P3b) and genetic variants within the dopamine and serotonin system in healthy females

The late positive components of the human event-related brain potential comprise electrocortical reflections of stimulus-driven attentional capture (the anteriorly distributed P3a) and top–down control detection of relevant events (the posteriorly distributed P3b). As of yet, the neuropharmacologic and neurogenetic origin of the P3a and P3b is not fully understood.In this study, we address the contribution of dopaminergic and serotoninergic mechanisms. Sixty healthy females completed an active auditory novelty oddball paradigm while EEG was recorded. In all subjects, genetic polymorphisms within the dopamine system (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT val158met]) and the serotonin system (serotonin transporter [5HTTLPR]) were assessed.Across genotypes, novels (relative to standards) elicited a fronto-centrally distributed P3a, and targets (relative to standards) a parieto-centrally distributed P3b. Genotypes effects were observed for both P3a (COMT, 5HTTPLR) and P3b (DAT1, COMT, 5HTTLPR) only at prefrontal electrode location (Fz). Specifically, the frontal P3a was enhanced in COMT met/met homozygotes, but not in DAT1 9R. The target-related P3b was enhanced in COMT met/met and DAT1 9R relative to its genetic counterparts, but only at frontal electrodes. This ‘anteriorized’ enhancement may reflect either an additional frontal component in the target-related P3 dependent on dopamine, or a more subtle shift in the neural ensemble that generates the target-related P3. Results for 5HTTLPR short allele homozygotes mimicked those in COMT met/met homozygotes.In all, the present findings suggest involvement of frontal-cortical dopaminergic and serotoninergic mechanisms in bottom-up attentional capture (COMT val158met, 5HTTLPR), with an additional top–down component sensitive to striatal signals (DAT1).

War Zone Stress Interacts With the 5-HTTLPR Polymorphism to Predict the Development of Sustained Attention for Negative Emotion Stimuli in Soldiers Returning From Iraq

Biased attention toward negative stimuli is a known vulnerability for affective psychopathology. However, factors that contribute to the development of this cognitive bias are largely unknown. Variation within the serotonin transporter gene (i.e., 5-HTTLPR) is associated with increased susceptibility to environmental influence and biased processing of negative stimuli. Using a passive viewing eye-tracking paradigm, this study examined gaze fixation for emotion stimuli in 91 U.S. Army soldiers before and after deployment to Iraq. In addition, participants underwent genetic assay and provided in situ measures of war zone stress exposure. 5-HTTLPR short allele homozygotes were more likely than other genotype groups to develop a gaze bias toward negative stimuli as a function of increasing war zone stress, even when controlling for postdeployment posttraumatic stress disorder and depression severity. Short allele homozygotes appear especially sensitive to environmental influence, which likely contributes to the development of cognitive vulnerability to anxiety and mood disorders.

5-HTTLPR Polymorphism Modulates Neural Mechanisms of Negative Self-Reflection

Cognitive distortion in depression is characterized by enhanced negative thoughts about both environment and oneself. Carriers of a risk allele for depression, that is, the short (s) allele of the serotonin transporter promoter polymorphism (5-HTTLPR), exhibit amygdala hyperresponsiveness to negative environmental stimuli relative to homozygous long variant (l/l). However, the neural correlates of negative self-schema in s allele carriers remain unknown. Using functional MRI, we scanned individuals with s/s or l/l genotype of the 5-HTTLPR during reflection on their own personality traits or a friend's personality traits. We found that relative to l/l carriers, s/s carriers showed stronger distressed feelings and greater activity in the dorsal anterior cingulate (dACC)/dorsal medial prefrontal cortex (dmPFC) and the right anterior insula (AI) during negative self-reflection. The 5-HTTLPR effect on the distressed feelings was mediated by the AI/inferior frontal (IF) activity during negative self-reflection. The dACC/dmPFC activity explained 20% of the variation in harm-avoidance tendency in s/s but not l/l carriers. The genotype effects on distress and brain activity were not observed during reflection on a friend's negative traits. Our findings reveal that 5-HTTLPR polymorphism modulates distressed feelings and brain activities associated with negative self-schema and suggest a potential neurogenetic susceptibility mechanism for depression.

IL-1RN VNTR polymorphism as a susceptibility marker for nasopharyngeal carcinoma in Portugal

BackgroundNasopharyngeal carcinoma (NPC) is a rare malignancy in Western countries that is widely associated with the infection by Epstein–Barr virus (EBV). Several studies have showed that a common allele (allele 2) of the 86-bp variable number of tandem repeats (VNTR) polymorphism within intron 2 of the interleukin 1 receptor antagonist (IL-1RN) gene is associated with several disorders, including viral-associated cancers. MethodsWe have developed a hospital-based case–control study to characterise the role of the IL-1RN 86-bp VNTR polymorphism in the development of NPC with 112 patients with the disease and 433 healthy individuals from the northern region of Portugal. IL-1RN genotypes were combined according to the number of repeats: allele 2 (A2), the short allele that corresponds to two repeats, and L, the long allele that corresponds to three or more repeats. ResultsOur study revealed that 31.2% of NPC patients were IL-1RN A2*A2, compared with 9.7% observed in the control group. The statistical analysis revealed that IL-1RN*A2 homozygosity for the A2 allele was associated with a fourfold increased risk for NPC development (p<0.001). Additionally, cumulative hazard analysis revealed that estimated median age of onset of NPC is significantly (p<0.001) different for A2*A2 homozygous versus non-A2*A2 (57.0 vs. 74.0, respectively). ConclusionsThis is the first study to evaluate the role of the IL-1RN VNTR in NPC development in Portugal. Our study indicates IL-1RN*A2 homozygosity as a significant risk marker in our population and that it should be further investigated for the potential role in the definition of a susceptibility profile for NPC onset.

Response to citalopram is not associated with SLC6A4 genotype in African-Americans and Caucasians with major depression

AimsEthnic differences in genotype frequency provide a natural condition for assessing the contribution of gene variations to the causes and treatments of disease. Accordingly, the purpose of this study was to determine whether ethnic variations in allele frequencies of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene were related to the response to the treatment of depression. Main methodsAfrican–Americans (n=101) and Caucasians (n=100) with major depressive disorder were treated with the antidepressant citalopram (20–60mg/day) for 8weeks. Genotyping for the long (L) and short (s) alleles (LL, Ls, and ss) of the SLC6A4 gene was performed and the association between genotype and treatment response was assessed. Key findingsSubjects in both ethnic groups showed a significant reduction in depression scores over time (p<.0001). However, in spite of a significantly greater frequency of the L allele in African–Americans as compared to Caucasians, a comparable clinical response between the two groups was found with 5-HTTLPR polymorphism not significantly associated with clinical response in either ethnic group. SignificanceThe results are consistent with a previous finding and in accord with most of the results obtained in Caucasian subjects that SLC6A4 genotype is not related, at least by itself, to a response to treatment in either ethnic group to any clinically significant degree.