Norepinephrine Transporter Gene Research Articles

MicroRNA Let-7e in the Mouse Prefrontal Cortex Differentiates Restraint-Stress-Resilient Genotypes from Susceptible Genotype.

Three strains of mice with various susceptibilities to restraint stress (RS), i.e., mice with a knocked out norepinephrine transporter gene (NET-KO), SWR/J and C57BL/6J (WT) mice were shown to serve as a good model to study the molecular mechanisms underlying different stress-coping strategies. We identified 14 miRNAs that were altered by RS in the PFC of these mice in a genotype-dependent manner, where the most interesting was let-7e. Further in silico analysis of its potential targets allowed us to identify five mRNAs (Bcl2l11, Foxo1, Pik3r1, Gab1 and Map2k4), and their level alterations were experimentally confirmed. A next-generation sequencing (NGS) approach, which was employed to find transcripts differentially expressed in the PFC of NET-KO and WT mice, showed that, among others, two additional mRNAs were regulated by mmu-let-7e, i.e., mRNAs that encode Kmt2d and Inf2. Since an increase in Bcl2l11 and Pik3r1 mRNAs upon RS in the PFC of WT mice resulted from the decrease in mmu-let-7e and mmu-miR-484 regulations, we postulated that MAPK, FoxO and PI3K-Akt signaling pathways were associated with stress resilience, although via different, genotype-dependent regulation of various mRNAs by let-7e and miR-484. However, a higher level of Kmt2d mRNA (regulated by let-7e) that was found with NGS analysis in the PFC of NET-KO mice indicated that histone methylation was also important for stress resilience.

Association between genetic variants of the norepinephrine transporter gene (SLC6A2) and bipolar I disorder

We aimed to investigate the associations between genetic variants of the norepinephrine transporter gene (NET, also known as SLC6A2) and diagnosis of bipolar I disorder. In addition, we examined the relationship between the genetic variants and manic and psychotic symptoms in patients with bipolar I disorder. The three SNPs rs28386840, rs2242446, and rs5569 were genotyped in 326 patients: patients with bipolar I disorder (n = 160) and a control group (n = 166). Subsequently, multivariate logistic regression analysis adjusting for age and sex was conducted to identify independent influences of the SNPs on diagnosis of bipolar I disorder. A possible association between manic and psychotic symptoms and variants of SLC6A2 was also investigated in patients with bipolar I disorder. The rs28836840 SNP in the 5’-UTR of SLC6A2 was significantly associated with bipolar I disorder and with severity of manic and psychotic symptoms in this disorder. Individuals carrying a T allele in the rs28836840 SNP were likely to have a lower risk of bipolar I disorder or lower severity of manic and psychotic symptoms in patients with bipolar I disorder (bipolar I disorder diagnosis: OR = 0.643, 95% Cl = 0.468–0.883, p = 0.006; manic symptoms: β = −2.457, 95% Cl = −4.674 ~ −0.239, p = 0.031; psychotic symptoms: β = −2.501, 95% Cl = −4.700 ~ −0.301, p = 0.027). For the rs2242446 and rs5569 SNPs, there were no significant differences between patients with bipolar I disorder and those without. Our results revealed associations of the rs28386840 SNP with bipolar I disorder diagnosis and with severity of manic and psychotic symptoms. However, the findings reported here require replication in larger samples and various ethnic groups.

The T-182C Polymorphism Enhances Promoter Activity of the Norepinephrine Transporter Gene, but may not be Associated with Antidepressant Response.

Background: Previous evidence has suggested that norepinephrine transporter (NET) gene (solute carrier family 6, member 2 [SLC6A2]) polymorphisms are involved in antidepressant response. Specifically, the polymorphism T-182C (rs2242446) located in the promoter region of SLC6A2 has been found to be associated with antidepressant response in multiple ethnic backgrounds. However, the results are inconsistent. Moreover, few studies have focused on how this T-182C polymorphism might regulate SLC6A2 promoter function. Methods: In this study, luciferase reporter assays were performed to examine the functional significance of the T-182C polymorphism. In addition, we performed a meta-analysis to explore whether this genetic variant is significantly involved in the antidepressant response. Results: We found that the -182(T) allele significantly increased promoter function compared to the C allele based on luciferase reporter assays. For the meta-analysis, six articles were identified that explored the relationship between the NET T-182C polymorphisms and antidepressant response. This study revealed no significant association between these polymorphisms and response to antidepressants (OR = 1.23, 95% CI = 0.77 - 1.97, p = 0.38 for T-182C). Conclusions: The T-182C polymorphism enhances promoter activity, but may not be associated with antidepressant response.

Age-dependent association of polymorphisms in the promoter and 5′-untranslated region of the norepinephrine transporter gene with generalized anxiety disorder

BackgroundNorepinephrine transporter (NET), which regulates synaptic norepinephrine for noradrenergic signaling, is involved in the pathogenesis of anxiety, while expression of the NET gene differs at different ages. Here, we examine whether genetic variants in the NET gene are associated, in an age-specific manner, with increased risk of generalized anxiety disorder (GAD), one of the most disabling anxiety disorders. MethodsThree common single-nucleotide polymorphisms (SNPs) in the promoter (rs168924: A/G; rs2242446: T/C) and 5′-untranslated region (5′-UTR) (rs2397771: G/C) of the NET gene were genotyped in 2,317 Han-Chinese participants (791 GAD patients and 1,526 controls; age: 20–65). Potential confounding factors, such as gender, stress levels and psychiatric comorbidities, were included as covariates. ResultsAn interaction between age and NET genotypes and haplotypes was found for the risk of GAD. In the younger participants, rs168924 minor allele G homozygotes had the lowest incidence of GAD; however, older subjects displayed an inverse pattern, with homozygous G/G carriers presenting the highest prevalence of GAD. Additionally, younger individuals carrying 2 copies of the GGT haplotype composed of rs2397771-rs168924-rs2242446 had the lowest rate of GAD. However, those with 2 copies of the same haplotype exhibited the highest risk of GAD in the older groups. LimitationsOnly 3 common SNPs in the promoter and 5′-UTR of the NET gene were analyzed. ConclusionsOur findings are the first to demonstrate that potentially functional SNPs in the NET promoter and 5′-UTR are associated with an increased risk of GAD, and that such associations are determined in an age-specific way.

The norepinephrine transporter gene modulates intrinsic brain activity, visual memory, and visual attention in children with attention-deficit/hyperactivity disorder.

The norepinephrine transporter gene (SLC6A2) and deficits in visual memory and attention were associated with attention-deficit/hyperactivity disorder (ADHD). The present study aimed to examine whether the SLC6A2 rs36011 (T)/rs1566652 (G) haplotype affected the intrinsic brain activity in children with ADHD and whether these gene-brain modulations were associated with visual memory and attention in this population. A total of 96 drug-naive children with ADHD and 114 typically developing children (TDC) were recruited. We analyzed intrinsic brain activity with regional homogeneity (ReHo) and degree centrality (DC). Visual memory and visual attention were assessed by the delayed matching to sample (DMS) and rapid visual information processing (RVIP) tasks, respectively. The SNP genotyping of rs36011 and rs1566652 was performed. Children with ADHD showed lower ReHo and DC in the cuneus and lingual gyri than TDC. The TG haplotype was associated with significantly increased DC in the right precentral and postcentral gyri. Significant interactions of ADHD status and the TG haplotype were found in the right postcentral gyrus and superior parietal lobule for ReHo. For the ADHD-TG group, we found significant correlations of performance on the DMS and RVIP tasks with ReHo in bilateral precentral-postcentral gyri and the right postcentral gyrus-superior parietal lobule and DC in bilateral precentral-postcentral gyri. A novel gene-brain-behavior association was identified in which the intrinsic brain activity of the sensorimotor and dorsal attention networks was related to visual memory and visual attention in ADHD children with the SLC6A2 rs36011 (T)/rs1566652 (G) haplotype.

Altered expression of norepinephrine transporter participate in hypertension and depression through regulated TNF-α and IL-6

ABSTRACTAim: We explored the role of histone modification in the association of depression-hypertension by comparing norepinephrine transporter (NET) gene levels in different depression-hypertensive patients. Then, we analyzed the expression of NET correlation with inflammatory cytokines to provide a new direction for detecting the association mechanism between depression and hypertension.Methods: NE expression levels in serum of diverse groups were detected by enzyme-linked immunosorbent assay. Then histone acetyltransferase (HAT), histone deacetylase (HDAC), H3K27ac, NET, TNF-α, and interleukin-6 (IL-6) were detected by western blot in nine female subjects in different depression and hypertension groups, and Chromatin immunoprecipitation-polymerase chain reaction (Chip-PCR) were used to confirm the degree of acetylation affecting on the transcription level of NET gene. Meanwhile, correlation between NET with TNF/IL-6 was analyzed by SPSS19.0 software program. Finally, Quantitative real-time polymerase chain reaction (qPCR) and western blot were used to detect TNF-α and IL-6 expression levels after NET overexpression or interference treatment in human umbilical vein endothelial cells and Neuro-2a cells.Results: The expression of HAT and H3K27ac had lower levels in D-H and nonD-H group than nonD-nonH group. The results showed that higher acetylation could promote expression of NET genes. Meanwhile, the expression of NET had a significant negative correlation with IL-6 (R = −0.933, p < 0.01) and tumor necrosis factor (TNF) (R = −0.817, p < 0.01) in subjects. In addition, the results confirmed that TNF-α and IL-6 mRNA and protein partial expressions could be inhibited by NET in both HUVECs and Neuronal cells (p < 0.01).Conclusion: In conclusion, differential expression of NET gene might function as an important factor in interaction between depression and hypertension by partially targeting TNF-α and IL-6.

Differential Genetic Effect of the Norepinephrine Transporter Promoter Polymorphisms on Attention Problems in Clinical and Non-clinical Samples.

Among the monoaminergic modulatory neurotransmitters, norepinephrine is involved in task orienting, hence noradrenergic genetic variants have been studied in connection to attentional processes. The role of this catecholamine system is also highlighted by the selective norepinephrine transporter blocking atomoxetine, which has proved to be effective in the pharmacological treatment of Attention Deficit Hyperactivity Disorder (ADHD). In the present genetic association study three single nucleotide polymorphisms (rs28386840, rs2242446, rs3785143 SNPs) were analyzed from the 5′ region of the norepinephrine transporter (NET, SLC6A2) gene, which have been linked to ADHD previously. Attention problems scores of the mother-rated Child Behavior Checklist (CBCL) were used in separate analyses of 88 preschoolers (59.1% male, 6 years of age) recruited from the general population and 120 child psychiatry patients with ADHD diagnosis (85.8% male, age: 9.8 ± 2.9). The NET SNPs showed associations with attention problems, but the direction was different in the two groups. Regarding the promoter variant rs28386840, which showed the most consistent association, the T-allele-carrier patients with ADHD had lower CBCL attention problems scores compared to patients with AA genotype (p = 0.023), whereas T-allele-carriers in the community sample had more attention problems (p = 0.042). Based on previous reports of lower NE levels in ADHD children and the inverted-U shape effect of NE on cognitive functions, we propose that rs28386840 (-3081) T-allele, which is associated with lower NET expression (and potentially higher synaptic NE level) would support attention processes among ADHD patients (similarly as atomoxetine increases NE levels), whereas it would hinder cortical functions in healthy children.

M3 - GENE-GENE INTERACTION BETWEEN COMT AND NET IN MODULATING ADHD BEHAVIORS

Background Cortico-subcortical circuit dysfunction plays an important role in the manifestation of ADHD symptoms. Dopamine (DA) and Norepinephrine (NE) are major players in the fine regulation of these circuits. Both of these neurotransmitters are major players in maintaining alertness, increasing focus, sustaining thoughts, and facilitating many cognitive functions. Thus, perturbation of either NE, DA (or both) signaling could be implicated in the pathogenesis of ADHD. Hypothesis: Given the dynamic nature of the brain neuromodulation, where any action on one system may reverberate in the other systems, we hypothesize that NE transporter gene could interact with a gene that is essential for the metabolism of DA (COMT Val108/158Met) on modulating ADHD behaviors. Methods 481 children with ADHD (9–12 years old) were included in a 2-week double blind placebo controlled study with methylphenidate. Teachers and parents were asked to evaluate the child's behavior at baseline, placebo, and MPH weeks. Repeated measure ANOVA with between-subject factor of both genes and within-subject factor of experimental conditions (EC) was used. Results A highly significant 3-way interaction (NET⁎COMT⁎EC) was revealed in three SNPs of the NET gene (rs41154 p= 0.002, rs187714 p= 0.001, and rs2242447 p= 0.006) according to the parents’ evaluation. By stratifying the children according to their COMT genotypes, we observe that all children behave in a similar fashion at baseline but respond differently to placebo and MPH. In the Met/Met and Val/Val genotype groups, children who are carrying the AG genotype of rs41154, CT genotype of rs41154, and CT genotype of rs41154 tend to respond poorly compared to patients with the GG, CC, and CT genotypes respectively on placebo and MPH. Discussion Taken together, the current results suggest the epistatic interaction between COMT and NET genetic polymorphisms on response to pharmacological probes. Suggesting that complex gene-by-gene interactions may be important.

Features of the structure, development, and activity of the zebrafish noradrenergic system explored in new CRISPR transgenic lines.

The noradrenergic (NA) system of vertebrates is implicated in learning, memory, arousal, and neuroinflammatory responses, but is difficult to access experimentally. Small and optically transparent, larval zebrafish offer the prospect of exploration of NA structure and function in an intact animal. We made multiple transgenic zebrafish lines using the CRISPR/Cas9 system to insert fluorescent reporters upstream of slc6a2, the norepinephrine transporter gene. These lines faithfully express reporters in NA cell populations, including the locus coeruleus (LC), which contains only about 14 total neurons. We used the lines in combination with two-photon microscopy to explore the structure and projections of the NA system in the context of the columnar organization of cell types in the zebrafish hindbrain. We found robust alignment of NA projections with glutamatergic neurotransmitter stripes in some hindbrain segments, suggesting orderly relations to neuronal cell types early in life. We also quantified neurite density in the rostral spinal cord in individual larvae with as much as 100% difference in the number of LC neurons, and found no correlation between neuronal number in the LC and projection density in the rostral spinal cord. Finally, using light sheet microscopy, we performed bilateral calcium imaging of the entire LC. We found that large-amplitude calcium responses were evident in all LC neurons and showed bilateral synchrony, whereas small-amplitude events were more likely to show interhemispheric asynchrony, supporting the potential for targeted LC neuromodulation. Our observations and new transgenic lines set the stage for a deeper understanding of the NA system.

Meta-analysis on the Association Between Norepinephrine Transporter Gene rs2242446, rs5569 Polymorphisms and Risk of Major Depressive Disorder

The association between norepinephrine transporter (NET) gene polymorphisms and the risk of major depressive disorder (MDD) has been investigated extensively, but with contradictory findings. To clarify such contradiction, a comprehensive meta-analysis was conducted by searching PubMed, EMBASE, Web of Science and China Knowledge Resource Integrated Database. Odd ratios (ORs) and 95% confidence intervals (Cis) were used to evaluate the strength of the association. Totally 23 case-control studies regarding rs2242446 and rs5569 polymorphisms were included. Overall analysis and subgroup analysis indicated no significant association between NET gene rs2242446 polymorphism and MDD risk. However, recessive and homozygous models revealed a significant association between NET rs5569 polymorphism and increased risk of MDD. The stratified analysis further indicated significant associations in Asians, hospital-based studies and studies with other genotyping methods. In conclusion, NET gene rs5569 polymorphism could increase the risk of MDD, especially among Asians.

Association between T-182C, G1287A polymorphism in NET gene and suicidality in major depressive disorder in Chinese patients

Objective: Previous studies have implicated norepinephrine transporter gene (NET) polymorphisms in the etiology of major depressive disorder (MDD). A functional NET T-182C polymorphism (rs2242446) in the promoter region and a synonymous polymorphisms G1287A in the exon 9 (rs5569) were associated with MDD in different populations. However, few studies have focused on the relationship between these polymorphisms and MDD patients with suicidality. The objective of the present study was to examine whether the two polymorphisms are associated with MDD patients with suicidality in the Han Chinese population.Methods: Two hundred and sixty-three suicidal depressed patients and 241 non-suicidal depressed patients who met DSM-IV criteria for MDD were recruited from our hospital. Three hundred and three unrelated, age- and sex-matched healthy control subjects participated in this case-control study. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton rating scale for depression (HAMD). Genotypes of T-182C polymorphism (rs2242446) and G1287A (rs5569) were screened by polymerase chain reaction.Results: No statistical significant differences between patients and controls were found for any of the analysed polymorphisms, either in the genotype or allele distribution.Conclusions: Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of MDD with suicidality. However, the results must be verified in larger samples and different ethnicities.

T62. A Haplotype of the Norepinephrine Transporter Gene Modulates White Matter Integrity in Children With Attention-Deficit/Hyperactivity Disorder

The norepinephrine transporter gene (SLC6A2) and movement time deficits have been consistently reported to be associated with attention-deficit hyperactivity disorder (ADHD). This study aimed to examine whether the SLC6A2 rs36011 (T)/rs1566652 (G) haplotype affected white matter (WM) structural property in children with ADHD and whether those alterations were associated with movement time deficits.

Association study between T-182C and G1287A polymorphisms in norepinephrine transporter gene and schizophrenia

Objective To explore whether the norepinephrine transporter(NET) gene T-182C and G1287A polymorphisms are involved in the etiology of schizophrenics among the Chinese Han population. Methods 249 schizophrenics(case group) and 309 healthy physical examiners(control group) of the Chinese Han population were collected.Ligase detection reaction was used to detect the genotype distributions and allele frequencies of NET rs2242446 and rs5569 polymorphisms in the two groups.The genotype distributions and allele frequencies of these two single nucleotide polymorphisms(SNPs) were also compared in the case and control groups. Results In the case group, the TT genotype of the NET gene loci rs2242446 was the most, 48.6%, and the CC genotype of which was the least, 8.4%.In the control group, the CT genotype was the most, 47.9%, and the CC genotype was the least, 11.3%, the minimum allele frequency was 29.9%.In the case group, the GG genotype of the NET gene loci rs5569 was the most, 46.2%, and the CC genotype was the least, 9.6%.In the control group, GG genotype was the most, 51.5%, and the AA genotype was the least, 10.3%, and the minimum allele frequency was 29.4%.No significant differences in the genotype and allele distribution of NET rs2242446 and rs5569 were found in Chinese-Han patients with schizophrenia and control participants(all P>0.05). In gender-specific analyses, similarly, no significant differences were found for rs2242446 and rs5569 genotype and allele distributions in either the male or the female case-control comparisons(all P>0.05). Conclusion The NET rs2242446 and rs5569 polymorphisms are not associated with schizophrenia in Chinese Han population. Key words: Norepinephrine transporter gene; Single nucleotide polymorphism; Schizophrenia

Association analysis of norepinephrine transporter polymorphisms and methylphenidate response in ADHD patients

AimsMethylphenidate (MPH) is the most frequently prescribed drug in Attention Deficit Hyperactivity Disorder (ADHD). Hitherto mostly the dopamine transporter gene has been studied in MPH-response and only a few studies analyzed the norepinephrine transporter (NET, SLC6A2) gene, although MPH is a potent inhibitor of both dopamine and norepinephrine transporters. We aimed to analyze this monoamine transporter gene in relation to ADHD per se and MPH-response in particular to gain further knowledge in ADHD pharmacogenetics using a Caucasian sample. MethodsSix single nucleotide polymorphisms (rs28386840, rs2242446, rs3785143, rs3785157, rs5569, rs7194256 SNP) were studied across the NET gene in 163 ADHD children (age: 9.3±2.6; 86.5% male) using ADHD-RS hyperactivity-impulsivity and inattention scales. For case-control analysis 486 control subjects were also genotyped. At the MPH-response analysis responders had minimum 25% decrease of ADHD-RS total score after 2months of treatment, and chi-square test compared 90 responders and 32 non-responders, whereas ANOVA was used to assess symptom improvement after the first month among the 122 ADHD patients. ResultsThe classical case-control analysis did not yield any association with ADHD diagnosis, which was supported by meta-analysis conducted on the available genetic data (combining previously published and the present studies). On the other hand, the intronic rs3785143 showed nominal association with inattention symptoms (p=0.01). The haplotype analysis supported this association, and indicated the importance of the first haploblock encompassing the intronic and 2 promoter SNPs. With MPH-response only the promoter rs28386840 showed nominal association: Those with at least one T-allele were overrepresented in the responder group (42% vs 19%, p=0.08), and they had better improvement on the hyperactivity-impulsivity scale compared to the AA genotype (p=0.04). ConclusionAlthough none of our single SNP findings remained significant after correcting for multiple testing, our results from the MPH-response analysis indicate the potential importance of promoter variants in the NET gene.

Genetic Association of the Norepinephrine Transporter Gene G1287A Polymorphism with Risk of Schizophrenia: A Case-Control Study and Meta-Analysis.

The G1287A polymorphism (rs5569) in exon 9 of the norepinephrine transporter (NET) gene has been associated with schizophrenia in several populations. However, the results are conflicting. Moreover, few studies have investigated the relationship between the G1287A polymorphism and schizophrenia among the Chinese Han population. A case-control study was designed to explore whether the G1287A genetic variant is related to schizophrenia in the Chinese Han population. The results from this study were then included in the performance of a meta-analysis to further analyze the association of the G1287A polymorphism with schizophrenia. No significant differences in the genotype and allele distributions of G1287A were found between Chinese Han patients with schizophrenia and control participants. Similarly, in gender-specific analyses, no significant differences were found for G1287A genotype and allele distributions in either the male or the female case-control comparisons. Finally, the results of this meta-analysis also showed that the NET gene G1287A polymorphism was not associated with schizophrenia in the total population under allelic, recessive, dominant, or homozygous genetic models. Our case-control study and meta-analysis suggest that the NET gene G1287A polymorphism may not be involved in the etiology of schizophrenia in the Chinese Han population.

No major role of norepinephrine transporter gene variations in the cardiostimulant effects of MDMA

PurposeMethylenedioxymethamphetamine (MDMA, ecstasy) is used recreationally and frequently leads to sympathomimetic toxicity. MDMA produces cardiovascular and subjective stimulant effects that were shown to partially depend on the norepinephrine transporter (NET)-mediated release of norepinephrine and stimulation of α1-adrenergic receptors. Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the NET gene (SLC6A2) may explain interindividual differences in the acute stimulant-type responses to MDMA in humans.MethodsWe characterized the effects of common genetic variants of the SLC6A2 gene (rs168924, rs47958, rs1861647, rs2242446, and rs36029) on cardiovascular and subjective stimulation after MDMA administration in 124 healthy subjects in a pooled analysis of eight double-blind, placebo-controlled studies.ResultsCarriers of the GG genotype of the SLC6A2 rs1861647 SNP presented higher elevations of heart rate and rate-pressure product after MDMA than subjects with one or no G alleles. Subjects with a C allele in the SLC6A2 rs2242446 SNP presented higher elevations of the heart rate after MDMA administration compared with the TT genotype. Subjects with the AA genotype of the SLC6A2 rs36029 SNP presented higher elevations of mean arterial pressure and rate pressure product after MDMA administration than carriers of the G allele. The SLC6A2 rs168924 and rs47958 SNPs did not alter the response to MDMA.ConclusionsGenetic polymorphisms of the SLC6A2 gene weakly moderated the acute cardiovascular response to MDMA in controlled studies and may play a minor role in adverse cardiovascular events when MDMA is used recreationally.

Gene variant associated with response to venlafaxine in elderly

Results of a new study add to evidence that variants of the norepinephrine transporter (NET) gene can be used to predict response to treatment with venlafaxine for depression in older adults. The study, involving 350 adults ages 60 and over, found that the NET variant rs2242446/T‐182C was significantly associated with remission in older patients.

DNA methylation in the norepinephrine transporter gene promoter region is not associated with depression and hypertension

ABSTRACTObjective: This study aims to detect the role of DNA methylation in norepinephrine transporter (NET) gene promoter region on the association between depression and hypertension. Methods: A total of 162 subjects were categorized into four groups based on depression scores and blood pressure. DNA was extracted from peripheral white blood cells and methylation levels of nine CpG sites in NET gene promoter region were investigated by pyrosequencing. Results: For each CpG site and the average value of nine CpG sites, there were no significant differences in DNA methylation of the NET gene promoter between healthy controls and patients with depression or hypertension. And there were no significant differences among groups after adjusting for age and body mass index. However, DNA methylation levels of the CpG sites adjacent to transcription start site tended to be low. In addition, CpG1.2–CpG5.2 were highly correlated with CpG4 as the first principle component, while CpG2 and the part of CpG1 and 3 were the second principle components. The total participants were clustered into three subgroups by hierarchical cluster analysis of methylated levels. Conclusion: Our study indicates that DNA methylation levels of nine CpG sites in NET gene promoter region are not associated with depression and hypertension.

Factors Influencing the Cardiovascular Response to Subanesthetic Ketamine: A Randomized, Placebo-Controlled Trial.

BackgroundThe increasing use of ketamine as a potential rapid-onset antidepressant necessitates a better understanding of its effects on blood pressure and heart rate, well-known side effects at higher doses. For the subanesthetic dose used for depression, potential predictors of these cardiovascular effects are important factors influencing clinical decisions. Since ketamine influences the sympathetic nervous system, we investigated the impact of autonomic nervous system-related factors on the cardiovascular response: a genetic polymorphism in the norepinephrine transporter and gender effects.MethodsBlood pressure and heart rate were monitored during and following administration of a subanesthetic dose of ketamine or placebo in 68 healthy participants (mean age 26.04 ±5.562 years) in a double-blind, randomized, controlled, parallel-design trial. The influences of baseline blood pressure/heart rate, gender, and of a polymorphism in the norepinephrine transporter gene (NET SLC6A2, rs28386840 [A-3081T]) on blood pressure and heart rate changes were investigated. To quantify changes in blood pressure and heart rate, we calculated the maximum change from baseline (ΔMAX) and the time until maximum change (TΔMAX).ResultsSystolic and diastolic blood pressure as well as heart rate increased significantly upon ketamine administration, but without reaching hypertensive levels. During administration, the systolic blood pressure at baseline (TP0Sys) correlated negatively with the time to achieve maximal systolic blood pressure (TΔMAXSys, P<.001). Furthermore, women showed higher maximal diastolic blood pressure change (ΔMAXDia, P<.001) and reached this peak earlier than men (TΔMAXDia, P=.017) at administration. NET rs28386840 [T] carriers reached their maximal systolic blood pressure during ketamine administration significantly earlier than [A] homozygous (TΔMAXSys, P=.030). In a combined regression model, both genetic polymorphism and TP0Sys were significant predictors of TΔMAXSys (P<.0005).ConclusionsSubanesthetic ketamine increased both blood pressure and heart rate without causing hypertensive events. Furthermore, we identified gender and NET rs28386840 genotype as factors that predict increased cardiovascular sequelae of ketamine administration in our young, healthy study population providing a potential basis for establishing monitoring guidelines.

P.3.027 - Norepinephrine transporter gene and protein expression of the human brain investigated with postmortem data and PET

IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP).IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined.IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs.These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression.