Polymorphism Rs4680 Research Articles

A Polymorphism in the BDNF Gene (rs11030101) is Associated With Negative Symptoms in Chinese Han Patients With Schizophrenia.

Objective: This study aimed to investigate the association between brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate response element binding protein (CREB) gene polymorphisms and schizophrenia. Methods: This study used a case-control design, and diagnoses were made based on the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria. One hundred and thirty-four patients with schizophrenia were recruited from the Third People’s Hospital of Zhongshan City from January 2018 to April 2020. Sixty-four healthy controls were recruited from the same region. Genotypes at the BDNF gene single nucleotide polymorphisms rs11030101, rs2030324, and rs6265 and the CREB gene single nucleotide polymorphisms rs6740584 and rs2551640 were determined using a MassARRAY mass spectrometer. Linkage disequilibrium and haplotype analyses were performed, and genotype and allele frequencies were compared between groups. The positive and negative symptom scale (PANSS) was used to evaluate the association between the BDNF and CREB gene polymorphisms and schizophrenic symptoms. Results: There was no significant difference in genotype or allele frequencies for rs11030101, rs2030324, rs6265, rs6740584, or rs2551640 between schizophrenic patients and controls (p > 0.05). In addition, there were no significant differences in rs11030101, rs2030324, rs6265, rs6740584, or rs2551640 genotype frequencies between the two groups in the dominant, recessive, or over-dominant models (p > 0.05). Three loci in the BDNF gene and two loci in the CREB gene were in a state of strong linkage disequilibrium. The frequency of haplotype AAC (rs11030101/rs2030324/rs626), composed of three loci in the BDNF gene, was significantly increased in schizophrenic patients compared with control subjects. There were significant differences in the subscores of PANSSS for negative symptoms, in patients with different rs11030101 genotypes of the BDNF gene (p < 0.05). There was also significant differences in the PANSS scores for the general symptom G12 (judgment and lack of insight) in patients with different rs6265 genotypes of the BDNF gene (p < 0.05). Conclusion: The BDNF gene rs11030101/rs2030324/rs6265 AAC haplotype was potentially associated with an increased risk of schizophrenia. In addition, genotypes at the rs11030101 and rs6265 loci may affect the negative symptoms and general symptoms of schizophrenic patients, respectively.

The Influence of 5-HTTLPR, BDNF Rs6265 and COMT Rs4680 Polymorphisms on Impulsivity in Bipolar Disorder: The Role of Gender.

Impulsivity has been proposed as an endophenotype for bipolar disorder (BD); moreover, impulsivity levels have been shown to carry prognostic significance and to be quality-of-life predictors. To date, reports about the genetic determinants of impulsivity in mood disorders are limited, with no studies on BD individuals. Individuals with BD and healthy controls (HC) were recruited in the context of an observational, multisite study (GECOBIP). Subjects were genotyped for three candidate single-nucleotide polymorphisms (SNPs) (5-HTTLPR, COMT rs4680, BDNF rs6265); impulsivity was measured through the Italian version of the Barratt Impulsiveness Scale (BIS-11). A mixed-effects regression model was built, with BIS scores as dependent variables, genotypes of the three polymorphisms as fixed effects, and centers of enrollment as random effect. Compared to HC, scores for all BIS factors were higher among subjects with euthymic BD (adjusted β for Total BIS score: 5.35, p < 0.001). No significant interaction effect was evident between disease status (HC vs. BD) and SNP status for any polymorphism. Considering the whole sample, BDNF Met/Met homozygosis was associated with lower BIS scores across all three factors (adjusted β for Total BIS score: −10.2, p < 0.001). A significant 5-HTTLPR x gender interaction was found for the SS genotype, associated with higher BIS scores in females only (adjusted β for Total BIS score: 12.0, p = 0.001). Finally, COMT polymorphism status was not significantly associated with BIS scores. In conclusion, BD diagnosis did not influence the effect on impulsivity scores for any of the three SNPs considered. Only one SNP—the BDNF rs6265 Met/Met homozygosis—was independently associated with lower impulsivity scores. The 5-HTTLPR SS genotype was associated with higher impulsivity scores in females only. Further studies adopting genome-wide screening in larger samples are needed to define the genetic basis of impulsivity in BD.

Consequences of the rs6265 (Val66Met) polymorphism in the BDNF gene in selected mental disorders and sport

Abstract Introduction: Brain-derived neurotrophic factor (BDNF) is a polypeptide of 247 amino acid residues and is widely distributed throughout the central nervous system of the CNS. It plays an important role in the survival, differentiation, growth, and development of neurons in the central nervous system. The human BDNF gene is located on chromosome 11 in the p13-14 region and covers approximately 70 kb. The gene has a complex structure as it consists of 11 exons (I-IX, plus Vh and VIIIh) and nine functional promoters. BDNF expression in the brain is relatively low but it is found in most major regions of the brain. Material and methods: The gene encoding the brain-derived neurotrophic factor BDNF has many polymorphisms, but one of them mainly attracts the attention of researchers. This is a common, non-conservative polymorphism - rs6265 - a single nucleotide SNP polymorphism that results in an amino acid change – valine (Val) to methionine (Met) - at codon 66. Results: Polymorphism rs6265 is associated with many neuropsychiatric disorders, including depression or a higher risk of addiction, but it also determines other features, such as e.g. sports performance. Few studies are investigating the relationship between rs6265 polymorphism and predisposition to play sports. Conclusions: The results on the effect of rs6265 BDNF polymorphic variants on the risk of depression and addition are inconsistent, indicating a significant association in some studies and none in others. Therefore, more studies are needed to determine how rs6265 affects gene expression and function.

Associations between alcohol use and peripheral, genetic, and epigenetic markers of oxytocin in a general sample of young and older adults.

IntroductionHuman and nonhuman animal research suggests that greater oxytocin (OT) activity is protective against harmful substance use. Most research on this topic is preclinical, with few studies evaluating the association between substance use and individual differences in the human OT system. The present study sought to fill this gap by evaluating the relationship between alcohol use and multiple biological measures of OT activity in an overall low to moderate‐drinking sample.MethodAs part of a larger study, generally healthy young (n = 51) and older (n = 53) adults self‐reported whether they regularly used alcohol and how much alcohol they consumed per week. Participants also provided blood samples from which peripheral OT, and in an age‐heterogeneous subset of participants (n = 56) variation in the oxytocin receptor gene (the OXTR rs53576 polymorphism) and OXTR DNA methylation levels (at cytosine–guanine dinucleotide sites ‐860, ‐924, ‐934), were obtained.ResultsA‐allele carriers of the OXTR rs53579 polymorphism were less likely to regularly consume alcohol. Among regular alcohol consumers, number of alcoholic drinks per week was positively associated with peripheral OT in regression models excluding observations of high influence (postdiagnostic models). Number of alcoholic drinks per week was consistently negatively associated with OXTR DNA methylation at site ‐860; and with OXTR DNA methylation at site ‐924 in postdiagnostic models.ConclusionsThe significant associations between alcohol use and individual differences in OT activity support the involvement of the OT system in alcohol use, which most likely reflect the role of OT when alcohol use is under control of its rewarding properties and/or the acute impacts of alcohol on the OT system. Additional research with markers of OT activity and alcohol use, particularly longitudinal, is needed to clarify the bidirectional effects of OT and alcohol use in moderate to harmful drinking and dependence.

The BDNF Val66Met Polymorphism (rs6265) Modulates Inflammation and Neurodegeneration in the Early Phases of Multiple Sclerosis

The clinical course of multiple sclerosis (MS) is critically influenced by the interplay between inflammatory and neurodegenerative processes. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265), one of the most studied single-nucleotide polymorphisms (SNPs), influences brain functioning and neurodegenerative processes in healthy individuals and in several neuropsychiatric diseases. However, the role of this polymorphism in MS is still controversial. In 218 relapsing–remitting (RR)-MS patients, we explored, at the time of diagnosis, the associations between the Val66Met polymorphism, clinical characteristics, and the cerebrospinal fluid (CSF) levels of a large set of pro-inflammatory and anti-inflammatory molecules. In addition, associations between Val66Met and structural MRI measures were assessed. We identified an association between the presence of Met and a combination of cytokines, identified by principal component analysis (PCA), including the pro-inflammatory molecules MCP-1, IL-8, TNF, Eotaxin, and MIP-1b. No significant associations emerged with clinical characteristics. Analysis of MRI measures evidenced reduced cortical thickness at the time of diagnosis in patients with Val66Met. We report for the first time an association between the Val66Met polymorphism and central inflammation in MS patients at the time of diagnosis. The role of this polymorphism in both inflammatory and neurodegenerative processes may explain its complex influence on the MS course.

Prediction of the Development of Depression in Patients with Autoimmune Thyroiditis and Hypothyroidism

BACKGROUND: Hypothyroidism is frequently accompanied by depression symptoms, whereas depression is considered the most common mental disorder. AIM: It is crucial to analyze the associations of the brain neurotrophic factor (BDNF) gene polymorphism (rs6265), the VDR gene polymorphism (rs2228570), and the NMDA gene polymorphism (rs4880213) with the depression in patients with autoimmune thyroiditis and hypothyroidism in the Western Ukrainian population and predict the development of depressive disorders in these patients. METHODS: The study involved a total of 153 patients with various forms of thyroid pathology. BDNF levels in the sera of the patients and healthy individuals were quantified using enzyme-linked immunosorbent assay with highly sensitive Human BDNF ELISA Kit (Elabscience®, United States, Catalog No: E-EL-H0010) on E.I.A. Reader Sirio S (Seac, Italy). Genotyping of the VDR (rs2228570), BDNF (rs6265), and NMDA (rs4880213) gene polymorphism using TaqMan probes and TaqMan Genotyping Master Mix (4371355) on CFX96™Real-Time Polymerase chain reaction (PCR) Detection System (Bio-Rad Laboratories, Inc., USA). PCR for TaqMan genotyping was carried out according to the kit instructions (Applied Biosystems, USA). We used the Student’s t-test, ANOVA, Pearson’s Chi-square test, ROC-analysis, odds ratio test, relative odds ratio test. The odds ratio and 95% confidence interval were computed by binary logistic regression. RESULTS: When comparing the presence of depression on the Hamilton scale, statistically significant differences were found depending on BDNF gene polymorphism (rs6265) (p &lt; 0.001), and non-statistically noticeable differences were detected depending on the VDR gene polymorphism (rs2228570) and NMDA gene polymorphism (rs4880213). Our study revealed a marked inverse connection between depression and BDNF levels (p &lt; 0.001) and a reverse moderate correlation between depression and fT4 (p &lt; 0.001) and 25-OH Vitamin D levels (p &lt; 0.001). In addition, we identified a direct moderate correlation between pronounced levels of depression and thyroid-stimulating hormone (TSH) in the blood (p &lt; 0.001). CONCLUSIONS: Indicators such as BDNF, TSH, fT4, anti-TPO, and 25-OH Vitamin D levels were found to be prognostically significant criteria for the risk of developing depression.

GENETICS OF PARANOIDPERSONALITYDISORDER

Paranoid personality disorder (PPD) is characterized by the following leading features: excessive sensitivity to failures and refusals; inclination to persistently endure even minor insults and injuries or slights, refusing to forgive them; suspicion and distortion of facts, interpretation of friendly or neutral actions of other people as hostile or contemptuous; unjustified suspicions of sexual infidelity of a partner; unfounded concern about the imaginary conspiracy of events both in relation to himself and around the world; feeling of one's own usually exaggerated significance; unfounded militant defense of their personal rights. The prevalence of PPD is 2.3-4.4% and is more often diagnosed in men. Heritability of PPD varies from 28% to 66%.&#x0D; By now various authors have described 16 genes associated with the development of PPD: SLC6A4, COMT, CACNA1C, NOS1AP, DYNC1I1 and 11 genes of mitochondrial complex 1. The SLC6A4 gene (17q11.2) encodes a reverse serotonin transporter. A slight deletion in the promoter of this gene reduces its activity and can minimize the expression of paranoid traits. The product of the COMT gene (22q11.21) is actively involved in dopamine metabolism. A G-to-A transition atcodon 158 of this gene increases its activity by 3-4 times and, as a consequence, decreases dopamine expression in the prefrontal cortex, which causes paranoid symptoms of personality disorders. The CACNA1C gene (12p13.33) encodes a protein that plays an important role in the formation and activity of brain neurons. The single nucleotide polymorphism rs1006737, located in the 3rd intron of this gene, is associated with PPD, schizophrenia, schizotypal personality disorder, major depressive disorder and bipolar disorder.&#x0D; Mitochondrial complex 1 and cellular bioenergetic pathways play a significant role in the etiology and features of PPD and schizophrenia. Significant changes in expression of 11 genes were detected in patients with PPD compared to the control sample. Expression of genes NDUFS1 (2q33.3), NDUFV1 (11q13.2), NDUFV2 (18p11.22), NDUFB5 (3q26.33), NDUFB9 (8q24.13), NDUFA13(19p13.11), NDUFA8 (9q33. 2) and NDUFA5 (7q31.32) was increased, and the genes NDUFB11 (Xp11.3), NDUFS7 (19p13.3) and NDUFS8 (11q13.2) were decreased. The NDUFS1 gene expression was particularly high. None of the sevenmitochondrial genes showed a change in expression,which may reduce the importance of a maternal patternin the heritance of PPD.The results of the study showed that the NDUFS1 gene may be a specific marker for PPD.&#x0D; In the presence of relevant genetic factors certain environmental conditions can provoke the development of PPD. It is possible to predict PPD on the presence of NOS1AP (1q23.3) gene polymorphisms and childhood abuse. The protein encoded by this gene is involved in the functioning of brain synapses. There is shown that emotional violence and SNPs rs348624 and rs4145621, located respectively in the 9th exon and 3rd intron of the NOS1AP gene, reliably predict PPD.&#x0D; In addition to described above 16 genes, whose variants are reliably involved in PPD, various researchers have identified at least 8 other genes that are likely to be associated with PPD, although they have been identified in the study of other mental disorders, mainly schizophrenia.&#x0D; A review of available scientific sources on PPD genetics shows that research of this problem isin its beginning. It is necessary to expand and deepen these studies on the basis of the most modern molecular genetic technologies, one of which is the genome-wide associations study. This technology makes it possible not only to detect candidate genes, but also to determine the nature of mutations that cause hereditary disease. Such mutations can be single nucleotide polymorphisms, small insertions / deletions and changes in the number of copies. In addition, they can be located not only within genes (in exons and introns), but also in intergenic regions of DNA. Gene expression can be affected not only by mutations within its exons, but also by mutations within its introns and intergenic DNA regions.

Investigation of possible associations of the BDNF, SNAP-25 and SYN III genes with the neurocognitive measures: BDNF and SNAP-25 genes might be involved in attention domain, SYN III gene in executive function

Objectives Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder and Sluggish Cognitive Tempo (SCT) might be a second inattention disorder that might be even affected by different attention pathways. SCT is characterized by daydreaming, mental confusion, staring blankly and hypoactivity. In the present study, we evaluated 5 common variants (rs6265, rs3746544, rs1051312, rs133946 and rs133945) located in 3 candidate genes (BDNF, SNAP25 and SYN III) that are known to take part in synaptic plasticity and neurotransmitter transmission. Methods We tested the effects of these variants on neuropsychological findings assessed by a computer-based neuropsychological test battery in children with inattention symptoms (SCT and/or ADHD). Results BDNF (rs6265), SNAP25 (rs3746544 and rs1051312) and SYN III (rs133946 and rs133945) polymorphisms were associated with variable cognitive measures. BDNF gene (rs6265) polymorphism Met allele carriers and SNAP25 gene (rs3746544) T allele carriers had an association with the attention domain. SNAP25 gene (rs1051312) C allele carriers were only associated with reaction time scores. Cognitive flexibility, which is one of the key components of executive function evaluation and shifting attention test scores were associated with BDNF (rs6265) Met allele and SYN III (rs133946) gene G allele. SYN III (rs133945) gene C allele carriers had an association with verbal memory correct hit scores. Conclusions As a conclusion, BDNF, SNAP25 and SYN III genes were associated with specific neurocognitive outcomes in children with inattention symptoms. It is important to note that exploring genotyping effects on neurocognitive functions instead of a heterogeneous psychiatric diagnosis can improve our understanding of psychopathologies.

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

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

Translocator Protein (18 kDa) Polymorphism (rs6971) in the Korean Population.

Background and PurposeThe expression of the 18-kDA mitochondrial translocator protein (TSPO) in the brain is an attractive target to study neuroinflammation. However, the binding properties of TSPO ligands are reportedly dependent on genetic polymorphism of the TSPO gene (rs6971). The objective of this study is to investigate the rs6971 gene polymorphism in the Korean population.MethodsWe performed genetic testing on 109 subjects including patients with mild cognitive impairment, Alzheimer’s disease (AD) dementia, non-AD dementia, and cognitively unimpaired participants. Magnetic resonance imaging scans and detailed neuropsychological tests were also performed, and 29 participants underwent 18F-DPA714 PET scans. Exon 4 of the TSPO gene containing the polymorphism rs6971 (Ala or Thr at position 147) was polymerase chain reaction amplified and sequenced using the Sanger method. The identified rs6971 genotype codes (C/C, C/T, or T/T) of the TSPO protein generated high-, mixed-, or low-affinity binding phenotypes (HABs, MABs, and LABs), respectively.ResultsWe found that 96.3% of the study subjects were HAB (105 out of 109 subjects), and 3.7% of the subjects were MAB (4 out of 109 subjects). 18F-DPA-714 PET scans showed nonspecific binding to the thalamus and brainstem, and increased tracer uptake throughout the cortex in cognitively impaired patients. The participant with the MAB polymorphism had a higher DPA714 signal throughout the cortex.ConclusionsThe majority of Koreans are HAB (aprox. 96%). Therefore, the polymorphism of the rs6971 gene would have a smaller impact on the availability of second-generation TSPO PET tracers.

Association of gene polymorphisms DRD3 rs6280, COMT rs4680 and HTR2A rs7322347 with schizophrenia

To check the association of genetic polymorphisms rs6280 of the DRD3 gene, rs4680 of the COMT gene, rs7322347 of the HTR2A gene with schizophrenia. The sample included 300 inpatients with paranoid schizophrenia. Inclusion criteria: age 18-50 years, established diagnosis «Schizophrenia, paranoid form», duration of psychiatric disorders not less than 5 years. The healthy control group consisted of 290 subjects. The association between polymorphisms and the study groups was assessed by logistic regression. The CC genotype of the rs6280 polymorphism is associated with schizophrenia (OR 3.37 (1.50; 8.03)). The TT genotype of the rs7322347 polymorphism is associated with controls (OR 1.83 (1.25; 2.68)). These analyses confirmed the hypothesis that the genetic polymorphisms rs7322347 of the HTR2A gene (p=0.006) and rs6280 of the DRD3 gene (p=0.004) were associated with the disease. The hypothesis of an association of the rs4680 polymorphism of the COMT gene could not be confirmed.

Development of a method for the identification of rs6265 polymorphism in the human brain neurotrophic factor gene

The analysis and generalization of data from the literature sources characterizing the structural organization, regulation of expression, and functional activity of the neurotrophic factor of the human brain, which is one of the most common regulators of biological processes in the nervous system, is carried out. The results of numerous studies demonstrating the association of the brain-derived neurotrophic factor (BDNF) gene with the pathophysiology of the affective disorders are noted, and its contribution to the development of neuroplasticity is confirmed. The results of the design of a pair of primers and adaptation of the amplification reaction of the BDNF region with a length of 433 nucleotide pairs containing the polymorphic locus RS6265 are presented. Restriction endonuclease was selected. The sequence of primers, their localization, and correlation with the restriction site provided the separation of alternative alleles necessary for the successful identification of this marker. The use of the proposed technique made it possible to uniquely identify the genotype in 38 examined whole blood samples and identify the rare allelic variants. Also, the frequency of polymorphic variants of RS6265 of the BDNF gene was established in all the samples. There was an increase in the proportion of genotypes G/A and A/A of the RS6265 polymorphism of the BDNF gene in the group of examined systematically exposed to extreme factors. Identification of people with a rare A/A genotype of the RS6265 polymorphic locus of the BDNF gene is of a great importance for the monitoring system of long-term potentiation processes leading to the development of neuropsychic pathology. The possibility of implementing this method of genotyping in a typical laboratory using a polymerase chain reaction is proved. The proposed version of the polymerase chain reaction with the subsequent analysis of the polymorphism of the lengths of restriction fragments could be used as a fast, inexpensive, and reliable system for identifying single-nucleotide genetic polymorphisms.

Childhood trauma and genetic variation in the DAT 40-bp VNTR contribute to HIV-associated neurocognitive disorders.

HIV/AIDS is a major public health burden in South Africa, currently affecting an estimated 13.5% of the population. Despite improved access to antiretroviral therapies, HIV-associated neurocognitive disorders (HAND), characterised by a spectrum of neurocognitive impairment, emotional disturbances and motor abnormalities, continue to persist. Gene-environment interactions contribute to HAND pathophysiology and previous research has identified childhood trauma as an environmental risk factor. Dopaminergic signalling in the prefrontal cortex plays a key role in cognitive function. Thus, variants in genes encoding the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT), which are responsible for dopamine transport and metabolism, could represent genetic risk factors for HAND. This study investigated whether the DAT variable number of tandem repeats (VNTR) and COMT Val158Met (rs4680) polymorphisms are associated with longitudinal change in cognitive function in the context of childhood trauma and HIV. Participants (n = 49 HIV-negative and n = 64 HIV-positive women) completed the Childhood Trauma Questionnaire – Short Form (CTQ-SF) and provided blood for genetic analyses. Global cognitive scores were generated from baseline and one-year follow-up assessments. Following polymerase chain reaction, genotypes were determined using gel electrophoresis and confirmed by Sanger sequencing. Baseline global cognitive scores, genotype, HIV status and CTQ-SF scores were regressed on one-year global cognitive scores in regression models. Analysis of variance was used to examine the effect of including predictor variable interactions on model fit. HIV seropositivity was associated with poorer cognitive performance at one-year follow-up (p = 2.46 ×10−4). The combination of HIV and DAT 10-repeat homozygosity (DAT 10/10) was associated with reduced global cognitive scores in longitudinal models (p = 0.010). Including the interaction between DAT 10/10, childhood trauma, and HIV explained significantly more of the variance in longitudinal cognitive scores (p = 0.008). There were no significant associations with the COMT genotype. Our research indicates that childhood trauma and genetic variation in DAT contribute toward the aetiology of HAND. Future studies in larger cohorts are warranted to verify these results.

Interplay between genetics and lifestyle on pain susceptibility in women with fibromyalgia: the al-Ándalus project.

ObjectivesIt is widely acknowledged that the experience of pain is promoted by both genetic susceptibility and environmental factors such as engaging in physical activity (PA), and that pain-related cognitions are also important. Thus, the purpose of the present study was to test the association of 64 polymorphisms (34 candidate genes) and the gene–gene, gene–PA and gene–sedentary behaviour interactions with pain and pain-related cognitions in women with FM.MethodsSaliva samples from 274 women with FM [mean (s.d.) age 51.7 (7.7) years] were collected for extracting DNA. We measured PA and sedentary behaviour by accelerometers for a week, pain with algometry and questionnaires, and pain-related cognitions with questionnaires. To assess the robustness of the results, a meta-analysis was also performed.ResultsThe rs6311 and rs6313 polymorphisms (5-hydroxytryptamine receptor 2A, HTR2A) were individually related to algometer scores. The interaction of rs4818 (catechol-O-methyltransferase, COMT) and rs1799971 (opioid receptor μ gene, OPRM1) was related to pain catastrophizing. Five gene–behaviour interactions were significant: the interactions of sedentary behaviour with rs1383914 (adrenoceptor alpha 1A, ADRA1A), rs6860 (charged multivesicular body protein 1A, CHMP1A), rs4680 (COMT), rs165599 (COMT) and rs12994338 (SCN9A) on bodily pain subscale of the Short Form 36. Furthermore, the meta-analysis showed an association between rs4680 (COMT) and severity of FM symptoms (codominant model, P-value 0.032).ConclusionThe HTR2A gene (individually), COMT and OPRM1 gene–gene interaction, and the interactions of sedentary behaviour with ADRA1A, CHMP1A, COMT and SCN9A genes were associated with pain-related outcomes. Collectively, findings from the present study indicate a modest contribution of genetics and gene–sedentary behaviour interaction to pain and pain catastrophizing in women with FM. Future research should examine whether reducing sedentary behaviour is particularly beneficial for reducing pain in women with genetic susceptibility to pain.

Experience of using the molecular genetic studies to assess the risk of suicide

In the recent decades, there has been widespread the opinion that genetic markers of the suicidal behavior (suicide, suicidal attempts, suicidal thoughts) can be used to predict the suicidal behavior.The purpose of the study was to determine the possibility of using the method of molecular genetic research to assess the risk of suicide in men of 18‒27 years.The study used the case-control method. The control group included 100 men of 18‒27 years who never had mental disorders. The suicide group included the persons who committed highly traumatic methods of self-harm and were motivated to commit suicide (30 persons). DNA isolation was performed using a NucleoSpin Blood kit (Macherey‒Nagel, Germany) according to the manufacturer’s protocol. Each DNA sample was analyzed for polymorphism by allelic discrimination using the real-time polymerase chain reaction (PCR).The frequencies of occurrence of genotypes and alleles of the following genes were analyzed: HTR1A, rs6295 (G/C); BDNF, rs6265 (G/A); COMT, rs4680 (G/A); SKA2, rs7208505 (C/T); SLC6A4 (5HTT), rs25531 (T/C); 5HTR2A, rs6313 (G/A); TPH2, rs4570625 (G/T); TPH1, rs1800532 (G/T).A statistically significant difference was found for the frequency of occurrence of genotypes and alleles of the rs25531 polymorphism of the SLC6A4 (5HTT) gene. The chance of being in the suicide group with a heterozygous genotype (T/C) carriage was 2.346 times higher.The significance of the rs25531 polymorphism of the SLC6A4 (5HTT) gene for the formation of the suicidal behavior was confirmed.

P.0516 Genotype rs25531 polymorphisms and quality in peer relationships adjust the neural response of the anterior prefrontal cortex to cry

P.0516 Genotype rs25531 polymorphisms and quality in peer relationships adjust the neural response of the anterior prefrontal cortex to cry

Low-dose ketamine infusion for treating subjective cognitive, somatic, and affective depression symptoms of treatment-resistant depression.

Whether the antidepressant effects of low-dose ketamine infusion and the therapeutic impact of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism vary across different depression symptom domains, namely affective, cognitive, and somatic, remains unclear. We-reanalyzed the data of Adjunctive Ketamine Study of Taiwanese Patients with Treatment-Resistant Depression (TRD). A total of 71 patients with TRD were randomized to three infusion groups: 0.5 and 0.2mg/kg ketamine groups and the normal saline placebo group. The Beck Depression Inventory-II (BDI-II) was used to obtain self-reported scores prior to infusion and 240min after infusion and sequentially on days 3, 7, and 14 after infusion. The three-factor model of cognitive, somatic, and affective depressive symptoms that is based on the BDI-II and proposed by Beck et al. was applied in the current study. The Val66Met BDNF polymorphism was genotyped. Ketamine infusion exerted rapid and sustained antidepressant effects on the affective (p=0.014) and cognitive (p=0.005) depression symptom domains but not on the somatic (p=0.085) depression symptom domain. Only patients with TRD harboring any Val allele at the BDNF rs6265 polymorphism were more likely to respond (p=0.011) to low-dose ketamine infusion. Additional studies should elucidate different mechanisms underlying the effects of ketamine infusion on cognitive, affective, and somatic depression symptom domains in patients with TRD.

Can COMT Val158Met Gene Polymorphism Predict Treatment Outcomes for Methylphenidates in ADHD Patients?

The COMT gene encodes for the Catechol-O-methyltransferase (COMT) enzyme, an enzyme responsible for the breakdown of dopamine and norepinephrine in the prefrontal cortical areas. The most common variation of the COMT gene is the Val158Met polymorphism (rs4680) which leads to a valine (Val) to methionine (Met) substitution at codon 158. It is plausible that variations in this gene may predict treatment outcomes to stimulants like methylphenidates used in the treatment of ADHD. The purpose of this study is to statistically evaluate this association to further the clinical implementation of personalized medicine. Quantitative data was collected from clinical trials where patients were genotyped for the COMT gene and were evaluated for treatment response to methylphenidates on a quantifiable scale. Correlational analysis (n=1094) showed a statistically significant association (p=0.003) between this genotype and treatment outcomes. The Odd’s ratio calculated from the binary outcomes (n=638 patients) depicted that the Val/Val carriers were 1.86 times more likely to respond positively to methylphenidate treatment compared to the Met allele carriers. Our analysis shows that variations in COMT gene can reliably predict treatment outcomes to Methylphenidates in ADHD patients. However, this association is based on the data extracted from 9 different clinical studies (n= 1094 patients). These studies had different sample sizes, ethnicities, and measurement scales which may have contributed to the heterogeneity in the overall sample data set, thereby diluting the power of the association. Nevertheless, this analysis adds to the body of pharmacogenomic evidence increasing the clinical utility of precision medicine.

Radiosynthesis and characterization of [18F]BS224: a next-generation TSPO PET ligand insensitive to the rs6971 polymorphism

PurposeTranslocator protein 18-kDa (TSPO) positron emission tomography (PET) is a valuable tool to detect neuroinflammed areas in a broad spectrum of neurodegenerative diseases. However, the clinical application of second-generation TSPO ligands as biomarkers is limited because of the presence of human rs6971 polymorphism that affects their binding. Here, we describe the ability of a new TSPO ligand, [18F]BS224, to identify abnormal TSPO expression in neuroinflammation independent of the rs6971 polymorphism.MethodsAn in vitro competitive inhibition assay of BS224 was conducted with [3H]PK 11195 using membrane proteins isolated from 293FT cells expressing TSPO-wild type (WT) or TSPO-mutant A147T (Mut), corresponding to a high-affinity binder (HAB) and low-affinity binder (LAB), respectively. Molecular docking was performed to investigate the interaction of BS224 with the binding sites of rat TSPO-WT and TSPO-Mut. We synthesized a new 18F-labeled imidazopyridine acetamide ([18F]BS224) using boronic acid pinacol ester 6 or iodotoluene tosylate precursor 7, respectively, via aromatic 18F-fluorination. Dynamic PET scanning was performed up to 90 min after the injection of [18F]BS224 to healthy mice, and PET imaging data were obtained to estimate its absorbed doses in organs. To evaluate in vivo TSPO-specific uptake of [18F]BS224, lipopolysaccharide (LPS)-induced inflammatory and ischemic stroke rat models were used.ResultsBS224 exhibited a high affinity (Ki = 0.51 nM) and selectivity for TSPO. The ratio of IC50 values of BS224 for LAB to that for HAB indicated that the TSPO binding affinity of BS224 has low binding sensitivity to the rs6971 polymorphism and it was comparable to that of PK 11195, which is not sensitive to the polymorphism. Docking simulations showed that the binding mode of BS224 is not affected by the A147T mutation and consequently supported the observed in vitro selectivity of [18F]BS224 regardless of polymorphisms. With optimal radiochemical yield (39 ± 6.8%, decay-corrected) and purity (> 99%), [18F]BS224 provided a clear visible image of the inflammatory lesion with a high signal-to-background ratio in both animal models (BPND = 1.43 ± 0.17 and 1.57 ± 0.37 in the LPS-induced inflammatory and ischemic stroke rat models, respectively) without skull uptake.ConclusionOur results suggest that [18F]BS224 may be a promising TSPO ligand to gauge neuroinflammatory disease-related areas in a broad range of patients irrespective of the common rs6971 polymorphism.

Evaluation of the Association of Htr2a Gene Rs6313 Polymorphism with Heroin Dependence in a Sample from Northwest Iran

Evaluation of the Association of Htr2a Gene Rs6313 Polymorphism with Heroin Dependence in a Sample from Northwest Iran