RESUMO
Alcohol Use Disorder (AUD) is a highly prevalent condition worldwide that produces a wide range of pathophysiological consequences, with a critical impact on health and social issues. Alcohol influences gene expression through epigenetic changes mainly through DNA methylation. In this sense, levels of 5-methylcytosine (5-mC), namely Global DNA methylation (GMe), which can be influenced by environmental and hormonal effects, represent a putative biological mechanism underlying alcohol effects. Our aim was to investigate the influence of AUD diagnosis and alcohol patterns (i.e., years of addiction, use in the last 30 days, and alcohol severity) on GMe levels. The sample consisted of 256 men diagnosed with AUD and 361 men without AUD. DNA samples from peripheral blood were used to assess GMe levels, measured through the levels of 5-mC using high-performance liquid chromatography. Results from multiple linear regression analysis indicated that the presence of AUD was associated with lower GMe levels (beta=-0.155, p=0.011). Other alcohol-related outcomes were not associated with DNA methylation. Our findings are consistent with the hypothesis that the impact of chronic and heavy alcohol use in GMe could be a potential mechanism mediating the multiple organ damages related to AUD.
RESUMO
We were pleased to read Pehlivanidis and Papanikolaou's article1 and see that more colleagues are recognizing Theophrastus' text as the first description of Attention Deficit Hyperactivity Disorder (ADHD).2 We agree with the authors' perspective that Theophrastus' description may suggest the presence of more than one neurodevelopmental disorder. In fact, Theophrastus' description aligns with the shared clinical symptoms and underlying neurodevelopmental mechanisms of ADHD and Social Pragmatic Communication Disorder (SPCD). It is fascinating that a description from over 2000 years ago already presented prototypical individual transdiagnostic aspects that are compatible with a modern biological view of psychiatry. Indeed, it is not unexpected that heritable traits with clear biological underpinnings should have been perceived since the dawn of medicine. A significant leap forward in the development of this field came a few decades ago when Clements (1966)3 published a NIH-sponsored project entitled 'Minimal Brain Dysfunction in Children.' This seminal work prepared the terrain for the ongoing understanding of the grouping of signs, symptoms, and biological factors observed across various neurodevelopmental disorders. This grouping can be present in different spectrums, proportions, and nuances, including children and adults with some impairments that are not solely explained by their cognitive abilities. Thus, the characterization of 'The Obtuse Man' by Theophrastus could be considered a prototypical case of this more integrated and less fragmented view of what we call neurodevelopmental disorders.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtornos do Neurodesenvolvimento , Masculino , Criança , Adulto , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estudos Longitudinais , Transtornos do Neurodesenvolvimento/diagnóstico , CogniçãoRESUMO
Genetic and environmental factors contribute to the etiology of Attention Deficit-Hyperactivity Disorder (ADHD). In this sense, the study of epigenetic mechanisms could contribute to the understanding of the disorder's neurobiology. Global DNA methylation (GMe) evaluated through 5-methylcytosine levels could be a promising epigenetic biomarker to capture long-lasting biological effects in response to environmental and hormonal changes. We conducted the first assessment of GMe levels in subjects with ADHD (n = 394) and its main comorbidities in comparison to populational controls (n = 390). Furthermore, given the high genetic contribution to ADHD (heritability of 80%), polygenic risk scores (PRS) were calculated to verify the genetic contribution to GMe levels in ADHD and the comorbidities associated with GMe levels. The GMe levels observed in patients were lower than controls (P = 1.1e-8), with women being significantly less globally methylated than men (P = 0.002). Regarding comorbidities, the presence of bipolar disorder (BD) among patients with ADHD was associated with higher methylation levels compared to patients with ADHD without BD (P = 0.031). The results did not change when pharmacological treatment was accounted for in the analyses. The ADHD and BD most predictive PRSs were negatively (P = 0.0064) and positively (P = 0.0042) correlated with GMe, respectively. This study is the first to report an association between GMe, ADHD, and its comorbidity with BD and associations between PRSs for specific psychiatric disorders and GMe. Our findings add to previous evidence that GMe may be a relevant piece in the psychiatric disorders' etiological landscape.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Bipolar , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/complicações , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Comorbidade , Metilação de DNA/genética , Feminino , Humanos , Masculino , Herança Multifatorial/genéticaRESUMO
ADHD is associated with smaller subcortical brain volumes and cortical surface area, with greater effects observed in children than adults. It is also associated with dysregulation of the HPA axis. Considering the effects of the glucocorticoid receptor (NR3C1) in neurophysiology, we hypothesize that the blurred relationships between brain structures and ADHD in adults could be partly explained by NR3C1 gene variation. Structural T1-weighted images were acquired on a 3 T scanner (N = 166). Large-scale genotyping was performed, and it was followed by quality control and pruning procedures, which resulted in 48 independent NR3C1 gene variants analyzed. After a stringent Bonferroni correction, two SNPs (rs2398631 and rs72801070) moderated the association between ADHD and accumbens and amygdala volumes in adults. The significant SNPs that interacted with ADHD appear to have a role in gene expression regulation, and they are in linkage disequilibrium with NR3C1 variants that present well-characterized physiological functions. The literature-reported associations of ADHD with accumbens and amygdala were only observed for specific NR3C1 genotypes. Our findings reinforce the influence of the NR3C1 gene on subcortical volumes and ADHD. They suggest a genetic modulation of the effects of a pivotal HPA axis component in the neuroanatomical features of ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Receptores de Glucocorticoides , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Glucocorticoides , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Imageamento por Ressonância Magnética , Sistema Hipófise-Suprarrenal , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismoRESUMO
There is an increasing body of knowledge on the influence of differential DNA methylation of specific genomic regions in psychiatric disorders. However, fewer studies have addressed global DNA methylation (GMe) levels. GMe is an estimative of biological functioning that is regulated by pervasive mechanisms able to capture the big picture of metabolic and environmental influences upon gene expression. In the present perspective article, we highlighted evidence for the relationships between cortisol and sex hormones and GMe in psychiatric disorders. We argue that the far-reaching effects of cortisol and sexual hormones on GMe may lie on the pathways linking stress and mental health. Further research on these endocrine-epigenetic links may help to explain the role of environmental stress as well as sex differences in the prevalence of psychiatric disorders.
Assuntos
Metilação de DNA , Hormônios Esteroides Gonadais/metabolismo , Hidrocortisona/metabolismo , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , Metilação de DNA/genética , Epigênese Genética , Humanos , Caracteres SexuaisRESUMO
OBJECTIVE: Our aim was to explore the feasibility, and efficacy of a Dialectical Behavior Therapy Skill Training Group (DBT-ST) as an add-on treatment for adult attention-deficit/hyperactivity disorder (ADHD) in Latin America. METHOD: Adults with ADHD (n = 31) with stable medication treatment for ADHD and residual symptoms (ASRS > 20) were randomly assigned to DBT-ST (n = 16) or treatment as usual (TaU; n = 15) for 12 weeks. Feasibility was accessed by attendance and completion rates at 12 weeks. Efficacy outcomes were measured with the ASRS, and performed at 0, 6, 12, and 16 weeks. RESULTS: The DBT-ST protocol had 81.25% completion rate, with a mean attendance of 87.25% of the sessions. No significant interactions between group and time were detected for outcome measures. DISCUSSION: The DBT-ST was feasible as add-on treatment for adult patients with ADHD in Latin America. Replicating previous findings, DBT-ST has shown no significantly higher improvement in ADHD symptoms in comparison with TaU. Registered at the Clinical Trials database (NCT03326427).
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/terapia , Terapia do Comportamento Dialético , Adulto , Estudos de Viabilidade , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
Genome-wide studies provide increasing evidence of association of genetic variants with different behaviors. However, there is a growing need for replication and subsequent characterization of specific findings. In this sense, the CHRNA5 gene has been associated with nicotine (with genome-wide significance), alcohol and cocaine addictions. So far, this gene has not been evaluated in smoked (crack) cocaine. We aimed to analyze the influence of CHRNA5 variants in crack addiction susceptibility and severity. The sample includes 300 crack-addicted patients and 769 non-addicted individuals. The CHRNA5 SNPs evaluated were rs588765, rs16969968, and rs514743. Homozygosity for rs16969968 and rs588765 major alleles was nominally associated with a risk to crack addiction (GG, P = 0.032; CC, P = 0.036, respectively). Haplotype analyses reveal significant associations (rs588765|rs16969968|rs514743 pglobal-corrected = 7.66 × 10-5) and suggest a substantial role for rs16969968. These findings corroborate previous reports in cocaine addiction-in line with the expected effects of cocaine in the cholinergic system-and in the opposite direction of significant GWAS findings for nicotine addiction susceptibility. These results are strengthened by the first report of an association of rs588765 with crack addiction and by the haplotype findings. In summary, our study highlights the relevance of the α5 subunit on crack cocaine addiction, replicating previous results relating CHRNA5 with the genetics and pathophysiology of addiction of different drugs.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína Crack/efeitos adversos , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Receptores Nicotínicos/genética , Adulto , Alelos , Estudos de Casos e Controles , Transtornos Relacionados ao Uso de Cocaína/epidemiologia , Simulação por Computador , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos/genética , Humanos , Masculino , Risco , Relação Estrutura-Atividade , Adulto JovemRESUMO
Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < -1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Metilfenidato/uso terapêutico , Adulto , Animais , Feminino , Humanos , Masculino , Farmacogenética , Proteômica , Distribuição Aleatória , Ratos , Ratos Endogâmicos WKYRESUMO
Synaptotagmin-1 is an essential regulator of synaptic vesicle exocytosis, and its encoding gene (SYT1) is a genome and transcriptome-wide association hit in cognitive performance, personality and cocaine use disorder (CUD) studies. Additionally, in candidate gene studies the specific variant rs2251214 has been associated with attention-deficit/hyperactivity disorder (ADHD), antisocial personality disorder and other externalizing phenotypes in adults with ADHD, as well as with response to methylphenidate (MPH) treatment. In this context, we sought to evaluate, in an independent sample, the association of this variant with CUD, a phenotype that shares common biological underpinnings with the previously associated traits. We tested the association between SYT1-rs2251214 and CUD susceptibility and severity (addiction severity index) in a sample composed by 315 patients addicted to smoked cocaine and 769 non-addicted volunteers. SYT1-rs2251214 was significantly associated with susceptibility to CUD, where the G allele presented increased risk for the disorder in the genetic models tested (Pâ¯=â¯0.0021, ORâ¯=â¯1.44, allelic; Pâ¯=â¯0.0012, ORâ¯=â¯1.48, additive; Pâ¯=â¯0.0127, ORâ¯=â¯1.41, dominant). This is the same allele that was associated with increased risk for ADHD and other externalizing behaviors, as well as poor response to MPH treatment in previous studies. These findings suggest that the neurotransmitter exocytosis pathway might play a critical role in the liability for psychiatric disorders, especially externalizing behaviors and CUD.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Predisposição Genética para Doença/genética , Sinaptotagmina I/genética , Adulto , Estudos de Casos e Controles , Cocaína Crack , Feminino , Estudos de Associação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
Neurodevelopmental disorders are prevalent, frequently occur in comorbidity and share substantial genetic correlation. Previous evidence has suggested a role for the ADGRL3 gene in Attention-Deficit/Hyperactivity Disorder (ADHD) susceptibility in several samples. Considering ADGRL3 functionality in central nervous system development and its previous association with neurodevelopmental disorders, we aimed to assess ADGRL3 influence in early-onset ADHD (before 7 years of age) and Autism Spectrum Disorder (ASD). The sample comprises 187 men diagnosed with early-onset ADHD, 135 boys diagnosed with ASD and 468 male blood donors. We tested the association of an ADGRL3 variant (rs6551665) with both early-onset ADHD and ASD susceptibility. We observed significant associations between ADGRL3-rs6551665 on ADHD and ASD susceptibilities; we found that G-carriers were at increased risk of ADHD and ASD, in accordance with previous studies. The overall evidence from the literature, corroborated by our results, suggests that ADGRL3 might be involved in brain development, and genetic modifications related to it might be part of a shared vulnerability factor associated with the underlying neurobiology of neurodevelopmental disorders such as ADHD and ASD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Adolescente , Adulto , Distribuição por Idade , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Encéfalo/embriologia , Encéfalo/metabolismo , Criança , Simulação por Computador , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Humanos , Masculino , Modelos Genéticos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/fisiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/fisiologia , Receptores de Peptídeos/biossíntese , Receptores de Peptídeos/fisiologia , Distribuição por Sexo , Adulto JovemRESUMO
There is evidence that dopamine receptors D2 (DRD2) and D4 (DRD4) polymorphisms may influence substance use disorders (SUD) susceptibility both individually and through their influence in the formation of DRD2-DRD4 heteromers. The dopaminergic role on the vulnerability to addiction appears to be influenced by sex. A cross-sectional study with 307 crack cocaine addicts and 770 controls was conducted. The influence of DRD2 rs2283265 and DRD4 48 bp VNTR in exon 3 variants, as well as their interaction on crack cocaine addiction susceptibility and severity were evaluated in women and men separately. An association between the DRD2 T allele and crack cocaine addiction was found in women. In this same group, interaction analysis demonstrated that the presence of DRD2-T allele and concomitant absence of DRD4-7R allele were associated with risk for crack cocaine addiction. No influence of DRD2 and DRD4 variants was observed in men regarding addiction severity. This study reinforces the role of dopaminergic genes in externalizing behaviors, especially the influence of DRD2-DRD4 interaction on SUD. This is the fourth sample that independently associated the DRD2-DRD4 interaction with SUD itself or related disorders. In addition, our findings point out to a potential difference of dopaminergic neurotransmission across sex influencing addiction susceptibility.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína Crack , Predisposição Genética para Doença/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D4/genética , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Repetições Minissatélites , Polimorfismo Genético , Fatores Sexuais , Adulto JovemRESUMO
Attention-deficit/hyperactivity disorder (ADHD) is a very common psychiatric disorder across the life cycle and frequently presents comorbidities. Since ADHD is highly heritable, several studies have focused in the underlying genetic factors involved in its etiology. One of the major challenges in this search is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we differentially tested the influence of HTR1B SNPs (rs11568817, rs130058, rs6296 and rs13212041) on ADHD susceptibility and on its major comorbidities according to sex. The sample comprised 564 adults with ADHD diagnosed according to DSM-IV criteria and 635 controls. There was no association of any HTR1B SNPs tested in relation to ADHD susceptibility. As for the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (Pcorr = 0.009 and Pcorr = 0.018, respectively) and for rs11568817 with nicotine dependence (Pcorr = 0.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (Pcorr = 0.031). The observed effects of rs11568817 G allele presence conferring risk to either substance use disorders or generalized anxiety disorder according to sex, suggest an overall scenario where a higher transcriptional activity of HTR1B, resulting from the presence of this allele, is related to externalizing behaviors in men and internalizing behaviors in women. These results are consistent with and expand previous evidence of sexual dimorphism of the serotoninergic system.
Assuntos
Transtornos de Ansiedade/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Receptor 5-HT1B de Serotonina/genética , Caracteres Sexuais , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Transtornos de Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tabagismo/epidemiologia , Tabagismo/genética , Adulto JovemRESUMO
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder. Despite the high heritability, the unraveling of specific genetic factors related to ADHD is hampered by its considerable genetic complexity. Recent evidence suggests that gene-gene interactions can explain part of this complexity. We examined the impact of strongly supported interaction effects between the LPHN3 gene and the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) in a 7-year follow-up of a clinical sample of adults with ADHD, addressing associations with susceptibility, symptomatology and stability of diagnosis. The sample comprises 548 adults with ADHD and 643 controls. Entropy-based analysis indicated a potential interaction between the LPHN3-rs6551665 and TTC12-rs2303380 SNPs influencing ADHD symptom counts. Further analyses revealed significant interaction effects on ADHD total symptoms (p=0.002), and with hyperactivity/impulsivity symptom counts (p=0.005). In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026). Also, the same allelic constellation is involved in maintenance of ADHD in a predominantly hyperactive/impulsive or combined presentation after a 7-year follow-up (p=0.008). These observations reinforce and replicate previous evidence suggesting that an interaction effect between the LPHN3 gene and the NTAD cluster may have a role in the genetic substrate associated to ADHD also in adults. Moreover, it is possible that the interactions between LPHN3 and NTAD are specific factors contributing to the development of an ADHD phenotype with increased hyperactivity/impulsivity that is maintained throughout adulthood.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Antígeno CD56/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas/genética , Receptores de Dopamina D2/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Família Multigênica , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos RetrospectivosRESUMO
This study examined the effects of glucocorticoid receptor (NR3C1), corticotropin-releasing hormone receptor 1 (CRHR1), and brain-derived neurotrophic factor (BDNF) genes on susceptibility to crack cocaine addiction and BDNF levels. Crack addicted patients who sought treatment (n = 280) and non-addicted individuals (n = 241) were assessed. Three SNPs in NR3C1 (rs6198, rs41423247, and rs10052957), three in CRHR1 (rs12944712, rs110402, and rs878886), and one in BDNF (rs6265) were genotyped. No significant effect was seen in the case-control analyses. Crack cocaine addicted patients showed significantly lower serum BDNF levels. Significant effects were observed for NR3C1 rs41423247 and rs10052957. These effects were restricted to non-addicted individuals and they were supported by significant gene-by-disease status interactions. For CRHR1, all SNPs were associated with BDNF levels. Although there were significant effects only in the analysis restricted to non-addicted individuals, the lack of significant results in the gene-by-disease status interaction analyses suggest a general effect on BDNF levels. The haplotype analyses presented the same effect seen in the single marker analyses. This study suggests that SNPs in the NR3C1 and CRHR1 genes may influence BDNF levels, but this effect is blunted in the context of crack cocaine addiction. Therefore, our data may be interpreted in light of several studies showing pronounced effects of crack cocaine on BDNF levels. Since peripheral BDNF is a biomarker for several psychiatric phenotypes, our results may be useful in interpreting previous associations between stress-related SNPs, drug addiction, and depression.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Glucocorticoides/genética , Adolescente , Adulto , Fator Neurotrófico Derivado do Encéfalo/genética , Criança , Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína Crack/administração & dosagem , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Receptores de Glucocorticoides/metabolismo , Adulto JovemRESUMO
The exposition to traumatic events related to urban violence is epidemic in Brazil, with rate of 80% in the general population, and is becoming a major cause of post-traumatic stress disorder (PTSD). The objective of the study was to compare serum levels of pro-inflammatory interleukin-6 (IL-6) and anti-inflammatory interleukin-10 (IL-10) in PTSD and resilient individuals. We hypothesized that resilient individuals present an attenuated pro-inflammatory and enhanced anti-inflammatory state. We conducted a case-control study comparing 30 resilient individuals and 30 PTSD patients exposed to traumatic events related to urban violence. The groups were evaluated using Self-Report Questionnaire (SRQ-20), Mini-International Neuropsychiatric Interview (MINI) and the Davidson Trauma Scale. For all individuals, blood samples were collected to determine IL-6, IL-10 and cortisol serum levels. All samples were frozen at -80°C until the assay and were analyzed with the same immunoassay kit and in duplicates. The resilient group presented higher IL-10 levels than PTSD patients [mean (CI95%); 1.03 (0.52-2.08) pg/mL vs. 0.29 (0.20-0.43) pg/mL; P=0.002]. There were no differences in terms of IL-6 or cortisol levels. The results provided evidence for increased levels of IL-10 in resilient individuals when compared to PTSD patients, probably conferring them a better anti-inflammatory response after exposition.
Assuntos
Interleucina-10/sangue , Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos/psicologia , Violência/psicologia , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Autorrelato , Transtornos de Estresse Pós-Traumáticos/sangue , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The corticotropin-releasing hormone receptor 1 (CRHR1) gene has been repeatedly implicated in Major Depressive Disorder (MDD) in humans and animal models; however, the findings are not absolutely convergent. Since recent evidence from genome-wide association studies suggests that narrowing the phenotypic heterogeneity may be crucial in genetic studies of MDD, the aim of this study was to evaluate the effects of CRHR1 polymorphisms on MDD while addressing the influence of sex and smoking status. METHODS: The association of the CRHR1 SNPs rs12944712, rs110402, and rs878886 with MDD was evaluated in 629 Brazilian adults of European descent recruited from the general population [180 (28.6%) with lifetime MDD]. The sample was subdivided according to sex and smoking status RESULTS: Among nonsmokers, there were nominal associations between MDD and all tested SNPs (rs12944712, P=0.042; rs110402, P=0.031, and rs878886, P=0.040), regardless of sex. In addition, there were significant effects of rs110402 in women (Pcorr=0.034) and rs878886 in men (Pcorr=0.013). Among lifetime smokers, there were no significant associations between CRHR1 SNPs and MDD LIMITATIONS: The lack of a depression rating scale; scarcity of information on the functionality of the CRHR1 SNPs; and relatively small sample sizes in some subgroups. CONCLUSIONS: Our results strengthen the evidence for the role of CRHR1 SNPs in MDD susceptibility and suggest that their effects may be modulated by sex and smoking status. These findings suggest the perspective that reducing phenotypic heterogeneity is warranted in genetic studies of MDD.