Candidate genes association study in obsessive-compulsive disorder: investigation of loci SLC6A4, HTR1B, HTR2A, SLC6A3, COMT e SLC6A2

O Transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico comum e heterogêneo caracterizado por obsessões (pensamentos, imagens ou impulsos intrusivos e recorrentes) e compulsões (comportamentos ou atos mentais repetitivos realizados para aliviar as obsessões). O TOC tem uma prevalência de 2 a 3% na população geral e apresenta distribuição aproximadamente igual entre os sexos, porém os homens tendem a apresentar os sintomas obsessivo-compulsivos mais precocemente quando comparado com as mulheres. Os estudos de genética epidemiológica têm demonstrado que o fator genético é um importante componente na etiologia do TOC. O principal objetivo desta dissertação foi investigar a influência de alguns genes candidatos na susceptibilidade para o TOC (estudo de genes candidatos) e também qual a influência destes mesmos genes na resposta terapêutica à clomipramina (estudo de farmacogenética). Realizamos o estudo de genes candidatos num total de 215 pacientes e 872 controles. Os loci investigados foram: SLC6A4, HTR1B, HTR2A, SLC6A3, COMT e SLC6A2. Os mesmos polimorfismos foram investigados em uma sub-amostra de 41 pacientes tratados com clomipramina e analisados de acordo com a resposta terapêutica. Foram classificados como respondedores ao tratamento, os pacientes que tiveram uma redução de 40% ou mais na escala YBOCS. Assim, 27 pacientes foram considerados respondedores e 14 nãorespondedores. Diferenças genotípicas e alélicas foram observadas em alguns resultados nos pacientes e controles. Entretanto, nenhuma associação foi observada nas análises para resposta à clomipramina. Os resultados sugerem que alguns polimorfismos estudados podem estar relacionados ao aumento do risco para o TOC, porém, nenhum polimorfismo foi associado à resposta terapêutica à clomipramina.Obsessive-compulsive disorder (OCD) is a common and heterogeneous psychiatric disorder characterized by obsessions (intrusive and recurrent thoughts, images or impulses) and compulsions (repetitive behaviors or mental acts performed to relive obsessions). OCD prevalence range from 2 to 3% in general population and has approximately equal sex distributions, however men tend to have an earlier age at onset of obsessive-compulsive symptoms comparing to women. Epidemiologic studies have demonstrated that genetic factor is an important component in the etiology of OCD. The aim of this study was to investigate participation of some candidate genes in the susceptibility to OCD and also their effects on clomipramine treatment. We performed a candidate gene study in a total of 215 OCD patients and 865 controls. The loci investigated were: SLC6A4, HTR1B, HTR2A, SLC6A3, COMT and SLC6A2. The same polymorphisms were investigated in a sub-sample of 41 patients treated with clomipramine, and analyzed according to therapeutic response. There were considered good responders to the drug those patients who presented a reduction of 40% or more in Y-BOCS scale. According to this, 27 patients were good responders and 14 poor responders. Genotypic and allelic differences were observed in some results for patients and controls. However, no association was observed in the analyses for clomipramine response. Our results suggest that some polymorphisms investigated may be related to the increase of risk to develop OCD, but they are not associated to therapeutic response to clomipramine

Investigation of possible association between Ser9Gly polymorphism of the D3 dopaminergic receptor gene and response to typical antipsychotics in patients with schizophrenia

Typical antipsychotics have a high affinity for dopamine receptors. It is therefore of interest to investigate such loci in pharmacogenetic studies on psychosis. We investigated the hypothesis that Ser9Gly polymorphism of the DRD3 gene may play a role in the differences in individual response to typical antipsychotics between schizophrenic patients. The sample was composed of 53 good responders and 59 poor ones. No significant differences between the good and poor responders were found in the allelic distribution (good responders: Ser9 61.32%, Gly9 38.67%; poor responders: Ser9 64.40%, Gly9 35.59%; odds ratio, OR = 0.88, 0.49 < OR < 1.56; chi2 = 0.23, 1 degree of freedom, df, p = 0.63) and genotype distribution (good responders: Ser9/Ser9 37.73%, Ser9/Gly9 47.16%, Gly9/Gly9 15.09%; poor responders: Ser9/Ser9 42.37%, Ser9/Gly9 44.06%, Gly9/Gly9 13.55%; chi2 = 0.25, 2 df, p = 0.88). Nor was there any association with homozygosity (good responders: homozygous: 52.82%, heterozygous: 47.16%; poor responders: homozygous: 55.92%, heterozygous: 44.06%; odds ratio, OR = 0.88, 0.39 < OR < 1.99; chi2 = 0.11, 1 df, p = 0.74). The results did not support the hypothesis that Ser9Gly polymorphism of the DRD3 gene influences the response to typical antipsychotics in our sample of schizophrenics

Candidate-Gene Approach in Posttraumatic Stress Disorder After Urban Violence: Association Analysis of the Genes Encoding Serotonin Transporter, Dopamine Transporter, and BDNF

Posttraumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder marked by behavioral and physiologic alterations which commonly follows a chronic course. Exposure to a traumatic event constitutes a necessary, but not sufficient, factor. There is evidence from twin studies supporting a significant genetic predisposition to PTSD. However, the precise genetic loci still remain unclear. The objective of the present study was to identify, in a case-control study, whether the brain-derived neurotrophic factor (BDNF) val66met polymorphism (rs6265), the dopamine transporter (DAT1) three prime untranslated region (3`UTR) variable number of tandem repeats (VNTR), and the serotonin transporter (5-HTTPRL) short/long variants are associated with the development of PTSD in a group of victims of urban violence. All polymorphisms were genotyped in 65 PTSD patients as well as in 34 victims of violence without PTSD and in a community control group (n = 335). We did not find a statistical significant difference between the BDNF val66met and 5-HTTPRL polymorphism and the traumatic phenotype. However, a statistical association was found between DAT1 3`UTR VNTR nine repeats and PTSD (OR = 1.82; 95% CI, 1.20-2.76). This preliminary result confirms previous reports supporting a susceptibility role for allele 9 and PTSD.FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[2004/15039-0]Ministry of Education (CAPES

RBD and Spike DNA-Based Immunization in Rabbits Elicited IgG Avidity Maturation and High Neutralizing Antibody Responses against SARS-CoV-2

Neutralizing antibodies (nAbs) are a critical part of coronavirus disease 2019 (COVID-19) research as they are used to gain insight into the immune response to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections. Among the technologies available for generating nAbs, DNA-based immunization methods are an alternative to conventional protocols. In this pilot study, we investigated whether DNA-based immunization by needle injection in rabbits was a viable approach to produce a functional antibody response. We demonstrated that three doses of DNA plasmid carrying the gene encoding the full-length spike protein (S) or the receptor binding domain (RBD) of SARS-CoV-2 induced a time-dependent increase in IgG antibody avidity maturation. Moreover, the IgG antibodies displayed high cross neutralization by live SARS-CoV-2 and pseudoviruses neutralization assays. Thus, we established a simple, low cost and feasible DNA-based immunization protocol in rabbits that elicited high IgG avidity maturation and nAbs production against SARS-CoV-2, highlighting the importance of DNA-based platforms for developing new immunization strategies against SARS-CoV-2 and future emerging epidemics