RESUMO
The serotonin transporter (5-HTT) is a candidate gene for bipolar disorder (BPD). It has been investigated for association with the illness in a series of studies, but overall results have been inconsistent and its role in the disorder remains controversial. Systematic reviews using meta-analytical techniques are a useful method for objectively and reproducibly assessing individual studies and generating combined results. We performed two meta-analyses of published studies--both population-based and family-based studies--investigating the association between BPD and the 5-HTT gene-linked polymorphic region (5-HTTLPR) and the intron 2 variable numbers of tandem repeats (VNTR) polymorphisms. The literature was searched using Medline and Embase to identify studies for inclusion. We statistically joined population-based and family-based studies into a single meta-analysis. For both polymorphisms, our review revealed significant pooled odds ratios (ORs): 1.12 (95% CI 1.03-1.21) for the 5-HTTLPR and 1.12 (95% CI 1.02-1.22) for the intron 2 VNTR. Meta-regression showed that neither the study type (population-based vs family-based; P=0.41 for the 5-HTTLPR and P=0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P=0.35 for the 5-HTTLPR and P=0.66 for the intron 2 VNTR) significantly contributed to the heterogeneity of the meta-analyses. The observed ORs could be regarded simply as a very small but detectable effect of the 5-HTT, which has an additive effect when combined with other susceptibility loci. Alternative hypotheses on this finding were also discussed: a stronger effect of the haplotypes involving the two polymorphisms or other SNP markers; a more direct effect of these polymorphisms on specific phenotypes of BPD; and the presence of gene-environment interaction as a mediator of the genetic effects of 5-HTT.
Assuntos
Transtorno Bipolar/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Transtorno Bipolar/etiologia , Meio Ambiente , Família , Feminino , Humanos , Masculino , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
Family and twin studies have supported a strong genetic factor in the etiology of obsessive-compulsive disorder (OCD), although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. In this cross-sectional study, we have examined the allelic and genotypic frequencies of a Val-158-Met substitution in the COMT gene, a 44-base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5-HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects. There were no observed differences in the frequencies of allele and genotype between patients and control groups for the COMT, the 5HTTLPR and the T102C 5HT2A gene polymorphisms. In contrast, a statistically significant difference between OCD patients and controls was observed on the genotypic distribution (chi(2) = 16.7, 2df, P = 0.0002) and on the allelic frequencies (chi(2) = 15.8, 1df, P = 0.00007) for the C516T 5HT2A gene polymorphism. The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in our sample. However, further studies using larger samples and family based methods are recommended to confirm these findings.
Assuntos
Proteínas de Transporte/genética , Catecol O-Metiltransferase/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Transtorno Obsessivo-Compulsivo/genética , Polimorfismo Genético/genética , Receptor 5-HT2A de Serotonina/genética , Adulto , Substituição de Aminoácidos/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Masculino , Valores de Referência , Sequências Reguladoras de Ácido Nucleico/genética , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
Several reports have suggested the presence of anticipation in bipolar affective disorder (BPAD). In addition, independent studies using the RED (repeat expansion detection) have shown association between BPAD and longer CAG/CTG repeats. Therefore loci with large CAG/CTG repeats are plausible candidates in the inheritance of BPAD. The present study assesses the length of the repeats in four loci: the ERDA-1 locus which is known to account for most of the long CAG repeats detected by RED, the SEF2-1b locus which is placed in a region where positive linkage results have been reported and the loci MAB21L and KCNN3 as functional candidate genes. A Brazilian case-control sample with 115 unrelated BPAD patients and 196 healthy control subjects and 14 multiply affected bipolar families was investigated. With the case-control design the distribution of alleles between the two groups did not approach statistical significance. The extended transmission disequilibrium test (ETDT) performed in our families did not show evidence for linkage disequilibrium. Parametric and non-parametric linkage analysis also did not provide support for linkage between any of the four loci and BPAD. Our data do not support the hypothesis that variation at the polymorphic CAG/CTG repeat loci ERDA-1, SEF2-1b, MAB21L or KCNN3 influence susceptibility to BPAD in our sample.
Assuntos
Transtorno Bipolar/genética , Proteínas de Ligação a DNA , Proteínas de Homeodomínio/genética , Polimorfismo Genético , Canais de Potássio Cálcio-Ativados , Canais de Potássio/genética , Transativadores/genética , Fatores de Transcrição , Repetições de Trinucleotídeos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Ligação Genética , Marcadores Genéticos , Genótipo , Sequências Hélice-Alça-Hélice , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Canais de Potássio Ativados por Cálcio de Condutância Baixa , Estatística como Assunto , Estatísticas não Paramétricas , Fatores de Transcrição TCF , Fator de Transcrição 4 , Proteína 2 Semelhante ao Fator 7 de TranscriçãoRESUMO
A possible participation of the renin-angiotensin system (RAS) components with mood disturbances has been suggested in both animal and pharmacological models. In this cross-sectional study, we examined the association between functional polymorphisms in the angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes in 115 bipolar affective disorder (BPAD) patients and 323healthy control subjects. The ACE I/D variant did not show any difference in allelic frequencies and genotypic distribution between the groups. In contrast, when studying the AGT M235T polymorphism we found that the M allele was more frequently observed in BPAD patients than in controls (chi(2)=6.766, d.f.=1, P=0.009). Using multivariate logistic models the strongest odds ratio resulted from a dominant genetic model (OR=3.0; CI (95%) 1.7-5.3] Our data suggest an association between the AGT M235 genotype and increased susceptibility for BPAD in these Brazilian patients. These findings are consistent with the hypothesis that the RAS system plays a role in regulating the mood
