Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder.

In the present study we investigated the influence of a series variants in genes (the serotonin transporter, glycogen synthase kinase-3beta, inositol polyphosphatase 1-phosphate, brain-derived neurotrophic factor and activator protein 2beta) related to the action of lithium carbonate, a drug used for prophylaxis in mood disorders. We used a sample of unrelated patients with bipolar disorder type I on lithium therapy for at least 2 years who met the proposed response criteria for prophylactic response. Of the 134 patients, 61 patients were considered full responders, 49 non-responders and 24 partial responders. No significant differences were observed for the genotype or allele frequencies for good, partial and poor responders for the five gene variants: for BDNF G196A (genotype: chi2 = 3.67, 4 d.f., p = 0.45; allele: chi2 = 2.31, 2 d.f., p = 0.31); for INPP1 C973A (genotype: chi2 = 1.35, 4 d.f., p = 0.85; allele: chi2 = 0.04, 2 d.f., p = 0.98); for AP-2beta [CAAA](4/5) (genotype: chi2 = 3.18; 4 d.f., p = 0.52; allele: chi2 = 0.92, 2 d.f., p = 0.063); for 5HTTLPR (genotype: chi2 = 0.67, 4 d.f., p = 0.96; allele: chi2 = 0.27, 2 d.f., p = 0.87); for GSK-3beta A-1727T (genotype: chi2 = 3.55, 4 d.f., p = 0.47; allele: chi2 = 0.48, 2 d.f., p = 0.78). These investigated variants are not predictive factors for lithium prophylactic response in our sample of bipolar disorder type I patients. However, it is still possible that a subgroup of a diverse ethnic ancestry may be predisposing to some of those variants for lithium response.

Allelic association analysis of the functional insertion/deletion polymorphism in the promoter region of the serotonin transporter gene in bipolar affective disorder.

The human serotonin transporter gene (5-HTT) is a candidate for the pathogenesis of mood disorders, including bipolar disorder (BPD). The 5-HTT gene has a 44-bp insertion/deletion polymorphism within the promoter region (5-HTTLPR) with 2 allelic forms, the long (l) and the short (s) variants, which affect transcriptional rates of the 5-HTT gene. Association between the low-activity s variant and BPD has been suggested but remains controversial, as replication has not been consistent. In the present study, we examined the frequency of this polymorphism in a group of 266 Brazilian BPD patients and 306 control subjects. Genotyping for the 5-HTTLPR was performed using PCR. The allele frequencies were found to differ between BPD patients and controls (p=0.03), with a higher frequency of the l allele in the patients compared with the controls (60.5% vs 54.4%). The distribution of genotypes also differed significantly between cases and controls (chi2=10.4, 2 df, p=0.005), with higher frequency of heterozygous l/s genotype in the BPD patient group (52.6% vs 44%). Because prior evidence from gene expression studies indicated that l/s and s/s genotypes are not distinguishable biochemically, we compared the distribution of the l/l genotype and the combined group l/s plus s/s between case and controls, but there was no significant difference (chi2=0.22). Likewise, a logistic regression model considering a dominant role for the s variant was not significant (OR=0.92, 95% CI 0.64-1.32). Our results suggest that the low-activity s variant does not influence susceptibility to BPD in our population.

Association study of dopamine D2 and D3 receptor gene polymorphisms with cocaine dependence.

Genetic factors play a role in the vulnerability to cocaine dependence. The reinforcing properties of cocaine are related to the dopaminergic system, and, in particular, the dopamine receptors have been linked to the reward mechanisms. The present study examines the role of the variants TaqI A of the dopamine D2 receptor gene and BalI of the dopamine D3 receptor gene in a Brazilian sample consisting of 730 cocaine dependents and 782 healthy controls. The studied polymorphisms did not show any difference in allelic frequencies or genotypic distribution between the groups. Our data do not support a role for the dopamine D2 receptor gene TaqI A and dopamine D3 receptor gene BalI gene polymorphisms in the susceptibility to cocaine dependence in a Brazilian sample.

Allelic association analysis of phospholipase A2 genes with schizophrenia.

Several studies suggest increased activity of phospholipase A2 in schizophrenic patients. In the present study, variants of four genes coding for phospholipase A2 enzyme groups (sPLA2, cPLA2, iPLA2 and PAFAH) were analysed in a case-control sample using 240 schizophrenic patients and 312 healthy controls. No difference was observed on the allelic and genotypic distribution of cPLA2 and sPLA2 gene polymorphisms among the groups. The PAFAH variant was very rare in our population and therefore not informative. A significant allelic (chi2=5.86, P=0.0085, odds ratio=1.38, 95% confidence interval, 1.08-1.77) and genotypic (chi2=5.4, P=0.02) association with the iPLA2 gene polymorphism was found. In conclusion, our data suggested that iPLA2 may play a role as a susceptibility gene for schizophrenia in our sample; however, confirmatory studies in independent samples are needed.

[Genes related to phospholipid metabolism as risk factors related to bipolar affective disorder]. / Genes relacionados ao metabolismo dos fosfolípides como fatores de risco para o transtorno afetivo bipolar.

The studies of genetic epidemiology provides consistent evidence of genetic factors having a major role on the risk for the bipolar affective disorder, although, vulnerability genes have not yet been identified in unequivocal form. The authors show that phospholipids play an important role in the cellular signalling processes, besides this, some studies with mood-stabilisers neurochemistry suggest that these drugs act in the phospholipase regulated signalling views. They conclude that analysis of gene variants that code enzymes of the phospholipids metabolism as potential susceptibility genes can extend the knowledge concerning the risk factors and the physiopatological mechanisms underling this mood disturbance.

Allelic association study between phospholipase A2 genes and bipolar affective disorder.

OBJECTIVES: In vivo studies demonstrating that lithium is a powerful phospholipase A2 (PLA2) inhibitor suggest that PLA2 activation, and subsequent cell signaling overactivation by increased fatty acid release may be the primary abnormality in bipolar affective disorder (BPAD), thus making PLA2 genes attractive candidates for the susceptibility to BPAD. The present study investigates polymorphisms in cytosolic phospholipase A2 (cPLA2), calcium-independent phospholipase A2 (iPLA2), and secretory phospholipase (sPLA2) genes in a Brazilian sample. METHODS: A cross-sectional study was performed with 181 unrelated DSM-IIIR BPAD subjects and 312 controls. A polymerase chain reaction-restriction fragment length polymorphism assay for BanI cPLA2 and AvrII iPLA2 polymorphisms was performed, and an ATT repeat in sPLA2 was assessed using a semiautomated genetic analyzer (ALFexpress). RESULTS: There was no significant difference observed in the allelic and genotypic distribution between the BPAD and control groups for cPLA2 (genotype: chi2 = 0.8, 2df, p = 0.6; allele chi2 = 0, 1df, p = 0.9), iPLA2 (genotype: chi2 = 1.7, 2df, p = 0.4; allele: chi2 = 0.3, 1df, p = 0.6), and sPLA2 (allele: chi2 = 3.6, 6df, p = 0.8). CONCLUSION: Our results failed to demonstrate that the studied PLA2 polymorphisms were associated with an increased risk for BPAD in our sample.

Alcoolismo no Nordeste do Brasil: prevalência e perfil sociodemográfico dos afetados / Alcolism in the Northeas of the Brazil – prevalence and social demographic profile of the sample

Objetivo: Esse inquérito epidemiológico verificou a prevalência de alcoolismo e o uso de álcool nas famílias mais antigas e numerosas da população da ilha de Fernando de Noronha, estado de Pernambuco, Brasil, e tentou identificar o perfil sociodemográfico associadoa este problema naquela região. Métodos: A amostra representativa da população foi composta por 119 pessoas. O instrumento de investigação incluiu perguntas sobre os dados sociodemográficos da amostra e caracterização do consumo de álcool. Para avaliar a prevalência de alcoolismo, entre estes indivíduos, utilizou-se instrumento de rastreamentopara distúrbios relacionados ao álcool û o CAGE û, levando-se em conta o ponto de corte de uma ou mais respostas positivas para definir alcoolistas. Resultados: Observou-se prevalênciade consumo global de álcool em 62,2% da amostra e de alcoolismo em 40,34%,sendo 50,9% para homens e 30,6% para mulheres. Homens, solteiros, separados e viúvos não praticantes da religião protestante apresentaram risco significativamente mais elevado de alcoolismo nessa região. Conclusão: Os resultados obtidos foram comparados com estudos anteriores em outras populações e novas linhas de pesquisa são sugeridas.

Objective: The epidemiological survey was conducted to determine the prevalence of alcoholism and use of alcohol among the oldest and biggest families which make up the populationof the island of Fernando de Noronha, state of Pernambuco, Brazil, as well as to identify a socio-demographic profile associated with this problem in that region. Methods: A representativesample of the population was composed by 119 individuals. The instrument of research included questions on demographic and social data of the sample, and characterization of alcoholconsumption. To assess the prevalence of alcoholism among these people, we used an instrument for screening alcohol related disturbances û the CAGE û and in this analyses it was taken into consideration, one or more positive answers to define the alcoholics. Results: Results show an overall prevalence of alcohol consumption at 62.2% of the sample and alcoholism of40.34%, with 50.9% for men and 30.6% for women. Male, unmarried, divorced and widowed individuals, not practitioners of the Protestant religion showed significant higher risk of alcoholism. Conclusion: The results were compared with previous studies in other populations and new lines of research are suggested.

Genes relacionados ao metabolismo dos fosfolípides como fatores de risco para o transtorno afetivo bipolar / Genes related to phospholipid metabolism as risk factors related to bipolar affective disorder

Os estudos de epidemiologia genética fornecem consistente evidência de que o componente genético tem um papel preponderante no risco para o Transtorno Afetivo Bipolar (TAB), embora genes de vulnerabilidade ainda näo tenham sido identificados de forma inequívoca. Nesta atualizaçäo os autores apresentam dados demonstrando que os fosfolípides exercem um relevante papel nos processos de sinalizaçäo intracelular e que estudos da neuroquímica dos estabilizadores do humor convergem em apontar para uma açäo destas drogas nas vias de transduçäo de sinais reguladas pelas fosfolipases. Concluem que investigações de variantes nos genes que codificam enzimas do metabolismo dos fosfolípides como potenciais genes de susceptibilidade podem ampliar o conhecimento acerca dos fatores de risco e dos mecanismos fisiopatológicos envolvidos no surgimento destes transtornos do humor

O fenômeno da antecipaçäo genética e a expansäo de repetiçöes trinucleotídicas no transtorno afetivo bipolar: análise de ligaçäo e associaçäo dos loci erda1, sef2-1b, hskca3 e mab21L com o transtorno afetivo bipolar / The Phenomenon of genetic anticipation and the trinucleotide repeats expansions in the bipolar affective disorder: linkage and association analysis of the erda1, sef2-1b, hSKCa3 and mab21L loci with the bipolar affective disorder

No início da década de 1990 descobriu-se que a base biológica para o fenômeno de antecipação genética era a expansão de grupos de três nucleotídios repetidos. Estudos recentes relatam a presença do fenômeno de antecipação em famílias com múltiplos afetados pelo transtorno afetivo bipolar. Ao lado disso, investigações independentes utilizando o método RED (Repeat Expansion Detection) - uma estratégia que detecta expansões de repetições trinucleotídicas no DNA genômico sem identificar sua localização têm mostrado associação entre este distúrbio do humor e longas repetições da seqüência nucleotídica CAG. No presente estudo testamos a hipótese de que loci com repetições CAG estão envolvidos na vulnerabilidade genética ao transtorno afetivo bipolar. Assim, analisamos o comprimento das repetições CAG presentes em quatro loci: o locus ERDA1 na região cromossômica l7q2l.3 ao qual tem sido atribuído a maioria das repetições CAG detectadas pelo RED, o locus SEF2-lb que situa-se na região l8q21.1, onde há relatos positivos de ligação e os loci hSKCa3 (região lq2l) e MAB2lL (região l3ql3), ambos devido a função do gene na qual as repetições residem. Inicialmente, investigamos quatorze famílias brasileiras com múltiplos afetados pelo transtorno bipolar, que tiveram a idade de início da doença comparada na 1ª e na 2ª geração revelando antecipação. Averiguamos ainda uma amostra de 115 pacientes bipolares não-aparentados e 196 indivíduos controles. As repetições CAG foram amplificadas por PCR, os produtos submetidos a eletroforese em gel de poliacrilamida e as bandas visualizadas após coloração com SYBR gold em aparelho de fluorescência direta (Fluorimager system), possibilitando definir os alelos de acordo com o tamanho da seqüência CAG. O teste ampliado para desequilíbrio de transmissão (ETDT) que utilizamos nas famílias não evidenciou transmissão preferencial de nenhum dos alelos para os membros afetados (ERDA1 X2=11,05/p=O,l36; SEF2-lb X2=4,42/p=O,62; hSKCa3 X2=0,88/p=O,92; MAB2lL X2=5,76/p=O,45). A análise de ligação por testes paramétricos e não-paramétricos excluiu ligação entre qualquer dos quatro loci e a doença bipolar (ERDA1 lod score= -lO,78/ p=O,27; SEF2-lb lod score= -5,87/p=O,6; hSKCa3 lod score=-2,Ol/p=O,59; MAB2lL lod score=-12,46/p=O,83). No estudo caso-controle, a distribuição dos alelos entre pacientes bipolares e controles foi comparada através do teste U de Mann-Whitney e não demonstrou diferenças significativas ...(au)