RESUMEN
BACKGROUND: Migraine is a common form of headache affecting about 12% of the population. Genetic studies in the rare form of familial hemiplegic migraine have identified mutations in 3 genes (CACNA1A, ATP1A2, and SCN1A) encoding proteins involved in ion homeostasis and suggesting that other such genes may be involved in the more common forms of migraine. OBJECTIVES: To test this proposition, the coding regions of 150 brain-expressed genes involved in ion homeostasis (ion channels, transporters, exchangers, and accessory subunits) were systematically screened to identify DNA variants in a group of 110 migraine probands and 250 control samples. METHODS: DNA variants were analyzed using a number of complementary in silico approaches. RESULTS: Several genes encoding potassium channels, including KCNK18, KCNG4, and KCNAB3, were identified as potentially linked to migraine. In situ hybridization studies of the mouse Kcnk18 ortholog show that it is developmentally expressed in the trigeminal and dorsal root ganglia, further supporting the involvement of this gene in migraine pathogenesis. CONCLUSIONS: Our study is the first to link variations in these K(+) channel genes to migraine, thus expanding on the view of migraine as a channelopathy and providing potential molecular targets for further study and therapeutic applications.
Asunto(s)
Canales Iónicos/genética , Trastornos Migrañosos/genética , Estudios de Asociación Genética , Humanos , Transporte Iónico/genéticaRESUMEN
Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.
Asunto(s)
Narcolepsia/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Animales , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 22/genética , Replicación del ADN/genética , Perros , Genotipo , Humanos , Hipotálamo/inmunología , Hipotálamo/patología , Ratones , Narcolepsia/inmunología , Polimorfismo de Nucleótido SimpleRESUMEN
Numerous studies suggest that the prevalence of depression is greater among cardiac patients than in the general population. However, little attention has been paid to the possibility of genetic contributions to depressive symptoms in cardiac patients. We conducted a candidate gene study focusing on genes related to inflammation, platelet aggregation, endothelial function and omega-3 fatty acid metabolism as predictors of depressive symptoms among 977 participants with established cardiovascular disease. Results suggested that genetic variation related to endothelial dysfunction is predictive of depressive symptoms and that endothelial dysfunction may be a novel mechanism contributing to depressive symptoms among cardiac patients.
Asunto(s)
Depresión/genética , Ácidos Grasos Omega-3/genética , Cardiopatías/genética , Inflamación/genética , Agregación Plaquetaria/genética , Alelos , Canadá/epidemiología , Depresión/complicaciones , Células Endoteliales/patología , Ácidos Grasos Omega-3/metabolismo , Femenino , Francia/etnología , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Haplotipos , Cardiopatías/epidemiología , Homocigoto , Humanos , Intrones , Modelos Lineales , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Infarto del Miocardio/genética , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Prevalencia , Factor de von Willebrand/genéticaRESUMEN
Schizophrenia is a common neuropsychiatric disorder of uncertain etiology that is believed to result from the interaction of environmental factors and multiple genes. To identify new genes predisposing to schizophrenia, numerous groups have focused on CAG-repeat-containing genes. We previously reported a CAG repeat polymorphism that was shown to be associated with both the severity of the phenotype and the response to medication in schizophrenic patients. In this article, we now report the genomic structure of this gene, the retinoic acid inducible-1 gene (RAI1), and present its characterization. This gene, located on chromosome 17p11.2, comprises six exons coding for a 7.6-kb mRNA. The RAI1 gene is highly homologous to its mouse counterpart and it is expressed at high levels mainly in neuronal tissues.