RESUMO
We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'-UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6-12 years) were assessed with regard to the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3'-UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p=0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3'-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.
Assuntos
Regiões 3' não Traduzidas/genética , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Metilfenidato/uso terapêutico , Repetições Minissatélites/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Criança , Estudos Cross-Over , Feminino , Genótipo , Humanos , Masculino , Metilfenidato/administração & dosagem , Polimorfismo Genético/genética , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Instituições AcadêmicasRESUMO
BACKGROUND: A short (s) allele in the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (5HTTLPR) has been associated with low transcription of the 5-HT transporter protein, and with clinical manifestations including impulsivity, affective disorder, and bulimia nervosa. METHODS: We studied implications of the 5HTTLPR s allele for eating symptoms, psychopathologic traits, and platelet [3H-] paroxetine binding in 59 women with bulimia spectrum syndromes. RESULTS: Compared with those without it, carriers of the s allele of 5HTTLPR showed significantly more affective instability, behavioral impulsivity, interpersonal insecurity, comorbid borderline personality disorder (BPD), and lower density (Bmax) of paroxetine-binding sites. CONCLUSIONS: Our results suggest that proneness to impulsivity, affective dysregulation, and reduced central 5-HT reuptake may (in part) be codetermined by the 5HTTLPR polymorphism. However, given inconsistent 5HTTLPR expression in different populations, we speculate that we may be observing a phenotype (i.e., eating disorder)-dependent manifestation.
Assuntos
Bulimia/genética , Bulimia/fisiopatologia , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/biossíntese , Proteínas de Membrana Transportadoras/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Paroxetina/metabolismo , Polimorfismo Genético , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Adolescente , Adulto , Afeto , Bulimia/psicologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/fisiopatologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/psicologia , Feminino , Humanos , Glicoproteínas de Membrana/farmacologia , Proteínas de Membrana Transportadoras/farmacologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/farmacologia , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
BACKGROUND: An association has been observed between the catechol-O-methyltransferase (COMT) gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC), and neuropsychological task performance in healthy and schizophrenic adults. Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD) are mediated by prefrontal dopamine (DA) mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children. METHODS: The Val108/158 Met polymorphism of the COMT gene was genotyped in 118 children with ADHD (DSM-IV). The Wisconsin Card Sorting Test (WCST), Tower of London (TOL), and Self-Ordered Pointing Task (SOPT) were employed to evaluate executive functions. Neuropsychological task performance was compared across genotype groups using analysis of variance. RESULTS: ADHD children with the Val/Val, Val/Met and Met/Met genotypes were similar with regard to demographic and clinical characteristics. No genotype effects were observed for WCST standardized perseverative error scores [F2,97 = 0.67; p > 0.05], TOL standardized scores [F2,99 = 0.97; p > 0.05], and SOPT error scores [F2,108 = 0.62; p > 0.05]. CONCLUSIONS: Contrary to the observed association between WCST performance and the Val108/158 Met polymorphism of the COMT gene in both healthy and schizophrenic adults, this polymorphism does not appear to modulate executive functions in children with ADHD.
