RESUMEN
Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not only as a susceptibility factor for attention-deficit hyperactivity disorder (ADHD), but also as a predictor of individual methylphenidate (MPH) response. Pharmacogenetic studies of MPH response in ADHD have mainly focused on the 40-bp variable number of tandem repeats (VNTR) in the 3' untranslated region (3'-UTR) of DAT1. Most studies were performed in samples of children and conflicting findings were obtained. Only two studies have assessed 3'-VNTR in samples of adults-one with positive and the other with negative findings. In the present study, we investigate three potentially relevant polymorphisms in DAT1 gene (-839 C > T; Int8 VNTR and 3'-VNTR), and their possible role in therapeutic response to MPH treatment in a sample of 171 Brazilian adults with ADHD. The diagnostic procedures followed the DSM-IV criteria and the outcome measures were the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. Drug response was assessed by both categorical and dimensional approaches. There was no effect of any DAT1 polymorphisms or haplotypes on MPH response. This is the second report demonstrating absence of differences in MPH response according to DAT1 genotypes in adults with ADHD. Although DAT protein is crucial for the effect of MPH, genetic variations in DAT1 gene probably do not have a significant clinical role in this sample of adults with ADHD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Inhibidores de Captación de Dopamina/uso terapéutico , Metilfenidato/uso terapéutico , Polimorfismo Genético , Regiones no Traducidas 3' , Adulto , Brasil , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Resultado del TratamientoRESUMEN
OBJECTIVE: The role of the human serotonin transporter protein (5-HTT) gene in psychiatric disorders suggests that its variation may influence the comorbidity pattern and the heterogeneity of alcoholism. The aim of the present study is to verify possible associations between the 5-HTTLPR control region polymorphism with alcoholism and comorbid disorders. METHODS: The polymorphic site was genotyped in 114 patients with alcohol dependence and 218 controls, all of them Brazilians of European descent. A comprehensive diagnostic interview identified the comorbid disorders. RESULTS: Study participants with alcohol dependence and controls did not differ in the genotype and allele frequencies (genotypes: chi(2) = 2.52, P = 0.28; alleles: chi(2) = 0.37; P = 0.54). Patients with comorbid major depressive disorder (chi(2) = 6.14, P = 0.01), drug abuse (chi(2) = 6.82, P = 0.01) and nicotine dependence (chi(2) = 4.10, P = 0.04), however, presented a higher frequency of the S allele than patients without these comorbidities. Patients with comorbid depression and drug abuse also presented a higher frequency of the S allele than controls. CONCLUSIONS: The present results are consistent with the importance of the 5-HTT gene in psychiatry. They suggest a role of the 5-HTTLPR polymorphism in a group of comorbid disorders among alcohol-dependent individuals, supporting a genetic influence in alcoholism heterogeneity.
Asunto(s)
Alcoholismo/genética , Polimorfismo Genético , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Alcoholismo/complicaciones , Alcoholismo/epidemiología , Brasil , Comorbilidad , Depresión/complicaciones , Depresión/genética , Genotipo , Humanos , Masculino , Valores de Referencia , Trastornos Relacionados con Sustancias/complicaciones , Trastornos Relacionados con Sustancias/genética , Tabaquismo/complicaciones , Tabaquismo/genética , Población BlancaRESUMEN
The DRD2 TaqI A and DBH-1021 C/T polymorphisms were genotyped in smoking alcoholics (N = 100), non-alcoholic smokers (N = 120) and nonsmoking controls (N = 112). Alcoholic and non-alcoholic smokers presented a higher frequency of the DRD2 TaqI A1 allele (P = 0.04) than non-smoking controls. Individuals who had at least one DBH-1021 T allele smoked fewer cigarettes per day than CC homozygotes (P = 0.03). These results are coherent with the expected effects of these polymorphisms on dopaminergic function.
Asunto(s)
Dopamina beta-Hidroxilasa/genética , Polimorfismo Genético/genética , Receptores de Dopamina D2/genética , Fumar/genética , Adulto , Alcoholismo/genética , Alelos , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 9/genética , Comorbilidad , Frecuencia de los Genes , Genotipo , Homocigoto , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Polimerasa Taq/genéticaRESUMEN
The enzyme monoamine oxidase A (MAO A) plays an important role in the metabolism of neurotransmitters. The MAOA gene presents several polymorphisms, including a 30-bp VNTR in the promoter region (MAOA-uVNTR). Alleles with 3.5 and 4 repeats are 2-10 times more efficient than the 3-repeat allele. Several studies have shown an association between the 3-repeat allele and a cluster of externalizing behaviors including alcoholism, antisocial personality, and impulsivity. The objective of the present study is to replicate in a different culture the associations between the MAOA-uVNTR with alcoholism and other phenotypes. The sample comprises 125 Brazilian alcoholics of European descent and 235 controls. The results suggest that the 3-repeat allele is associated to: (1) alcohol dependence (P < 0.05); (2) an earlier onset of alcoholism (P < 0.01); (3) comorbid drug abuse among alcoholics (P < 0.05); and (4) a higher number of antisocial symptoms (P < 0.02). Our results confirmed previous reports showing an association of the low activity 3-repeat allele of MAOA-uVNTR polymorphism with substance dependence and impulsive/antisocial behaviors. These findings in a different culture further support the influence of the MAOA-uVNTR in psychiatric disorders.