RESUMO
STUDY OBJECTIVE: To investigate potential associations between the histamine N-methyltransferase (HNMT) gene, HNMT, C314T (Thr105Ile) polymorphism and atopic dermatitis in a cohort of Caucasian children. DESIGN: Prospective, multicenter, genotype-association study. SETTING: Four academic, tertiary care medical centers within the Pediatric Pharmacology Research Unit network. PARTICIPANTS: Two hundred forty-nine Caucasian children aged 6 months-5 years with atopic dermatitis (127 patients) or without (122 control subjects). INTERVENTION: Buccal swabs (one swab/cheek) were performed to obtain epithelial cells for extraction of genomic DNA. MEASUREMENTS AND MAIN RESULTS: Data were collected on severity of atopic dermatitis, oral antihistamine treatment, and treatment response through parental report. The HNMT genotypes were successfully obtained in 116 control subjects and 122 patients with atopic dermatitis. Frequencies of the T314 variant allele (0.12 vs 0.06, p=0.04) and combined CT/TT genotype (0.24 vs 0.12, p=0.02) were significantly higher in children with atopic dermatitis compared with control subjects. Children with genotypes conferring reduced HNMT activity were 2 times more likely to have atopic dermatitis than those who were homozygous for the C314 reference allele. CONCLUSION: Increased histamine levels in patients with atopic dermatitis may result, at least in part, from reduced enzymatic inactivation via HNMT. Genetically associated reduction in histamine biotransformation may therefore contribute to the pathogenesis, persistence, and progression of atopic dermatitis. If confirmed, these data indicate that HNMT genotype might represent a common risk factor for development of atopic dermatitis, asthma, and allergic rhinitis and may be useful in identifying individuals who are candidates for early preventive pharmacotherapeutic intervention. Additional longitudinal studies will be required to assess the relationship between genotype, disease severity, and antihistamine response.
Assuntos
Dermatite Atópica/genética , Histamina N-Metiltransferase/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Alelos , Pré-Escolar , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Lactente , Masculino , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
Pediatric pharmacogenetic studies have the potential to improve the quality of medical care for children. The pediatric population presents a unique pharmacogenetic challenge as children have the additional complexity of ontological phenotypes that impact their drug response. Prescribing medications in children has historically been largely empirical, but utilization of pharmacogenetic information will allow pediatricians to gain key information regarding which patients are best suited for a particular therapeutic agent and which patients may be at risk for serious potentially life-threatening complications from standard treatment regimens. Although large, prospective, multisite investigators are still needed, we illustrate selective clinical examples of the pharmacogenetics for treatment of transplantation, asthma, leukemia and attention-deficit hyperactivity disorder in pediatric patients.
Assuntos
Tratamento Farmacológico/métodos , Farmacogenética/métodos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Asma/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Tratamento Farmacológico/normas , Humanos , Leucemia/genética , Transplante de Órgãos , Polimorfismo GenéticoRESUMO
Arylamine N-acetyltransferases (Nat) 1 and 2 catalyze the N-acetylation of aromatic amine and hydrazine drugs and carcinogens. After N-hydroxylation, they also catalyze the metabolic activation of N-hydroxy-arylamines via O-acetylation. Functional characterization of mouse Nat1 and Nat2 was investigated in an Nat2 knockout (KO) model and compared with the wild-type (WT) strain. Nat1- and Nat2-specific mRNA, determined by quantitative real-time polymerase chain reaction, was detected in all tissues examined and did not differ significantly (p > 0.05) between Nat2 KO and WT mice. Nat1 catalytic activity was present in all tissues examined and did not differ significantly (p > 0.05) between the Nat2 KO and WT mice. In contrast, Nat2 catalytic activity was present in all tissues examined from male WT mice but was below the limit of detection in all tissues of Nat2 KO mice. N-acetyltransferase activity toward the aromatic amine carcinogen 4-aminobiphenyl and O-acetyltransferase activity toward its proximate metabolite N-hydroxy-4-aminobiphenyl were both present in tissue cytosols of WT mice but were undetectable in Nat2 KO mice. Nat2 protein was readily detectable in liver cytosols of WT mice but not in liver cytosols from Nat2 KO mice. Since the reductions in Nat2 activity correlated with reductions in Nat2-specific protein but not mRNA, these results strongly suggest that insertion of the LacZ ablation cassette eliminated Nat2 protein and catalytic activity via disruption of the Nat2 protein, without significantly affecting transcription rates or transcript stability. The Nat2 KO model will be useful in future studies to assess the role of Nat2 in arylamine carcinogenesis.