Análise de variantes genéticas no gene CYP2D6 em crianças com transtorno do espectro autista irresponsivas à terapia farmacológica com risperidona e/ou aripiprazol
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TCC
Date
2024-06-13
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Authors
Takii, Fernanda Arissa
Kertscher, Isadora
Kertscher, Isadora
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Wormsbecker, Lya Regina Mikami
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Abstract
O Transtorno do Espectro Autista (TEA) é um transtorno que compromete o desenvolvimento neuropsicomotor, dificultando a cognição, linguagem e interação social. É considerado uma condição multifatorial, com etiologia genética estimada entre 40 a 80% dos casos. Atualmente, o tratamento de sintomas comportamentais graves relacionados ao TEA é realizado com antipsicóticos, principalmente com a risperidona e o aripiprazol. Esses medicamentos são metabolizados no fígado pela enzima codificada pelo gene CYP2D6, e, alterações nesse gene podem alterar o metabolismo desses medicamentos, tornando-os ineficazes. Objetivo: Analisar as variantes genéticas polimórficas rs35742686 e rs3892097 do gene CYP2D6 em pacientes com TEA atendidos em um hospital de referência e em uma clínica de reabilitação de Curitiba. Metodologia: Estudo transversal, realizado com 42 pacientes diagnosticados com TEA que fazem/fizeram uso de risperidona e/ou aripiprazol, sendo eles 24 respondedores e 18 não respondedores à medicação. Através de coleta de swab bucal, o DNA dos pacientes foi extraído e submetido à RT- PCR para análise dos polimorfismos rs35742686 e rs3892097. Resultados: O estudo revelou uma prevalência de 6 vezes mais pacientes do sexo masculino. As características clínicas comuns incluíram déficit de comunicação e interação social (66,7% nos respondedores e 83,3% nos não respondedores) e interesses restritos (50% e 61,1%, respectivamente). Efeitos adversos aos medicamentos foram mais comuns nos irresponsivos (66,7%). Na análise genética, para rs35742686, a frequência alélica de CYP2D6*1 foi 92,09% e CYP2D6*3 7,1%. O genótipo CYP2D6*1/*1 foi encontrado em 85,71% dos indivíduos e CYP2D6*1/*3 em 14,28%. Para o rs3892097, a frequência alélica do CYP2D6*1 foi 84,5% e CYP2D6*4 foi 15,5%. O genótipo CYP2D6*1/*1 foi encontrado em 69,04% dos indivíduos e CYP2D6*1/*4 em 30,95%. Foi constatado que os alelos CYP2D6*3 e CYP2D6*4 não se segregam juntos, estando a população em equilíbrio de Hardy-Weinberg. Discussão: Foram identificadas frequências alélicas e genotípicas significativas para CYP2D6*1/*3 e CYP2D6*1/*4, embora não tenha sido encontrada diferença significativa na resposta medicamentosa. Esses resultados podem ser afetados pelo número amostral limitado e a complexidade do genótipo CYP2D6, destacando a necessidade de estudos adicionais para uma melhor compreensão das associações entre variantes genéticas e resposta medicamentosa em pacientes com TEA. Conclusão: O estudo destaca a complexidade da análise do gene CYP2D6 e a importância de fatores genéticos e não genéticos na resposta ao tratamento com antipsicóticos. Este é o primeiro estudo a fazer essa associação na população brasileira, oferecendo dados importantes para futuras pesquisas.
Autism Spectrum Disorder (ASD) is a condition that compromises neuropsychomotor development, affecting cognition, language, and social interaction. It is considered a multifactorial condition with genetic etiology estimated in 40 to 80% of cases. Currently, the treatment of severe behavioral symptoms related to ASD is done with antipsychotics, mainly risperidone and aripiprazole. These drugs are metabolized in the liver by the enzyme encoded by the CYP2D6 gene, and alterations in this gene can affect the metabolism of these drugs, making them ineffective. Objective: To analyze the polymorphic genetic variants rs35742686 and rs3892097 of the CYP2D6 gene in patients with ASD treated at a reference hospital and a rehabilitation clinic in Curitiba. Methodology: This cross-sectional study included 42 patients diagnosed with ASD who were using or had used risperidone and/or aripiprazole, of whom 24 were responders and 18 were non-responders to these medications. Oral swab samples were collected, and the patients' DNA was extracted and subjected to RT-PCR to analyze the rs35742686 and rs3892097 polymorphisms. Results: The study revealed a sixfold prevalence of male patients. The most common clinical characteristics included deficits in communication and social interaction (66.7% in responders and 83.3% in non-responders) and restricted interests (50% and 61.1%, respectively). Adverse effects of medications were more common in non-responders (66.7%). In the genetic analysis for rs35742686, the allelic frequency of CYP2D6*1 was 92.09% and CYP2D6*3 was 7.1%. The CYP2D6*1/*1 genotype was found in 85.71% of the individuals and the CYP2D6*1/*3 in 14.28%. For rs3892097, the allelic frequency of CYP2D6*1 was 84.5% and CYP2D6*4 was 15.5%. The CYP2D6*1/*1 genotype was found in 69.04% of individuals and the CYP2D61/*4 in 30.95%. It was found that the CYP2D6*3 and CYP2D6*4 alleles do not segregate together, and the population was in equilibrium by the Hardy-Weinberg calculation. Discussion: Significant allelic and genotypic frequencies for CYP2D6*1/*3 and CYP2D6*1/*4 were identified, although no significant difference was found in medication response. These results may be affected by the limited sample size and the complexity of the CYP2D6 genotype, highlighting the need for additional studies to understand better the associations between genetic variants and drug response in patients with ASD. Conclusion: This study highlights the complexity of analyzing the CYP2D6 gene and the importance of both genetic and non-genetic factors in the response to antipsychotic treatment. This is the first study to make this association in the Brazilian population, providing important data for future research.
Autism Spectrum Disorder (ASD) is a condition that compromises neuropsychomotor development, affecting cognition, language, and social interaction. It is considered a multifactorial condition with genetic etiology estimated in 40 to 80% of cases. Currently, the treatment of severe behavioral symptoms related to ASD is done with antipsychotics, mainly risperidone and aripiprazole. These drugs are metabolized in the liver by the enzyme encoded by the CYP2D6 gene, and alterations in this gene can affect the metabolism of these drugs, making them ineffective. Objective: To analyze the polymorphic genetic variants rs35742686 and rs3892097 of the CYP2D6 gene in patients with ASD treated at a reference hospital and a rehabilitation clinic in Curitiba. Methodology: This cross-sectional study included 42 patients diagnosed with ASD who were using or had used risperidone and/or aripiprazole, of whom 24 were responders and 18 were non-responders to these medications. Oral swab samples were collected, and the patients' DNA was extracted and subjected to RT-PCR to analyze the rs35742686 and rs3892097 polymorphisms. Results: The study revealed a sixfold prevalence of male patients. The most common clinical characteristics included deficits in communication and social interaction (66.7% in responders and 83.3% in non-responders) and restricted interests (50% and 61.1%, respectively). Adverse effects of medications were more common in non-responders (66.7%). In the genetic analysis for rs35742686, the allelic frequency of CYP2D6*1 was 92.09% and CYP2D6*3 was 7.1%. The CYP2D6*1/*1 genotype was found in 85.71% of the individuals and the CYP2D6*1/*3 in 14.28%. For rs3892097, the allelic frequency of CYP2D6*1 was 84.5% and CYP2D6*4 was 15.5%. The CYP2D6*1/*1 genotype was found in 69.04% of individuals and the CYP2D61/*4 in 30.95%. It was found that the CYP2D6*3 and CYP2D6*4 alleles do not segregate together, and the population was in equilibrium by the Hardy-Weinberg calculation. Discussion: Significant allelic and genotypic frequencies for CYP2D6*1/*3 and CYP2D6*1/*4 were identified, although no significant difference was found in medication response. These results may be affected by the limited sample size and the complexity of the CYP2D6 genotype, highlighting the need for additional studies to understand better the associations between genetic variants and drug response in patients with ASD. Conclusion: This study highlights the complexity of analyzing the CYP2D6 gene and the importance of both genetic and non-genetic factors in the response to antipsychotic treatment. This is the first study to make this association in the Brazilian population, providing important data for future research.
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Keywords
autismo , antipsicótico , CYP2D6 , autism , antipsychotic , CYP2D6