Characterization of polymorphisms associated with genetic metabolic disorders in the field of pharmacogenetics

• Autor(a) principal: Alves, Diana Lopes
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/41006
• topic: Personalized medicine; Pharmacogenetics; Inherited metabolic diseases; Phenylketonuria; Trimethylaminuria; Dihydropyrimidine dehydrogenase deficiency; Mutational spectrum; Single nucleotide polymorphisms

The existence of pathogenic variants and single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in metabolic pathways can not only cause inherited metabolic disorders (HMDs) but also have a significant impact on the pharmacokinetics of certain drugs, influencing therapeutic responses and patients' clinical prognosis. Currently, SNPs are recognized as essential biomarkers to assess drug susceptibility in various HMDs. This study aimed to broaden the mutational spectrum associated with some HMDs in the Portuguese population, such as phenylketonuria (PKU), trimethylaminuria (TMAU), and dihydropyrimidine dehydrogenase (DPD) deficiency. Additionally, we sought to correlate the impact of certain identified variants and SNPs in the context of pharmacogenetics and personalized medicine, especially regarding the therapeutic response of patients to sapropterin dihydrochloride (BH4), drugs metabolized by the FMO3 enzyme, and fluoropyrimidines. To achieve these objectives, molecular characterization was performed in a cohort of 134 patients from the Neonatal Screening, Metabolism, and Genetics Unit of the National Institute of Health Dr. Ricardo Jorge. The results allowed us to identify four new variants in the DPYD gene, thus expanding the mutational spectrum associated with DPD deficiency. We also demonstrated that the genetic variants currently available in laboratory kits for qualitative pharmacogenetic analysis of the DPYD gene are insufficient for safe therapeutic prescriptions. Regarding trimethylaminuria and phenylketonuria, we were able to establish strong associations between genotype/phenotype and predict the possible pharmacotherapeutic responses of the studied patients. This study emphasizes the importance of implementing molecular studies as a predictive tool before initiating therapy, particularly involving BH4, drugs metabolized by the FMO3 enzyme, and fluoropyrimidines. This personalized approach allows clinicians to predict the likelihood of drug efficacy and toxicity, thus individualizing treatment and improving the therapeutic safety of patients.