RESUMO
AIM: In humans, fetal hemoglobin (HbF) production is controlled by many intricate mechanisms that, to date, remain only partly understood. PATIENTS & METHODS: Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production was undertaken in a collection of Hellenic ß-thalassemia and sickle cell disease (SCD) compound heterozygotes and a collection of healthy and KLF1-haploinsufficient Maltese adults, to identify genomic signatures that follow high HbF patterns. RESULTS: KLF10 emerged as a top candidate. Moreover, genotype analysis of ß-thalassemia major and intermedia patients and an independent cohort of ß-thalassemia/SCD compound heterozygous patients that do or do not respond to HU treatment showed that the homozygous mutant state of a tagSNP in the KLF10 3'UTR is not present in ß-thalassemia intermedia patients and is underrepresented in ß-thalassemia/SCD compound heterozygous patients that respond well to HU treatment. CONCLUSION: These data suggest that KLF10 may constitute a pharmacogenomic marker to discriminate between response and nonresponse to HU treatment.
Assuntos
Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Hemoglobina Fetal/metabolismo , Hemoglobinopatias/tratamento farmacológico , Hemoglobinopatias/genética , Hidroxiureia/uso terapêutico , Fatores de Transcrição Kruppel-Like/genética , Regiões 3' não Traduzidas , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Antidrepanocíticos/uso terapêutico , Células Precursoras Eritroides/metabolismo , Feminino , Hemoglobina Fetal/genética , Expressão Gênica , Marcadores Genéticos , Hemoglobinopatias/sangue , Heterozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Transcriptoma , Talassemia beta/sangue , Talassemia beta/tratamento farmacológico , Talassemia beta/genéticaRESUMO
The implementation of genetic data for a better prediction of response to medications and adverse drug reactions is becoming a reality in some clinical fields. However, to be successful, personalized medicine should take advantage of an informational structured framework of genetic, phenotypic and environmental factors in order to provide the healthcare system with useful tools that can optimize the effectiveness of specific treatment. The impact of personalized medicine is potentially enormous, but the results that have so far been gathered are often difficult to translate into clinical practice. In this article we have summarized the most relevant applications of pharmacogenomics on diseases to which they have already been applied and fields in which they are currently emerging. The article provides an overview of the opportunities and shortcomings of the implementation of genetic information into personalized medicine and its full adoption in the clinic. In the second instance, it provides readers from different fields of expertise with an accessible interpretation to the barriers and opportunities in the use/adoption of pharmacogenomic testing between the different clinical areas.
