RESUMO
A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334,563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio.
Assuntos
Antipsicóticos/uso terapêutico , Isoxazóis/uso terapêutico , Proteínas do Tecido Nervoso/genética , Piperidinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Método Duplo-Cego , Feminino , Estudo de Associação Genômica Ampla/métodos , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/efeitos dos fármacos , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/efeitos dos fármacos , Farmacogenética , Piperazinas/uso terapêutico , Polimorfismo de Nucleotídeo Único , Pseudogenes/genética , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/genética , Tenascina/efeitos dos fármacos , Tenascina/genética , Tiazóis/uso terapêutico , Fatores de Transcrição/efeitos dos fármacos , Adulto JovemRESUMO
Administration of certain drugs (for example, antiarrhythmics, antihistamines, antibiotics, antipsychotics) may occasionally affect myocardial repolarization and cause prolongation of the QT interval. We performed a whole genome association study of drug-induced QT prolongation after 14 days of treatment in a phase 3 clinical trial evaluating the efficacy, safety and tolerability of a novel atypical antipsychotic, iloperidone, in patients with schizophrenia. We identified DNA polymorphisms associated with QT prolongation in six loci, including the CERKL and SLCO3A1 genes. Each single nucleotide polymorphism (SNP) defined two genotype groups associated with a low mean QT change (ranging from -0.69 to 5.67 ms depending on the SNP) or a higher mean QT prolongation (ranging from 14.16 to 17.81 ms). The CERKL protein is thought to be part of the ceramide pathway, which regulates currents conducted by various potassium channels, including the hERG channel. It is well established that inhibition of the hERG channel can prolong the QT interval. SLCO3A1 is thought to play a role in the translocation of prostaglandins, which have known cardioprotective properties, including the prevention of torsades de pointes. Our findings also point to genes involved in myocardial infarction (PALLD), cardiac structure and function (BRUNOL4) and cardiac development (NRG3). Results of this pharmacogenomic study provide new insight into the clinical response to iloperidone, developed with the goal of directing therapy to those patients with the optimal benefit/risk ratio.
