RESUMO
Preferential conversion of azathioprine or 6-mercaptopurine into methylated metabolites is a major cause of thiopurine resistance. To seek potentially Mendelian causes of thiopurine hypermethylation, we recruited 12 individuals who exhibited extreme therapeutic resistance while taking azathioprine or 6-mercaptopurine and performed whole-exome sequencing (WES) and copy-number variant analysis by array-based comparative genomic hybridisation (aCGH). Exome-wide variant filtering highlighted four genes potentially associated with thiopurine metabolism (ENOSF1 and NFS1), transport (SLC17A4) or therapeutic action (RCC2). However, variants of each gene were found only in two or three patients, and it is unclear whether these genes could influence thiopurine hypermethylation. Analysis by aCGH did not identify any unusual or pathogenic copy-number variants. This suggests that if causative mutations for the hypermethylation phenotype exist they may be heterogeneous, occurring in several different genes, or they may lie within regulatory regions not captured by WES. Alternatively, hypermethylation may arise from the involvement of multiple genes with small effects. To test this hypothesis would require recruitment of large patient samples and application of genome-wide association studies.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Resistência a Medicamentos/genética , Hepatite Autoimune/genética , Adulto , Azatioprina/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Hibridização Genômica Comparativa , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/análogos & derivados , Redes e Vias Metabólicas/genética , Metiltransferases/genética , Metiltransferases/metabolismo , Pessoa de Meia-Idade , MutaçãoRESUMO
BACKGROUND: High on-treatment platelet reactivity has been associated with poor outcomes following acute coronary syndromes (ACS). Both the loss of function CYP2C19*2 allele and the gain of function CYP2C19*17 allele along with a range of clinical characteristics have been associated with variation in the response to clopidogrel. AIM: The study aims to examine the frequency of CYP2C19 variants and understand the factors associated with on-treatment platelet reactivity in a New Zealand ACS population. METHODS: We prospectively enrolled 312 ACS patients. We collected clinical characteristics and measured on-treatment platelet reactivity using two validated point-of-care assays, VerifyNow and Multiplate. DNA was extracted and CYP2C19*2 and *17 alleles were identified using real-time polymerase chain reaction. RESULTS: CYP2C19*2 or CYP2C19*17 alleles were observed in 101 (32%) and 106 (34%) of patients, respectively, with significant differences in distribution by ethnicity. In Maori and Pacific Island patients, 47% (confidence interval (CI) 31-63%) had CYP2C19*2 and 11% (CI 4-19%) CYP2C19*17 compared with 26% (CI 19-32%) and 41% (CI 32-49%) in white people. Carriage of CYP2C19*2 alleles was associated with higher levels of platelet reactivity measured by either assay, but we observed no relationship between platelet reactivity and CYP2C19*17. In multivariate analysis diabetes, clopidogrel dose and CYP2C19*2 status were all significant independent predictors of platelet reactivity. CONCLUSIONS: Both CYP2C19*2 and *17 were common in a New Zealand ACS population, with CYP2C19*2 observed in almost half the Maori and Pacific Island patients. CYP2C19*2, diabetes and clopidogrel dose were independent contributors to on-treatment platelet reactivity.
Assuntos
Síndrome Coronariana Aguda/genética , Plaquetas/patologia , Citocromo P-450 CYP2C19/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/epidemiologia , Alelos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Testes de Função Plaquetária , Prevalência , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de DoençaRESUMO
Direct-to-consumer (DTC) DNA testing has grown from contentious beginnings into a global industry, by providing a wide range of personal genomic information directly to its clients. These companies, typified by the well-established 23andMe, generally carry out a gene-chip analysis of single-nucleotide polymorphisms (SNPs) using DNA extracted from a saliva sample. These genetic data are then assimilated and provided direct to the client, with varying degrees of interpretation. Although much debate has focused on the limitations and ethical aspects of providing genotypes for disease risk alleles, the provision of pharmacogenetic results by DTC companies is less studied. We set out to evaluate current DTC pharmacogenetics offerings, and then to consider how these services might best evolve and adapt in order to play a potentially useful future role in delivery of personalized medicine.
