RESUMO
Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.
Assuntos
Negro ou Afro-Americano/genética , Inibidores de Calcineurina/administração & dosagem , Citocromo P-450 CYP3A/genética , Cálculos da Dosagem de Medicamento , Imunossupressores/administração & dosagem , Transplante de Rim , Variantes Farmacogenômicos , Tacrolimo/administração & dosagem , Transplantados , Adolescente , Adulto , Idoso , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacocinética , Canadá/epidemiologia , Citocromo P-450 CYP3A/metabolismo , Feminino , Frequência do Gene , Genótipo , Rejeição de Enxerto/etnologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Masculino , Taxa de Depuração Metabólica/genética , Pessoa de Meia-Idade , Modelos Genéticos , Farmacogenética , Testes Farmacogenômicos , Fenótipo , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinética , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto JovemRESUMO
We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.
Assuntos
Negro ou Afro-Americano/genética , Citocromo P-450 CYP3A/genética , Estudo de Associação Genômica Ampla , Rejeição de Enxerto/genética , Polimorfismo de Nucleotídeo Único/genética , Complicações Pós-Operatórias/genética , Tacrolimo/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Pré-Escolar , Feminino , Seguimentos , Genótipo , Taxa de Filtração Glomerular , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etnologia , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Falência Renal Crônica/genética , Falência Renal Crônica/cirurgia , Testes de Função Renal , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Doadores de Tecidos , Transplantados , População Branca/genética , Adulto JovemRESUMO
This paper provides an overview of issues in the integration of genetic (related to hereditary DNA) and genomic (related to genes and their functions) information in cancer care for individuals and families who are part of health care systems worldwide, from low to high resourced. National and regional cancer plans have the potential to integrate genetic and genomic information with a goal of identifying and helping individuals and families with and at risk of cancer. Healthcare professionals and the public have the opportunity to increase their genetic literacy and communication about cancer family history to enhance cancer control, prevention, and tailored therapies.
Assuntos
Atenção à Saúde , Aconselhamento Genético , Neoplasias/genética , Neoplasias/terapia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Biomarcadores Tumorais/genética , Família , Testes Genéticos , Genômica , Humanos , Relações Médico-Paciente , Medição de RiscoRESUMO
Of the 430 children referred for the evaluation of short stature 100 (23%) were confirmed to have growth hormone deficiency. The male to female ratio was 1.94:1. Less than 10% belonged to the lower socio-economic group. Most of the cases (73%) presented between the ages of 6-15 years though growth failure was usually recognised earlier. Minimum of two stimulation tests were performed in each case. Seventy five GH deficient children had idiopathic GHD (IGHD) and 31% of these were familial. Fourteen had organic causes and 11 had GH resistance. Of 75 with IGHD, 18 had abnormal deliveries, breech or birth asphyxia. Multitropic pituitary hormone deficiency (MPHD) was found in 9/75 cases of idiopathic GHD and in three of the organic group. The height age was much more retarded than chronologic age in the GH resistant group (p less than 0.05) and the HA/BA ratio was also lowest in this group (p less than 0.001). Growth velocity was less than 4 cm/year in all the GHD children but was lowest in those with MPHD. The interesting feature of this study is the marked predominance of the familial cases 31% and a high incidence of growth hormone resistant cases (11%).
