RESUMO
OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, ß [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (ß [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, ß [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/genética , Genes MHC da Classe II/genética , Genes MHC Classe I/genética , Testes Genéticos , Diabetes Autoimune Latente em Adultos/genética , Adolescente , Adulto , Idade de Início , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 6/genética , Estudos de Coortes , Diabetes Mellitus Tipo 1/classificação , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Diagnóstico Diferencial , Feminino , Estudos de Associação Genética , Testes Genéticos/métodos , Humanos , Diabetes Autoimune Latente em Adultos/classificação , Diabetes Autoimune Latente em Adultos/diagnóstico , Masculino , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
OBJECTIVE: To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure. DESIGN: Prospective pharmacokinetic-pharmacogenomic observational study. SETTING: Thirteen PICUs across the United States. PATIENTS: Pediatric subjects (n = 66) mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions. INTERVENTIONS: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation. MEASUREMENTS AND MAIN RESULTS: Concentrations of morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed-effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified. CONCLUSIONS: The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors.
Assuntos
Analgésicos Opioides/sangue , Analgésicos Opioides/farmacocinética , Morfina/sangue , Morfina/farmacocinética , Respiração Artificial , Insuficiência Respiratória/terapia , Doença Aguda , Adolescente , Fatores Etários , Analgésicos Opioides/administração & dosagem , Peso Corporal , Criança , Pré-Escolar , Estado Terminal , Feminino , Genótipo , Glucuronosiltransferase/genética , Humanos , Lactente , Masculino , Morfina/administração & dosagem , Derivados da Morfina/sangue , Testes Farmacogenômicos , Estudos Prospectivos , Fatores de TempoRESUMO
OBJECTIVES: To develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically ill children with primary respiratory failure. DESIGN: Prospective pharmacokinetic-pharmacogenomic observational study. SETTING: Thirteen PICUs across the United States. PATIENTS: Pediatric subjects mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions. INTERVENTIONS: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation. MEASUREMENTS AND MAIN RESULTS: Concentrations of midazolam, the 1' (1`-hydroxymidazolam metabolite) and 4' (4`-hydroxymidazolam metabolite) hydroxyl, and the 1' and 4' glucuronide metabolites were measured. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. Body weight, age, hepatic and renal functions, and the UGT2B7 rs62298861 polymorphism are relevant predictors of midazolam pharmacokinetic variables. The estimated midazolam clearance was 0.61 L/min/70kg. Time to reach 50% complete mature midazolam and 1`-hydroxymidazolam metabolite/4`-hydroxymidazolam metabolite clearances was 1.0 and 0.97 years postmenstrual age. The final model suggested a decrease in midazolam clearance with increase in alanine transaminase and a lower clearance of the glucuronide metabolites with a renal dysfunction. In the pharmacogenomic analysis, rs62298861 and rs28365062 in the UGT2B7 gene were in high linkage disequilibrium. Minor alleles were associated with a higher 1`-hydroxymidazolam metabolite clearance in Caucasians. In the pharmacokinetic-pharmacogenomic model, clearance was expected to increase by 10% in heterozygous and 20% in homozygous for the minor allele with respect to homozygous for the major allele. CONCLUSIONS: This work leveraged available knowledge on nonheritable and heritable factors affecting midazolam pharmacokinetic in pediatric subjects with primary respiratory failure requiring mechanical ventilation, providing the basis for a future implementation of an individual-based approach to sedation.
Assuntos
Estado Terminal/terapia , Hipnóticos e Sedativos/farmacocinética , Midazolam/farmacocinética , Síndrome do Desconforto Respiratório/tratamento farmacológico , Criança , Relação Dose-Resposta a Droga , Humanos , Hipnóticos e Sedativos/administração & dosagem , Masculino , Midazolam/administração & dosagem , Testes Farmacogenômicos , Estudos Prospectivos , Respiração Artificial , Síndrome do Desconforto Respiratório/fisiopatologiaRESUMO
OBJECTIVE: To identify, in a non-hypothesis manner, novel genetic factors associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P). STUDY DESIGN: We performed a genome-wide association study in a pediatric cohort of European decent consisting of 111 NSCL/P cases and 5951 control subjects. All subjects were consecutively recruited from the Greater Philadelphia area from 2006 to 2009. High throughput genome-wide single nucleotide polymorphism genotyping was carried out with the Illumina Infinium II HumanHap550 BeadChip technology. RESULTS: We observed association at the genome-wide significance level with SNP rs987525 at a locus on 8q24, which harbors no characterized genes to date (P = 9.18 x 10(-8); odds ratio = 2.09, 95% confidence interval = 1.59 to 2.76). While searching for a replication cohort, the same genetic determinant was established through a genome-wide association study of NSCL/P in Germany, so this previous report acts as a de novo replication for our independent observation outlined here. CONCLUSIONS: These results strongly suggest that a locus on 8q24 is involved in the pathogenesis of NSCL/P.