RESUMO
OBJECTIVE: To identify links between altered gene imprinting in the placenta and infant neurobehavioral profiles. STUDY DESIGN: Quantitative reverse-transcription polymerase chain reaction was used to examine the expression of 22 imprinted candidate genes in a series of 106 term human primary placenta tissues. The expression pattern uncovered was associated with Neonatal Intensive Care Unit Network Neurobehavioral Scales summary scores in the corresponding infants. Clustering of the expression data was used to define distinct classes of expression. RESULTS: Significant associations were identified between classes of expression and the Neonatal Intensive Care Unit Network Neurobehavioral Scales quality of movement (P = .02) and handling (P = .006) scores. Multivariate regression demonstrated an independent effect of imprinted gene expression profile on these neurobehavioral scores after controlling for confounders. CONCLUSION: These results suggest that alterations in imprinted gene expression in the placenta are associated with infant neurodevelopmental outcomes, and suggest a role for the placenta and genomic imprinting in the placenta beyond intrauterine growth regulation.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Impressão Genômica , Transtornos Mentais/genética , Placenta/metabolismo , Metilação de DNA , Feminino , Seguimentos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Lactente , Comportamento do Lactente , Recém-Nascido , Modelos Lineares , Transtornos Mentais/fisiopatologia , Análise Multivariada , Valor Preditivo dos Testes , Gravidez , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estudos de Amostragem , Sensibilidade e Especificidade , Nascimento a TermoRESUMO
Acute lymphoblastic leukemia (ALL) likely has a multistep etiology, with initial genetic aberrations occurring early in life. An abnormal immune response to common infections has emerged as a plausible candidate for triggering the proliferation of pre-leukemic clones and the fixation of secondary genetic mutations and epigenetic alterations. We investigated whether evidence of infection with a specific common myelotropic childhood virus, parvovirus B19 (PVB19), relates to patterns of gene promoter DNA methylation in ALL patients. We serologically tested bone marrow samples at diagnosis of B-cell ALL for PVB19 infection and DNA methylation using a high-throughput bead array and found that 4.2% and 36.7% of samples were seroreactive to PVB19 IgM and IgG, respectively. Leukemia samples were grouped by DNA methylation pattern. Controlling for age and immunophenotype, unsupervised modeling confirmed that the DNA methylation pattern was associated with history of PVB19 (assessed by IgG, p = 0.02), but not recent infection (assessed by IgM). Replication assays on single genes were consistent with the association. The data indicate that a common viral illness may drive specific DNA methylation patterns in susceptible B-precursor cells, contributing to the leukemogenic potential of such cells. Infections may impact childhood leukemia by altering DNA methylation patterns and specific key genes in susceptible cells; these changes may be retained even after the clearance of infection.