RESUMO
OBJECTIVE: Exposure to antenatal maternal anxiety and complex genetic variations may shape fetal brain development. In particular, the catechol-O-methyltransferase (COMT) gene, located on chromosome 22q11.2, regulates catecholamine signaling in the prefrontal cortex and is implicated in anxiety, pain, and stress responsivity. This study examined whether individual single-nucleotide polymorphisms (SNPs) of the COMT gene and their haplotypes moderate the association between antenatal maternal anxiety and in utero cortical development. METHOD: A total of 146 neonates were genotyped and underwent MRI shortly after birth. Neonatal cortical morphology was characterized using cortical thickness. Antenatal maternal anxiety was assessed using the State-Trait Anxiety Inventory at week 26 of pregnancy. RESULTS: Individual COMT SNPs (val158met, rs737865, and rs165599) modulated the association between antenatal maternal anxiety and the prefrontal and parietal cortical thickness in neonates. Based on haplotype trend regression analysis, findings also showed that among rs737865-val158met-rs165599 haplotypes, the A-val-G (AGG) haplotype probabilities modulated positive associations of antenatal maternal anxiety with cortical thickness in the right ventrolateral prefrontal cortex and the right superior parietal cortex and precuneus. In contrast, the G-met-A (GAA) haplotype probabilities modulated negative associations of antenatal maternal anxiety with cortical thickness in bilateral precentral gyrus and the dorsolateral prefrontal cortex. CONCLUSIONS: These results suggest that the association between maternal anxiety and in utero neurodevelopment is modified through complex genetic variation in COMT. Such genetic moderation may explain, in part, the variation in phenotypic outcomes in offspring associated with maternal emotional well-being.
Assuntos
Ansiedade , Catecol O-Metiltransferase/genética , Desenvolvimento Fetal/genética , Lobo Parietal , Córtex Pré-Frontal , Complicações na Gravidez , Ansiedade/diagnóstico , Ansiedade/genética , Ansiedade/psicologia , Feminino , Haplótipos , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Relações Materno-Fetais , Lobo Parietal/crescimento & desenvolvimento , Lobo Parietal/patologia , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/patologia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/genética , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal , Escalas de Graduação Psiquiátrica , SingapuraRESUMO
We describe a methodology for detecting differentially methylated regions (DMRs) and variably methylated regions (VMRs), in data from Infinium 450K arrays that are very widely used in epigenetic studies. Region detection is more specific than single CpG analysis as it increases the extent of common findings between studies, and is more powerful as it reduces the multiple testing problem inherent in epigenetic whole-genome association studies (EWAS). In addition, results driven by single erroneous probes are removed. We have used multiple publicly available Infinium 450K data sets to generate a consensus list of DMRs for age, supporting the hypothesis that aging is associated with specific epigenetic modifications. The consensus aging DMRs are significantly enriched for muscle biogenesis pathways. We find a massive increase in VMRs with age and in regions of the genome associated with open chromatin and neurotransmission. Old age VMRs are significantly enriched for neurotransmission pathways. EWAS studies should investigate the role of this interindividual variation in DNA methylation, in the age-associated diseases of sarcopenia and dementia.
Assuntos
Envelhecimento/genética , Metilação de DNA/genética , Músculos/metabolismo , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Transdução de Sinais/genética , Adolescente , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cromatina/metabolismo , Ilhas de CpG/genética , Sondas de DNA/metabolismo , Desoxirribonuclease I/metabolismo , Feminino , Genes , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors.