The aim of this study was to investigate the association between three polymorphisms involved in the oxidative stress pathway and fetal hemoglobin (Hb F) levels in patients with sickle cell anemia in a Brazilian population. One hundred and seven patients with sickle cell anemia were recruited for genomic DNA extraction. The levels of Hb F, sex and age were evaluated. Three polymorphisms, rs4673:T>C and rs9932581:G>A in the CYBA gene and rs2071746:A>T in the HMOX1 gene, were identified through direct sequencing. Hb F levels were not associated with sex, age, or the polymorphisms rs4673:T>C and rs9932581:G>A. However, the TT genotype of the rs2071746:A>T polymorphism was associated with increased levels of Hb F (p value = 0.0131). We observed an association between the TT genotype of the rs2071746:A>T polymorphism, present in the HMOX1 gene, and increased levels of Hb F, indicating the presence of a new marker related to Hb F levels in sickle cell anemia patients.
Pregnancy in Sickle Cell Disease (SCD) women is associated to increased risk of clinical and obstetrical complications. Placentas from SCD pregnancies can present increased abnormal findings, which may lead to placental insufficiency, favoring adverse perinatal outcome. These placental abnormalities are well known and reported, however little is known about the molecular mechanisms, such as epigenetics. Thus, our aim was to evaluate the DNA methylation profile in placentas from women with SCD (HbSS and HbSC genotypes), compared to uncomplicated controls (HbAA). We included in this study 11 pregnant women with HbSS, 11 with HbSC and 21 with HbAA genotypes. Illumina Methylation EPIC BeadChip was used to assess the whole placental DNA methylation. Pyrosequencing was used for array data validation and qRT-PCR was applied for gene expression analysis. Our results showed high frequency of hypermethylated CpGs sites in HbSS and HbSC groups with 73.5% and 76.2% respectively, when compared with the control group. Differentially methylated regions (DMRs) also showed an increased hypermethylation status for the HbSS (89%) and HbSC (86%) groups, when compared with the control group methylation data. DMRs were selected for methylation validation (4 DMRs-HbSS and 3 DMRs the HbSC groups) and after analyses three were validated in the HbSS group, and none in the HbSC group. The gene expression analysis showed differential expression for the PTGFR (-2.97-fold) and GPR56 (3.0-fold) genes in the HbSS group, and for the SPOCK1 (-2.40-fold) and ADCY4 (1.80-fold) genes in the HbSC group. Taken together, these data strongly suggest that SCD (HbSS and HbSC genotypes) can alter placental DNA methylation and lead to gene expression changes. These changes possibly contribute to abnormal placental development and could impact in the clinical course, especially for the fetus, possibly leading to increased risk of abortion, fetal growth restriction (FGR), stillbirth, small for gestational age newborns and prematurity.
A ata de defesa com as respectivas assinaturas dos membros encontra-se no SIGA/Sistema de Fluxo de Dissertação/Tese e na Secretaria do Programa da FCM. Data deDefesa: 21/02/2020 DEDICATÓRIA Á minha família: Aos meus pais Roselaine e Roberto pelo ensinamento de vida: simplicidade, honestidade, solidariedade, justiça e ao mais sublime de todos, o amor incondicional. Aos meus queridos e admiráveis irmãos Vanessa, Simone e Murilo pelo carinho e apoio sempre constantes. Exemplos de dedicação, responsabilidade e muita generosidade. "A família é a base da sociedade e o lugar onde as pessoas aprendem pela primeira vez os valores que as guiarão durante toda a vida" João Paulo II AGRADECIMENTOS Agradeço primeiramente a Deus por ter me dado forças para chegar até aqui. Depois de tantos momentos tristes e desafiadores foi Ele quem me deu forças para seguir e concluir esta importante etapa da minha vida.Agradeço à Dra Mônica Barbosa de Melo pela confiança depositada em meu trabalho, a qual foi de extrema importância para a conclusão deste projeto, pela atenção, paciência, ajuda em todos os momentos e a amizade construída ao longo desses anos.À Dra Maria Laura Costa, pela paciência, atenção e disponibilidade em ajudar sempre, mesmo depois de horas de plantão médico.Agradeço imensamente a minha finada, querida e amada mãe, Roselaine Gil, que tanto me incentivou, apoiou e acreditou que eu pudesse chegar até aqui. Hoje, sem sombra de dúvida, ela está alegre e radiante por eu ter alcançado essa conquista 'Muito obrigada por todo seu apoio e amor, minha mãe querida'.Agradeço aos meus irmãos Vanessa, Simone e Murilo e ao meu pai, Roberto, pela confiança e apoio em todos os momentos.Agradeço também ao Gabriel, com quem frequentemente compartilhei o meu cansaço, preocupação e os vários momentos de alegria. Agradeço pelo seu apoio, atenção e incentivo.
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