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- Polimorfismos genéticos e a sua interação na suscetibilidade para a hipertensão na população portuguesaPublication . Aguiar, Laura; Semente, Ildegário; Ferreira, Joana; Matos, Andreia; Mascarenhas, Mário Rui; Menezes Falcão, Luiz; Faustino, Paula; Bicho, Manuel; Inácio, ÂngelaIntrodução: A Hipertensão Arterial (HTA) é um fator de risco cardiovascular muito prevalente em Portugal. Esta patologia é multifatorial, envolvendo fatores genéticos e ambientais. Objetivo: Este estudo teve como objetivo investigar a potencial implicação de polimorfismos genéticos nos genes eNOS e ECA e da sua interação na suscetibilidade para a HTA na população portuguesa. Métodos: Foi realizado um estudo de caso-controlo para uma amostra de 377 indivíduos portugueses, dos quais 243 hipertensos (90 hipertensos ligeiros e 153 hipertensos graves) e 134 normotensos. As análises polimórficas do VNTR no intrão 4 do gene eNOS e do polimorfismo ECA inserção/deleção (I/D) foram realizadas por reação em cadeia da polimerase (PCR). Resultados: Encontrou-se uma associação entre o alelo 4a do gene eNOS e a hipertensão (p=0,001), sendo mais forte para a hipertensão grave (p<0,001). Em relação ao gene ECA, não se encontraram diferenças estatisticamente significativas entre doentes e controlos. No entanto, ao analisar os 2 polimorfismos em epistasia, encontrou-se uma tendência para associação entre a combinação do alelo 4a do gene eNOS e do alelo D do gene ECA e a hipertensão ligeira (p=0,061). Conclusão: Os nossos resultados evidenciam o contributo do gene eNOS na HTA, assim como da interação epistática entre os genes eNOS e ECA e a suscetibilidade para a hipertensão ligeira na população portuguesa. A identificação de polimorfismos genéticos que possam influenciar o desenvolvimento e gravidade da HTA, bem como as suas interações epistáticas, pode permitir um diagnóstico mais precoce e específico para esta doença tão prevalente em Portugal.
- Ancestry of the major long-range regulatory site of the α-globin genes in the Portuguese population with the common 3.7 kb α-thalassemia deletionPublication . Pena, Rita; Lopes, Pedro; Gaspar, Gisela; Miranda, Armandina; Faustino, PaulaBackground: The α-Major Regulatory Element (α-MRE), also known as HS-40, is located upstream of the α-globin gene cluster and has a crucial role in the long-range regulation of the α-globin gene expression. This enhancer is polymorphic and several haplotypes were identified in different populations, with haplotype D almost exclusively found in African populations. The purpose of this research was to identify the HS-40 haplotype associated with the 3.7 kb α-thalassemia deletion (-α3.7del) in the Portuguese population, and determine its ancestry and influence on patients' hematological phenotype. Methods and results: We selected 111 Portuguese individuals previously analyzed by Gap-PCR to detect the presence of the -α3.7del: 50 without the -α3.7del, 34 heterozygous and 27 homozygous for the -α3.7del. The HS-40 region was amplified by PCR followed by Sanger sequencing. Four HS-40 haplotypes were found (A to D). The distribution of HS-40 haplotypes and genotypes are significantly different between individuals with and without the -α3.7del, being haplotype D and genotype AD the most prevalent in patients with this deletion in homozygosity. Furthermore, multiple correspondence analysis revealed that individuals without the -α3.7del are grouped with other European populations, while samples with the -α3.7del are separated from these and found more closely related to the African population. Conclusion: This study revealed for the first time an association of the HS-40 haplotype D with the -α3.7del in the Portuguese population, and its likely African ancestry. These results may have clinical importance as in vitro analysis of haplotype D showed a decrease in its enhancer activity on α-globin gene.
- Analysis of Genes Involved in Oxidative Stress and Iron Metabolism in Heart Failure: A Step Forward in Risk StratificationPublication . Silva, Pedro X.; Aguiar, Laura; Gaspar, Marcos; Faustino, Paula; Falcão, Luiz M.; Barbosa, Mário; Bicho, Manuel; Inácio, ÂngelaIntroduction: Heart failure (HF) is a clinical syndrome characterized by cardinal symptoms that may be accompanied by signs. It results from structural and/or functional abnormalities of the heart leading to elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. The prevalence of iron deficiency and anemia justifies the current guidelines recommendation of screening. Genes HP, ACE, MTHFR, HFE, and CYBA are involved in oxidative mechanisms, iron metabolism, and hematologic homeostasis. This study investigates the contribution of variants Hp1/2 (HP), I/D (ACE), C677T (MTHFR), C282Y and H63D ( HFE), and C242T (CYBA) to the development of HF, either independently or in epistasis. Methods: We used a database of 389 individuals, 143 HF patients, and 246 healthy controls. Genotypes were characterized through PAGE electrophoresis, PCR, PCR-RFLP, and multiplex-ARMS. Data analysis was performed with the SPSS® 26.0 software (IBM Corp., Armonk, NY). Results: We observed a significant association between the MTHFR gene and HF predisposition. The presence of allele T and genotype CT constituted risk, while genotype CC granted protection. Epistatic interactions revealed risk between genotype II of the ACE gene and genotypes CC (C282Y) or HH (H63D) of the HFE gene. Risk was also observed for interactions between genotype CC (CYBA) and genotypes 2-2 (HP), CT (MTHFR), or HH (HFE-H63D). Conclusion: We concluded that genes HP, ACE, MTHFR, HFE, and CYBA contribute to the susceptibility for HF, individually or in epistasis. This study contributes to the clarification of the role that genes involved in oxidative mechanisms and iron metabolism play in the physiopathology of HF. It is, therefore, a step forward in risk stratification and personalized medicine.