Biomarcadores moleculares relacionados à presença de acidente vascular encefálico e síndrome torácica aguda em anemia falciforme
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Data
2017-02-22
Autores
Salvarani, Mariana [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A Anemia Falciforme (AF) é caracterizada pela presença da hemoglobina S em homozigose (Hb SS). As pessoas com AF frequentemente apresentam manifestações clínicas relacionadas a processos de vaso-oclusão como o acidente vascular encefálico (AVE) e síndrome torácica aguda (STA). A regulação da vasoconstrição e vasodilatação é um fator importante na modulação destas manifestações clínicas, sendo alvo de estudos. Neste trabalho, os polimorfismos nos genes de duas enzimas – enzima conversora de angiotensina 1 e 2 (ECA1 e ECA2) e o polimorfismo do inibidor do ativador do plasminogênio tipo 1, relacionado com a fibrinólise, foram avaliados. O Sistema Renina-Angiotensina-Aldosterona atua na manutenção da pressão arterial e do volume sanguíneo por meio do equilíbrio hídrico e eletrolítico e regulação do tônus vascular. A ECA 1 é a principal enzima desse sistema, e cliva a Angiotensina I em Angiotensina II, um potente vasoconstritor. Uma enzima homóloga, a ECA 2, é capaz de clivar a Angiotensina II em Angiotensina 1-7, uma vasodilatadora. Os polimorfismos I/D no gene ECA1 (rs1799752) e A/G (rs2106809) no gene ECA2 foram estudados neste trabalho. Além disso, a regulação fibrinolítica também está relacionada às manifestações clínicas na AF. O inibidor do ativador do plasminogênio tipo 1 (PAI-1) é um regulador da fibrinólise, inibindo os ativadores do plasminogênio e a formação de plasmina, responsável pela degradação do coágulo. O polimorfismo mais estudado no gene PAI1, de inserção de uma guanina (4G/5G) (rs1799889) na região promotora do gene, aumenta a atividade de enzima e diminui a ação fibrinolítica. Para verificar se estes polimorfismos estão relacionados à presença das manifestações clínicas, STA e AVE, foram genotipadas 392 pessoas com AF. As amostras foram caracterizadas segundo seu perfil hemoglobínico, e submetidas à extração de DNA, e utilizadas para a detecção dos polimorfismos por PCR-RFLP. As frequências dos polimorfismos foram analisadas em conjunto com as informações de ocorrência das manifestações clínicas, que foram obtidas dos prontuários médicos. O genótipo mais frequente encontrado para o polimorfismo I/D no gene ECA1 foi o heterozigoto ID (47,2%) e o alelo mais frequente foi o D (57,3%). Para o polimorfismo A/G no gene ECA2 o genótipo mais frequente foi o homozigoto GG (45,3%) entre as mulheres, e o alelo G foi mais frequente entre homens e mulheres (60% e 65,4%, respectivamente). Para o polimorfismo no gene PAI1 encontramos maior frequência do genótipo 5G/5G (48%) e do alelo 5G (67,4%). No grupo estudado não há diferença significativa entre as frequências dos polimorfismos. Foi realizada análise de regressão logística múltipla para verificar se a presença dos polimorfismos estaria relacionada a ocorrência de STA e AVE nesse grupo. Não encontramos diferença estatística significante para os valores de Odds Ratio para a relação entre os polimorfismos e as manifestações clinicas nos modelos de herança dominante e recessivo, indicando que os polimorfismos estudados não estão associados com a presença de STA e AVE no grupo estudado.
Sickle cell anemia (SCA) is characterized by the presence of hemoglobin S in homozygous (Hb SS). People with AF frequently presents clinical manifestations related to vaso-occlusion processes such as stroke and acute chest syndrome (ACS). The regulation of vasoconstriction and vasodilation is an important factor in the modulation of these complications, being the object of many studies. In this work, the polymorphisms in the genes of two enzymes - angiotensin-converting enzyme 1 and 2 (ACE1 and ACE2) - and fibrinolysis-related plasminogen activator inhibitor type 1 polymorphism were evaluated. The Renin-Angiotensin-Aldosterone System acts in the maintenance of blood pressure and blood volume through fluid and electrolyte balance and vasodilation and vasoconstriction. ACE 1 is the main enzyme in this system, and cleaves Angiotensin I in Angiotensin II, a potent vasoconstrictor. A homologous enzyme, ACE 2, is capable of cleaving Angiotensin II in Angiotensin I-7, a vasodilator. The I/D polymorphisms in the ACE1 gene (rs1799752) and A/G (rs2106809) in the ACE2 gene are studied in this paper. In addition, fibrinolytic regulation is also related to clinical complications in SCD. The plasminogen activator inhibitor type 1 (PAI-1) is a regulator of fibrinolysis, inhibiting plasminogen activators and the formation of plasmin, responsible for clot degradation. The most studied polymorphism in the PAI1 gene, of insertion of a guanine (4G/5G) in the promoter region of the gene, increases the enzyme activity and decreases the fibrinolytic action. To verify if these polymorphisms are related to the presence of the clinical manifestations, stroke and ACS, we genotyped 392 people with SCA. The samples were characterized according to their hemoglobin profile, subjected to DNA extraction, and used for the detection of polymorphisms by PCR-RFLP. The frequencies of the polymorphisms were analyzed mutually with the occurrence information of the clinical manifestations, which were obtained from the medical records. The most frequent genotype found for the I/D polymorphism in the ACE1 gene was heterozygous ID (47.2%) and the most frequent allele was D (57.3%). For the A/G polymorphism in the ACE2 gene, the most common genotype was the G/G homozygote (45.3%) among the women, and the G allele was more frequent between men and women (60% and 65.4%, respectively). For polymorphism in the PAI1 gene we found a higher frequency of the 5G/5G genotype (48%) and the 5G allele (67.4%). In the studied group there is no significant difference between the frequencies of the polymorphisms. Multiple logistic regression analysis was performed to verify if the presence of polymorphisms would be related to the occurrence of stroke and ACS in this group. There were no significant statistical difference for Odds Ratio values for the relationship between polymorphisms and clinical manifestations in dominant and recessive inheritance models, indicating that the polymorphisms studied are not associated with the presence of ACS and stroke in the studied group.
Sickle cell anemia (SCA) is characterized by the presence of hemoglobin S in homozygous (Hb SS). People with AF frequently presents clinical manifestations related to vaso-occlusion processes such as stroke and acute chest syndrome (ACS). The regulation of vasoconstriction and vasodilation is an important factor in the modulation of these complications, being the object of many studies. In this work, the polymorphisms in the genes of two enzymes - angiotensin-converting enzyme 1 and 2 (ACE1 and ACE2) - and fibrinolysis-related plasminogen activator inhibitor type 1 polymorphism were evaluated. The Renin-Angiotensin-Aldosterone System acts in the maintenance of blood pressure and blood volume through fluid and electrolyte balance and vasodilation and vasoconstriction. ACE 1 is the main enzyme in this system, and cleaves Angiotensin I in Angiotensin II, a potent vasoconstrictor. A homologous enzyme, ACE 2, is capable of cleaving Angiotensin II in Angiotensin I-7, a vasodilator. The I/D polymorphisms in the ACE1 gene (rs1799752) and A/G (rs2106809) in the ACE2 gene are studied in this paper. In addition, fibrinolytic regulation is also related to clinical complications in SCD. The plasminogen activator inhibitor type 1 (PAI-1) is a regulator of fibrinolysis, inhibiting plasminogen activators and the formation of plasmin, responsible for clot degradation. The most studied polymorphism in the PAI1 gene, of insertion of a guanine (4G/5G) in the promoter region of the gene, increases the enzyme activity and decreases the fibrinolytic action. To verify if these polymorphisms are related to the presence of the clinical manifestations, stroke and ACS, we genotyped 392 people with SCA. The samples were characterized according to their hemoglobin profile, subjected to DNA extraction, and used for the detection of polymorphisms by PCR-RFLP. The frequencies of the polymorphisms were analyzed mutually with the occurrence information of the clinical manifestations, which were obtained from the medical records. The most frequent genotype found for the I/D polymorphism in the ACE1 gene was heterozygous ID (47.2%) and the most frequent allele was D (57.3%). For the A/G polymorphism in the ACE2 gene, the most common genotype was the G/G homozygote (45.3%) among the women, and the G allele was more frequent between men and women (60% and 65.4%, respectively). For polymorphism in the PAI1 gene we found a higher frequency of the 5G/5G genotype (48%) and the 5G allele (67.4%). In the studied group there is no significant difference between the frequencies of the polymorphisms. Multiple logistic regression analysis was performed to verify if the presence of polymorphisms would be related to the occurrence of stroke and ACS in this group. There were no significant statistical difference for Odds Ratio values for the relationship between polymorphisms and clinical manifestations in dominant and recessive inheritance models, indicating that the polymorphisms studied are not associated with the presence of ACS and stroke in the studied group.
Descrição
Palavras-chave
Vaso-occlusion, Vaso-oclusão, Plasminogen activator inhibitor type 1, Polimorfismo, Polymorphism, Enzima conversora de angiotensina, Angiotensin-converting enzyme, Inibidor do ativador do plasminogênio tipo 1