Perfil fenotípico de gravidade na doença falciforme: interação gênica e/ou características intrínsecas da manifestação clínica?
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Data
2017-02-23
Autores
Okumura, Jéssika Viviani [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
Os indivíduos com Doença Falciforme (DF) apresentam manifestações clínicas variáveis que podem ser decorrentes de fatores genéticos e ambientais. O presente trabalho teve como objetivo investigar se os marcadores genéticos relacionados à vasoatividade e coagulação modulam a gravidade clínica em pessoas com DF em quatro faixas etárias. Para isso, dois grupos longitudinais foram formados, o prospectivo, que avaliou 59 crianças com DF nascidas no período de maio de 2012 a dezembro de 2013, e o retrospectivo, que avaliou 392 pessoas com DF no ano de 2011. Estes dois grupos foram divididos em quatro subgrupos de estudo, de acordo com a faixa etária, em: Crianças I (de 0 a 4 anos de idade, N=59), Crianças II (de 5 a 10 anos, N=53), Adolescentes (11 a 19 anos, N=127) e Adultos (acima de 20 anos de idade, N=212). Todos os indivíduos foram genotipados para a DF, para os haplótipos da globina beta-S, e para os polimorfismos genéticos nos genes da cistationina beta-sintase (CBS, 844ins68), enzima conversora de angiotensina I (ECA1, I/D 287 pb), enzima conversora de angiotensina II (ECA2, A1075G), inibidor do ativador do plasminogênio tipo I (PAI1, -675pb 4G/5G) e adenosina deaminase (ADA, G22A). A classificação do perfil fenotípico de gravidade do subgrupo Crianças I foi realizado pelo hematologista do HEMORIO (RJ), e dos subgrupos Crianças II, Adolescentes e Adultos pela calculadora online “Sickle Cell Disease Severity Calculator”. Com excessão do genótipo SC que foi mais frequente no subgrupo Crianças I, as frequências genotípicas e alélicas para os marcadores genéticos avaliados não diferiram entre os quatro subgrupos amostrais, porém foi verificada elevada frequência de: genótipo SS (anemia falciforme - AF), haplótipo Bantu, alelo Ins- para a CBS, alelo 5G para o PAI1, alelo D para ECA1, alelo G para ECA2 e o alelo G para ADA. Quanto aos perfis fenotípicos de gravidade clínica, no subgrupo Crianças I, Crianças II e Adolescentes, as formas leve e moderado se destacaram. No subgrupo Adultos, perfís moderado e grave estiveram presentes em aproximadamente 90% dos indivíduos. Na avaliação dos marcadores genéticos como interferentes na gravidade clínica dos indivíduos, foi verificado para o grupo prospectivo que o genótipo SS contribui com aproximadamente 22 vezes mais risco de ocorrência de clínica moderada e grave. Quando avaliados somente os indivíduos com AF do grupo prospectivo, o genótipo GG para o polimorfismo A1075G da ECA2 apresentou efeito protetor, por diminuir a ocorrência das manifestações moderadas e graves. Para o grupo retrospectivo, a presença do genótipo SS aumentou a chance de ocorrência de clínica moderada e grave em aproximadamente oito vezes e só grave um aumento de quatro vezes. Com esses resultados foi possível concluir que o genótipo SS interfere diretamente na gravidade clínica dos indivíduos com DF, e o genótipo GG do gene ECA2, apresentou efeito protetor contra perfis moderado e grave nas crianças com AF.
Sickle Cell Disease (SCD) is characterized to several clinics manifestations that vary among subjects and this clinical diversified can be caused by genetic and environmental factors. The study aim was to investigate whether genetic markers related to vaso-activity modulate clinical severity in SCD people in four age groups. Then, two longitudinal groups were formed: the prospective groups that evaluated 59 SCD children born in May 2012 to December 2013, and the retrospective group that evaluated 392 people with SCD in 2011. These groups were separated in four study subgroups according to age in: Children I (of 0 at 4 years-old, N=59), Children II (of 5 at 10 years-old, N=53), Adolescents (of 11 at 19 years-old, N=127) and Adults (above of 20 years-old, N=212). All the subjects were genotyped SCD presence, beta-S haplotypes and genetics polymorphisms in cystathionine beta-synthase (CBS, 844ins68), angiotensin converting enzyme I (ACE1, I/D 287 pb), angiotensin converting enzyme II (ACE2, A1075G), plasminogen-activator inhibitor type 1 (PAI1, -675pb 4G/5G) and adenosine deaminase (ADA, G22A) genes. The clinical severity profile classification of Children I subgroup was accomplished by Hematologist of HEMORIO, and to Children II, Adolescents and Adults subgroups was used the software online named “Sickle Cell Disease Severity Calculator”. Except for the SC genotype that was more frequent in the Children I subgroup, the genotypic and allelic frequencies for the genetic markers evaluated did not differ between the four sample subgroups, but was verified high frequence of SS genotype (Sickle Cell Anemia - SCA), Bantu haplotype, Ins-allele to CBS gene, 5G allele to PAI1 gene, D allele to ECA1 gene, G allele to ECA2 gene and G allele to ADA gene. Regarding to clinical severity profile in the Children I, Children II and Adolescents subgroups, the severity more frequent were light and moderate, and the Adults subgroup the moderate and severe classification were present in approximately 90% of subjects. In the evaluation of genetic markers as interfering in the clinical severity of subjects, was verifield to prospective group that the SS genotype contributes with approximately 22 times more the risk of moderate and severe clinical. When evaluated just the SCA patients of the prospective group, the GG genotype to A1075G of ECA2 polymorphism, presented a protective effect by reducing the occurrence of moderate and severe clinical. For the retrospective group, the presence of SS genotype increased the occurrence chance the moderate and severe clinical in approximately eight times, and, just severe clinical the presence of SS genotype increased the occurrence chance to four times. These results showed that the SS genotype directly interferes in the clinical severity of SCD individuals, and the GG genotype of the ECA2 gene had a protective effect against moderate and severe profiles in children with SCA.
Sickle Cell Disease (SCD) is characterized to several clinics manifestations that vary among subjects and this clinical diversified can be caused by genetic and environmental factors. The study aim was to investigate whether genetic markers related to vaso-activity modulate clinical severity in SCD people in four age groups. Then, two longitudinal groups were formed: the prospective groups that evaluated 59 SCD children born in May 2012 to December 2013, and the retrospective group that evaluated 392 people with SCD in 2011. These groups were separated in four study subgroups according to age in: Children I (of 0 at 4 years-old, N=59), Children II (of 5 at 10 years-old, N=53), Adolescents (of 11 at 19 years-old, N=127) and Adults (above of 20 years-old, N=212). All the subjects were genotyped SCD presence, beta-S haplotypes and genetics polymorphisms in cystathionine beta-synthase (CBS, 844ins68), angiotensin converting enzyme I (ACE1, I/D 287 pb), angiotensin converting enzyme II (ACE2, A1075G), plasminogen-activator inhibitor type 1 (PAI1, -675pb 4G/5G) and adenosine deaminase (ADA, G22A) genes. The clinical severity profile classification of Children I subgroup was accomplished by Hematologist of HEMORIO, and to Children II, Adolescents and Adults subgroups was used the software online named “Sickle Cell Disease Severity Calculator”. Except for the SC genotype that was more frequent in the Children I subgroup, the genotypic and allelic frequencies for the genetic markers evaluated did not differ between the four sample subgroups, but was verified high frequence of SS genotype (Sickle Cell Anemia - SCA), Bantu haplotype, Ins-allele to CBS gene, 5G allele to PAI1 gene, D allele to ECA1 gene, G allele to ECA2 gene and G allele to ADA gene. Regarding to clinical severity profile in the Children I, Children II and Adolescents subgroups, the severity more frequent were light and moderate, and the Adults subgroup the moderate and severe classification were present in approximately 90% of subjects. In the evaluation of genetic markers as interfering in the clinical severity of subjects, was verifield to prospective group that the SS genotype contributes with approximately 22 times more the risk of moderate and severe clinical. When evaluated just the SCA patients of the prospective group, the GG genotype to A1075G of ECA2 polymorphism, presented a protective effect by reducing the occurrence of moderate and severe clinical. For the retrospective group, the presence of SS genotype increased the occurrence chance the moderate and severe clinical in approximately eight times, and, just severe clinical the presence of SS genotype increased the occurrence chance to four times. These results showed that the SS genotype directly interferes in the clinical severity of SCD individuals, and the GG genotype of the ECA2 gene had a protective effect against moderate and severe profiles in children with SCA.
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Palavras-chave
Vaso-oclusão, Polimorfismos genéticos, Gravidade clínica, Doença falciforme