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Variabilidade genética e hematológica dos portadores de beta-talassémia
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Resumo(s)
A β-talassémia é uma doença genética resultante de mutações que afetam a expressão do gene HBB e, consequentemente, a síntese da hemoglobina. Neste trabalho, caracterizámos a variabilidade genética e fenotípica dos portadores de β-talassémia (indivíduos heterozigóticos) em Portugal. Investigámos, também, a contribuição da anemia ferropénica, α-talassémia, δ-talassémia e polimorfismos em gene associados com o metabolismo do ferro (HFE e TMPRSS6), para essa variabilidade.
A população de estudo consistiu em 139 portadores de β-talassémia cujos fenótipos já se encontravam caracterizados. Os genes HBB, HBA, HBD, HFE e TMPRSS6 foram genotipados por PCR, Gap-PCR e sequenciação de Sanger. As análises estatísticas foram efetuadas em SPSS v23.0.
Identificámos sete mutações β-talassémicas diferentes: β0Cd39(C>T), β0IVS-I- 1(G>A), β++IVS-I-6(T>C), β+IVS-I-110(G>A), β0Cd15(G>A), β0Cd6(-A) e β0Cd41/42(- CTTT). Concluímos que o tipo de mutação afeta o fenótipo hematológico, pois o grupo com mutações β0 apresenta valores mais baixos de hemoglobina, microcitose e hipocromia mais acentuadas e HbA2 mais elevada. Onze casos tinham HbA2 borderline, seis devido a mutação β++IVS-I-6T>C e um por co-herança de HbA2-Yialousa. A dupla heterozigotia α-β-talassémia foi detetada em três casos e tende a melhorar os parâmetros eritrocitários.
A anemia ferropénica foi observada em 18,7% dos casos. Contudo, a co-herança do polimorfismo V736A em TMPRSS6 não afeta o fenótipo hematológico, nem a homeostase do ferro nos portadores de β-talassémia. A sobrecarga em ferro também foi observada em alguns participantes. A saturação da transferrina estava elevada em 13,2% dos casos e em associação com maior frequência de H63D em HFE (46,7% versus 33,1%), o que sugere que este polimorfismo estará a contribuir para o desenvolvimento deste fenótipo.
Com este estudo contribuímos para o conhecimento da fisiopatologia da doença e, igualmente, para a diminuição de falsos diagnósticos negativos. Um portador de β- talassémia não diagnosticado desconhece o seu risco de ter descendência gravemente afetada com a doença.
The β-thalassemia is a genetic disease resulting from mutations that affect the expression of the HBB gene and, consequently, the synthesis of hemoglobin. In this work, we characterized the genetic and phenotypic variability of β-thalassemia carriers (heterozygous individuals) in Portugal. We also investigated the contribution of iron deficiency anemia, α-thalassemia, δ-thalassemia, and polymorphisms in genes associated with iron metabolism (HFE and TMPRSS6) to this variability. The study population consisted of 139 β-thalassemia carriers whose phenotypes has already been characterized. The HBB, HBA, HBD, HFE and TMPRSS6 genes were genotyped by PCR, Gap-PCR and Sanger sequencing. Statistical analyses were performed using SPSS v23.0. We identified seven different β-thalassemia mutations: β0Cd39(C>T), β0IVS-I- 1(G>A), β++IVS-I-6(T>C), β+IVS-I-110(G>A), β0Cd15(G>A), β0Cd6(-A) and β0Cd41/42(-CTTT). We conclude that the type of mutation affects the hematological phenotype, as the group with β0 mutations has lower hemoglobin values, more pronounced microcytosis and hypochromia and higher HbA2. Eleven cases had borderline HbA2, six due to β++IVS-I-6T>C mutation and one by HbA2-Yialousa co-heritance. The α-β-thalassemia double heterozygosity was detected in three cases and tends to improve erythrocyte parameters. Iron deficiency anemia was observed in 18.7% of cases. However, co-inheritance of the V736A polymorphism in TMPRSS6 does not affect the hematological phenotype or iron homeostasis in β-thalassemia carriers. Iron overload was also observed in some participants. Transferrin saturation was elevated in 13.2% of cases and in association with higher frequency of H63D in HFE (46.7% versus 33.1%), which suggests that this polymorphism is contributing to the development of this phenotype. With this study, we contribute to the knowledge of the pathophysiology of the disease and to the reduction of false negative diagnoses. An undiagnosed β-thalassemia carrier is unaware of his risk of having offspring severely affected with the disease.
The β-thalassemia is a genetic disease resulting from mutations that affect the expression of the HBB gene and, consequently, the synthesis of hemoglobin. In this work, we characterized the genetic and phenotypic variability of β-thalassemia carriers (heterozygous individuals) in Portugal. We also investigated the contribution of iron deficiency anemia, α-thalassemia, δ-thalassemia, and polymorphisms in genes associated with iron metabolism (HFE and TMPRSS6) to this variability. The study population consisted of 139 β-thalassemia carriers whose phenotypes has already been characterized. The HBB, HBA, HBD, HFE and TMPRSS6 genes were genotyped by PCR, Gap-PCR and Sanger sequencing. Statistical analyses were performed using SPSS v23.0. We identified seven different β-thalassemia mutations: β0Cd39(C>T), β0IVS-I- 1(G>A), β++IVS-I-6(T>C), β+IVS-I-110(G>A), β0Cd15(G>A), β0Cd6(-A) and β0Cd41/42(-CTTT). We conclude that the type of mutation affects the hematological phenotype, as the group with β0 mutations has lower hemoglobin values, more pronounced microcytosis and hypochromia and higher HbA2. Eleven cases had borderline HbA2, six due to β++IVS-I-6T>C mutation and one by HbA2-Yialousa co-heritance. The α-β-thalassemia double heterozygosity was detected in three cases and tends to improve erythrocyte parameters. Iron deficiency anemia was observed in 18.7% of cases. However, co-inheritance of the V736A polymorphism in TMPRSS6 does not affect the hematological phenotype or iron homeostasis in β-thalassemia carriers. Iron overload was also observed in some participants. Transferrin saturation was elevated in 13.2% of cases and in association with higher frequency of H63D in HFE (46.7% versus 33.1%), which suggests that this polymorphism is contributing to the development of this phenotype. With this study, we contribute to the knowledge of the pathophysiology of the disease and to the reduction of false negative diagnoses. An undiagnosed β-thalassemia carrier is unaware of his risk of having offspring severely affected with the disease.
Descrição
Tese de mestrado, Análises Clínicas, 2023, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
β-talassémia α-talassémia Metabolismo do ferro Modificadores genéticos Portugal Teses de mestrado - 2023