Estudo do trato polimórfico CAG do gene do receptor androgênico em pacientes com eritrocitose em terapia com testosterona
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Tipo
TCC
Data de publicação
2024-12
Periódico
Citações (Scopus)
Autores
Herrera, Fernanda Orio
Orientador
Costa, Ana Paula Pimentel
Domenice , Sorahia
Domenice , Sorahia
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Resumo
A testosterona é o principal hormônio sexual masculino e é essencial para a diferenciação
pré-natal e para o desenvolvimento das genitálias interna e externa e das características
sexuais secundárias. Para exercer seu papel, a testosterona se liga a um receptor
específico localizado no citoplasma das células, chamado de receptor androgênico (AR).
O gene do AR está localizado no braço curto do cromossomo X (banda Xq11-12) e é
composto de 8 éxons. No primeiro éxon há dois tratos polimórficos, sendo eles o trato
poliglutamínico, composto de repetições CAG, e o trato poliglicínico, composto de
repetições GGN. Variações no número de repetições desses nucleotídeos estão
associadas ao desenvolvimento de doenças andrógeno-dependentes, como o câncer de
próstata. O uso terapêutico da testosterona é benéfico nas condições clínicas em que a
produção hormonal testicular é inadequada (diminuída ou ausente), porém também
possui seus riscos, podendo causar eritrocitose, um distúrbio sanguíneo que causa um
aumento da quantidade de hemácias no sangue. Uma pesquisa prévia demonstrou que
repetições CAG mais curtas no AR contribuíram para a elevação dos nîveis de
hematócrito em pacientes hipogonádicos e com idade superior a 40 anos. Este trabalho
estudou a possível relação entre a quantidade de repetições CAG e o risco de
desenvolvimento de eritrocitose de 30 pacientes homens 46,XY, tendo doze dos paciente
eritrocitose e o restante um nível de hematócrito considerado normal. Foram realizados
o sequenciamento pelo método de Sanger e a contagem manual das repetições de
glutamina. Os pacientes com eritrocitose apresentaram uma média de 21,6 ± 2,87
repetições CAG, enquanto os pacientes sem eritrocitose tiveram uma média de 21,8 ±
2,09 repetições. Os alelos variaram de 18 a 27 repetições CAG e os mais frequentes
foram os com 20 e 22 repetições CAG. Os resultados indicaram que há uma baixa
correlação entre o número de repetições CAG e os níveis de hematócrito, sendo as
variações do hematócrito independentes do tamanho dos alelos, o que sugere que o
número de repetições CAG não seria um marcador genético eficaz para o risco de
eritrocitose. A pluralidade de resultados na literatura reforça a necessidade de ampliar o
alvo de estudos futuros, garantindo uma análise mais representativa do trato CAG do AR.
Testosterone is the main male sex hormone and it is essential for prenatal differentiation and for the development of internal and external genitalia and secondary sexual characteristics. Testosterone acts by binding to a specific receptor located in the cytoplasm of cells, called the androgen receptor (AR). The AR gene is located on the short arm of the X chromosome (locus Xq11-12) and it is composed of 8 exons. In the first exon there are two polymorphic tracts, the first being the polyglutamine tract, composed of CAG repeats, and the second the polyglycine tract, composed of GGN repeats. Variations in the number of these nucleotide repeats are associated with the development of androgen dependent diseases, such as prostate cancer. The therapeutic use of testosterone is beneficial in clinical conditions in which testicular hormone production is insufficient (decreased or absent), however, this therapy also has its risks. One of them is erythrocytosis, a blood disorder characterized by an increase in the number of red blood cells, which is measured by hematocrit levels. Previous research demonstrated that shorter CAG repeats in the AR are associated with an increased hematocrit level in hypogonadal patients over the age of 40. This project investigated the possible correlation between the number of CAG repeats and the risk of developing erythrocytosis in thirty 46,XY male patients, twelve of them having erythrocytosis (hematocrit levels higher than 50%) and eighteen having normal hematocrit levels. The technique used was the Sanger sequencing method and the manual count of the CAG repeats. Patients with erythrocytosis had a mean of 21,6 ± 2,87 CAG repeats and patients without erythrocytosis had a mean of 21,8 ± 2,09 CAG repeats. The alleles ranged from 18 to 27 glutamine repeats and the most frequent were those with 20 and 22 repeats, similar to normal controls. The results indicated a low correlation between the number of CAG repeats and hematocrit levels, with variations in hematocrit independent to allele size. These findings suggest that this index is not an effective genetic marker for the risk of erythrocytosis. The diversity of results in literature highlights the need for broader and more diverse cohorts to ensure a robust and representative genetic analysis of the polymorphic CAG and GGN tracts of the AR.
Testosterone is the main male sex hormone and it is essential for prenatal differentiation and for the development of internal and external genitalia and secondary sexual characteristics. Testosterone acts by binding to a specific receptor located in the cytoplasm of cells, called the androgen receptor (AR). The AR gene is located on the short arm of the X chromosome (locus Xq11-12) and it is composed of 8 exons. In the first exon there are two polymorphic tracts, the first being the polyglutamine tract, composed of CAG repeats, and the second the polyglycine tract, composed of GGN repeats. Variations in the number of these nucleotide repeats are associated with the development of androgen dependent diseases, such as prostate cancer. The therapeutic use of testosterone is beneficial in clinical conditions in which testicular hormone production is insufficient (decreased or absent), however, this therapy also has its risks. One of them is erythrocytosis, a blood disorder characterized by an increase in the number of red blood cells, which is measured by hematocrit levels. Previous research demonstrated that shorter CAG repeats in the AR are associated with an increased hematocrit level in hypogonadal patients over the age of 40. This project investigated the possible correlation between the number of CAG repeats and the risk of developing erythrocytosis in thirty 46,XY male patients, twelve of them having erythrocytosis (hematocrit levels higher than 50%) and eighteen having normal hematocrit levels. The technique used was the Sanger sequencing method and the manual count of the CAG repeats. Patients with erythrocytosis had a mean of 21,6 ± 2,87 CAG repeats and patients without erythrocytosis had a mean of 21,8 ± 2,09 CAG repeats. The alleles ranged from 18 to 27 glutamine repeats and the most frequent were those with 20 and 22 repeats, similar to normal controls. The results indicated a low correlation between the number of CAG repeats and hematocrit levels, with variations in hematocrit independent to allele size. These findings suggest that this index is not an effective genetic marker for the risk of erythrocytosis. The diversity of results in literature highlights the need for broader and more diverse cohorts to ensure a robust and representative genetic analysis of the polymorphic CAG and GGN tracts of the AR.
Descrição
Palavras-chave
receptor andrôgenico , trato polimórfico CAG , eritrocitose , androgen receptor , CAG repeat polymorphism , erythrocytosis , testosterone