Impacto de las variantes genéticas de las enzimas GGCx, CYP4F2 y del transportador MDR1 con el ajuste de dosis de antivitamínicos K
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Fecha
2019
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Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
Las enfermedades cardiovasculares (ECV) son la primera causa de muerte en Chile y el mundo,
una de las causas por las cuales se originan las ECV se debe a una falla en el proceso de
hemostasia. La cascada de la coagulación está regulada por el ciclo de la vitamina K, ya que
cuatro factores de coagulación debe modificarse post-traduccionalmente para ser activos y en
esta modificación participa la vitamina K. El ciclo de la vitamina K está formado por dos
enzimas VKORC1 y GGCx, también participa CYP4F2 eliminando la vitamina K reducida del
ciclo. Aquellos individuos que presentan una ECV como profilaxis deben tratarse con fármacos
cumarínicos también denominados antivitamínicos K (AVK), el mecanismo de acción de estos
fármacos es inhibir de manera competitiva el complejo 1 de VKORC1 inhibiendo la cascada de
la coagulación. Se han descrito polimorfismos genéticos que influyen en la dosis de AVK que
explican en el mejor de los casos un 60 % de la variabilidad de la dosis. El objetivo de esta
tesis fue evaluar la presencia de polimorfismos en los genes GGCx (rs11676382), CYP4F2
(rs2108622) y ABCB1 (rs1045642) y su asociación individual o en combinación, con la
variabilidad en la dosis de anticoagulantes orales de tipo AVK en pacientes del SSMOC. Se
reclutaron 304 pacientes del SSMOC, se obtuvo DNA genómico y se realizó una
genotipificación usando PCR en tiempo real con tecnología de sondas TaqMan® para los
polimorfismos de estudio. El polimorfismo del gen GGCx (rs11676382) presenta una
frecuencia del alelo G de 0,03 y no se asoció con una variación en la dosis de Acenocumarol
según los modelos codominante (valor p = 0,711 para genotipo G/C), recesivo (valor p
indeterminado) y dominante (valor p = 0,739). El polimorfismo del gen CYP4F2 (rs2108622)
presenta una frecuencia del alelo T de 0,23 y se asoció con una variación en la dosis de
Acenocumarol según el modelo codominante (valor p = 0,031) para los individuos con genotipo
heterocigoto respecto a los con genotipo no mutado. El polimorfismo del gen ABCB1
(rs105642) presenta una frecuencia del alelo T de 0,627 y no se asoció con variaciones en la
dosis de Acenocumarol en los modelos codominante (valor p = 0,762), recesivo (valor p =
0,247) y dominante (valor p = 0,524). Finalmente, se encontró una asociación estadísticamente
significativa entre la dosis terapéutica semanal con el género (valor p < 0,05). La presencia de
la variante polimórfica del gen CYP4F2 (rs2108622) se relaciona con un aumento de dosis de
Acenocumarol en pacientes chilenos. Un modelo de asociación basado en la presencia de la
variante de CYP4F2 (rs2108622) en conjunto con el género, logran explicar un 4% del
requerimiento de mayor dosis de Acenocumarol en pacientes chilenos, lo que no había sido
descrito previamente.
Cardiovascular diseases (CVD) are the leading cause of death in Chile and the world, one of the causes of CVD is due to a failure in the process of hemostasis. The coagulation cascade is regulated by the vitamin K cycle, since four coagulation factors must be modified posttranslationally to be active and in this modification vitamin K participates. The vitamin K cycle consists of two enzymes VKORC1 and GGCx, CYP4F2 also participates by eliminating reduced vitamin K in the cycle. Those individuals who present a CVD as prophylaxis should be treated with coumarin drugs also called antivitamin K (VKA), the mechanism of action of these drugs is to competitively inhibit complex 1 of VKORC1 by inhibiting the coagulation cascade. Genetic polymorphisms have been described that influence the dose of VKA that explain at best 60% of the variability of the dose. The objective of this thesis was to evaluate the presence of polymorphisms in the genes GGCx (rs11676382), CYP4F2 (rs2108622) and ABCB1 (rs1045642) and their association individually or in combination, with the variability in the dose of oral anticoagulants of type VKA in patients of the SSMOC. We recruited 304 patients from the SSMOC, genomic DNA was obtained and genotyping was performed using real-time PCR with TaqMan® probe technology for the study polymorphisms. The polymorphism of the GGCx gene (rs11676382) has a G allele frequency of 0.03 and was not associated with a variation in the dose of Acenocoumarol according to the codominant models (p value = 0.711 for genotype G/C), recessive (p value indeterminate) and dominant (value p = 0.739). The polymorphism of the CYP4F2 gene (rs2108622) shows a frequency of the T allele of 0.23 and was associated with a variation in the dose of Acenocoumarol according to the codominant model (p value = 0.031) for individuals with heterozygous genotype with respect to those with genotype. not mutated. The polymorphism of the ABCB1 gene (rs105642) has a T allele frequency of 0.627 and was not associated with variations in the dose of Acenocoumarol in the codominant (p-value = 0.762), recessive (p-value = 0.247) and dominant models. (p-value = 0.524). Finally, a statistically significant association was found between weekly therapeutic dose and gender (p value <0.05). The presence of the polymorphic variant of the CYP4F2 gene (rs2108622) is related to an increase in the dose of Acenocoumarol in Chilean patients. An association model based on the presence of the CYP4F2 variant (rs2108622) together with the female sex, explain 4% of the requirement for a higher dose of Acenocoumarol in Chilean patients, which had not been previously described.
Cardiovascular diseases (CVD) are the leading cause of death in Chile and the world, one of the causes of CVD is due to a failure in the process of hemostasis. The coagulation cascade is regulated by the vitamin K cycle, since four coagulation factors must be modified posttranslationally to be active and in this modification vitamin K participates. The vitamin K cycle consists of two enzymes VKORC1 and GGCx, CYP4F2 also participates by eliminating reduced vitamin K in the cycle. Those individuals who present a CVD as prophylaxis should be treated with coumarin drugs also called antivitamin K (VKA), the mechanism of action of these drugs is to competitively inhibit complex 1 of VKORC1 by inhibiting the coagulation cascade. Genetic polymorphisms have been described that influence the dose of VKA that explain at best 60% of the variability of the dose. The objective of this thesis was to evaluate the presence of polymorphisms in the genes GGCx (rs11676382), CYP4F2 (rs2108622) and ABCB1 (rs1045642) and their association individually or in combination, with the variability in the dose of oral anticoagulants of type VKA in patients of the SSMOC. We recruited 304 patients from the SSMOC, genomic DNA was obtained and genotyping was performed using real-time PCR with TaqMan® probe technology for the study polymorphisms. The polymorphism of the GGCx gene (rs11676382) has a G allele frequency of 0.03 and was not associated with a variation in the dose of Acenocoumarol according to the codominant models (p value = 0.711 for genotype G/C), recessive (p value indeterminate) and dominant (value p = 0.739). The polymorphism of the CYP4F2 gene (rs2108622) shows a frequency of the T allele of 0.23 and was associated with a variation in the dose of Acenocoumarol according to the codominant model (p value = 0.031) for individuals with heterozygous genotype with respect to those with genotype. not mutated. The polymorphism of the ABCB1 gene (rs105642) has a T allele frequency of 0.627 and was not associated with variations in the dose of Acenocoumarol in the codominant (p-value = 0.762), recessive (p-value = 0.247) and dominant models. (p-value = 0.524). Finally, a statistically significant association was found between weekly therapeutic dose and gender (p value <0.05). The presence of the polymorphic variant of the CYP4F2 gene (rs2108622) is related to an increase in the dose of Acenocoumarol in Chilean patients. An association model based on the presence of the CYP4F2 variant (rs2108622) together with the female sex, explain 4% of the requirement for a higher dose of Acenocoumarol in Chilean patients, which had not been previously described.
Notas
Tesis (Bioquímico, Magíster en Bioquímica)
Palabras clave
Polimorfismo Genético, Enfermedades Cardiovasculares, Tratamiento Farmacológico, Anticoagulantes