Polimorfismos em genes relacionados ao metabolismo da homocisteína na arterite de Takayasu
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Data
2024-02-27
Autores
Zarur, Eduarda Bonelli [UNIFESP]
Orientadores
Souza, Alexandre Wagner Silva de [UNIFESP]
Tipo
Tese de doutorado
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Introdução. A arterite de Takayasu (AT) é uma vasculite sistêmica que afeta artérias de grande calibre, especialmente a aorta e seus ramos principais. Eventos isquêmicos, especialmente envolvendo o sistema nervoso central, são complicações relativamente frequentes da AT e trazem impacto ao prognóstico. Pacientes com AT apresentam concentrações plasmáticas de homocisteína mais elevadas em relação a controles e, entre pacientes com AT, elevação da concentração plasmática de homocisteína parece representar um fator de risco independente para eventos arteriais isquêmicos.
Objetivos. Comparar a frequência de polimorfismos de nucleotídeo único (SNP) em genes da via de metabolismo da homocisteína entre pacientes com AT e controles e avaliar suas associações com a concentração de homocisteína, extensão de acometimento arterial e eventos isquêmicos agudos na AT.
Métodos. Foi realizado um estudo transversal, onde foram incluídos pacientes com AT e controles. Tempo desde o diagnóstico de AT, tratamento medicamentoso, extensão de doença e dados laboratoriais foram avaliados em pacientes com AT, enquanto fatores de risco para hiperhomocisteinemia (HHcy), histórico de eventos arteriais isquêmicos agudos foram avaliados em ambos os grupos. Foram pesquisados os seguintes SNP nos genes das enzimas metilenotetrahidrofolato redutase (MTHFR) (C667T e A1298C), metionina sintase redutase (MTRR) (A66G), metionina sintetase (MTR) (A2756G) e do carreador reduzido do folato (RFC-1) (G80A) por sequenciamento genético de Sanger e realizada a dosagem de homocisteína pelo método de cromatografia líquida de alta performance, em ambos os grupos.
Resultados. Foram incluídos 73 pacientes com AT e 71 controles no estudo, com média de idade semelhantes (p > 0,05). Pacientes com AT apresentaram maior frequência de fatores de risco para HHcy em comparação a controles: obesidade, sedentarismo, hipertensão arterial sistêmica (HAS), uso de inibidor de bomba de prótons e de metotrexato (p < 0,05). Eventos isquêmicos arteriais agudos foram observados em 32,9% dos pacientes com AT. Não houve diferenças significantes entre pacientes com AT e controles quanto à frequência dos SNP dos genes pesquisados (p > 0,05). A concentração de homocisteína foi mais elevada nos pacientes com AT em comparação a controles (13,85 ± 5,61 µmol/L vs. 8,61 ± 4,00 µmol/L; p < 0,0001). Pacientes com o polimorfismo MTHFRC677T em homozigose apresentavam uma maior concentração de homocisteína em comparação aos em heterozigose (20,4± 7,8 µmol/L vs. 13,0±4,7 µmol/L) e aos em homozigose para o alelo selvagem (13,7±5,2 µmol/L, p = 0,024 e p = 0,009), enquanto nos controles não houve diferença (p = 0,989). Não foram observadas associações entres os SNP ou a concentração de homocisteína com eventos isquêmicos agudos nos pacientes com AT, e pacientes em remissão apresentaram tendência a maiores níveis de homocisteína (11,53 ± 5,28 µmol/L vs. 14,62 ± 5,59 µmol/L; p = 0,054). Houve uma correlação negativa moderada entre função renal e tempo de doença (rho = -0,432 p <0,0001) e correlação fraca entre idade e concentração de homocisteína nos pacientes (rho = 0,242; p = 0,043). Finalmente, a AT foi um fator de risco independente para HHcy [Odds ratio (OR) = 10,2; 95% intervalo de confiança (IC): 4,162-25,002; p < 0,0001] e, entre pacientes com AT, HAS foi um fator de risco independente para HHcy (OR = 4,591; 95% IC 1,046-20,153; p = 0,043).
Conclusões. A HHCy já descrita em pacientes com AT foi confirmada nesse estudo, mas não se deve à maior frequência de SNP de genes que codificam enzimas do metabolismo da homocisteína e não houve relação entre homocisteína e eventos isquêmicos agudos. A AT foi associada de forma independente a maior risco de HHcy e, entre pacientes, a HAS foi associada de forma independente. A HHcy em AT não se deve a fatores genéticos e pode estar associada a inflamação crônica e HAS. Mais estudos são necessários para destrinchar a patogênese da HHcy em AT e para avaliar possível benefício de medidas redutoras de homocisteína e uma possível aplicabilidade da HHcy como biomarcador de risco cardiovascular na AT.
Introduction. Takayasu arteritis (TA) is a systemic vasculitis that affects large arteries, especially the aorta and its main branches. Ischemic events, especially those involving the central nervous system, are relatively frequent complications of TA with great impact on its prognosis. Patients with TA have higher plasma homocysteine concentrations compared to controls, and elevated plasma homocysteine concentration seems to be an independent risk factor for ischemic arterial events in TA patients. Objective. To compare the frequency of single nucleotide polymorphisms (SNP) of genes involved in the homocysteine metabolism pathway between TA patients and controls and to analyze associations with homocysteine levels, extent of arterial involvement and acute ischemic events in TA. Methods. A cross-sectional study was carried out including TA patients and controls. Time since diagnosis of TA, therapy, laboratory findings and the extent of arterial involvement were assessed in patients with TA, while risk factors for hyperhomocysteinemia (HHcy), and history of acute ischemic arterial events were assessed in both groups. The following SNP of the enzymes methylenetetrahydrofolate reductase (MTHFR) (e.g., C667T and A1298C), methionine synthase reductase (MTRR) (e.g., A66G), methionine synthetase (MTR) (e.g., A2756G) and reduced folate carrier (RFC-1) (e.g., G80A) were investigated by the Sanger sequencing technique, and plasma homocysteine was measured by high-performance liquid chromatography, in both groups. Results. Seventy-three TA patients and 71 controls with similar median age (p > 0,05) were included in the study. Patients with TA had a higher frequency of risk factors for Hhcy compared to controls that is obesity, sedentary lifestyle, arterial hypertension, proton pump inhibitor and methotrexate use (p < 0.05). Acute arterial ischemic events were observed in 32.9% of TA patients. There were no significant differences between both groups regarding the frequency of individual SNPs (p > 0.05). Patients showed higher homocysteine levels than controls (13.85 ± 5.61 µmol/L vs. 8.61 ± 4.00 µmol/L; p < 0.0001). Patients with the MTHFR C677T SNP in homozygosis had higher homocysteine levels than those in heterozygosis (20.4± 7.8 µmol/L vs. 13.0±4.7 µmol/L) and wildtype (13.7±5.2 µmol/L; p = 0.024 and p = 0.009). In addition, no relations were observed between SNP carriage and acute arterial ischemic events in TA and patients in remission tended to have higher homocysteine levels (14.62 ± 5.59 µmol/L vs. 11.53 ± 5.28 µmol/L; p = 0.054). There was a moderate negative correlation between disease duration and estimated glomerular filtration rate (EGFR) (rho = -0.432; p <0.0001), and a weak positive correlation between age and homocysteine levels, only in patients (rho = 0.242; p = 0.043). Finally, TA was an independent risk factor for HHcy [Odds ratio (OR) = 10.2; 95% confidence interval (CI): 4.162-25.002; p < 0.0001] and, among TA patients, hypertension was an independent risk factor for Hhcy (OR = 4.591; 95% CI 1.046-20.153; p = 0.043). Conclusions. The previously described HHcy in TA was confirmed in this study; however, it is not due to a higher frequency of SNP in genes encoding homocysteine metabolism enzymes and there was no association between HHcy and acute arterial ischemic events. TA was independently associated to HHcy, and among patients, hypertension was independently associated to HHcy. The higher homocysteine level observed in TA is not due to genetic factors and might be due to the burden of chronic arterial inflammation in TA and hypertension. Further studies are needed to unravel the pathogenesis of HHcy in TA and to assess potential benefit of homocysteine lowering therapies as well as the utility of HHcy as a biomarker of cardiovascular events.
Introduction. Takayasu arteritis (TA) is a systemic vasculitis that affects large arteries, especially the aorta and its main branches. Ischemic events, especially those involving the central nervous system, are relatively frequent complications of TA with great impact on its prognosis. Patients with TA have higher plasma homocysteine concentrations compared to controls, and elevated plasma homocysteine concentration seems to be an independent risk factor for ischemic arterial events in TA patients. Objective. To compare the frequency of single nucleotide polymorphisms (SNP) of genes involved in the homocysteine metabolism pathway between TA patients and controls and to analyze associations with homocysteine levels, extent of arterial involvement and acute ischemic events in TA. Methods. A cross-sectional study was carried out including TA patients and controls. Time since diagnosis of TA, therapy, laboratory findings and the extent of arterial involvement were assessed in patients with TA, while risk factors for hyperhomocysteinemia (HHcy), and history of acute ischemic arterial events were assessed in both groups. The following SNP of the enzymes methylenetetrahydrofolate reductase (MTHFR) (e.g., C667T and A1298C), methionine synthase reductase (MTRR) (e.g., A66G), methionine synthetase (MTR) (e.g., A2756G) and reduced folate carrier (RFC-1) (e.g., G80A) were investigated by the Sanger sequencing technique, and plasma homocysteine was measured by high-performance liquid chromatography, in both groups. Results. Seventy-three TA patients and 71 controls with similar median age (p > 0,05) were included in the study. Patients with TA had a higher frequency of risk factors for Hhcy compared to controls that is obesity, sedentary lifestyle, arterial hypertension, proton pump inhibitor and methotrexate use (p < 0.05). Acute arterial ischemic events were observed in 32.9% of TA patients. There were no significant differences between both groups regarding the frequency of individual SNPs (p > 0.05). Patients showed higher homocysteine levels than controls (13.85 ± 5.61 µmol/L vs. 8.61 ± 4.00 µmol/L; p < 0.0001). Patients with the MTHFR C677T SNP in homozygosis had higher homocysteine levels than those in heterozygosis (20.4± 7.8 µmol/L vs. 13.0±4.7 µmol/L) and wildtype (13.7±5.2 µmol/L; p = 0.024 and p = 0.009). In addition, no relations were observed between SNP carriage and acute arterial ischemic events in TA and patients in remission tended to have higher homocysteine levels (14.62 ± 5.59 µmol/L vs. 11.53 ± 5.28 µmol/L; p = 0.054). There was a moderate negative correlation between disease duration and estimated glomerular filtration rate (EGFR) (rho = -0.432; p <0.0001), and a weak positive correlation between age and homocysteine levels, only in patients (rho = 0.242; p = 0.043). Finally, TA was an independent risk factor for HHcy [Odds ratio (OR) = 10.2; 95% confidence interval (CI): 4.162-25.002; p < 0.0001] and, among TA patients, hypertension was an independent risk factor for Hhcy (OR = 4.591; 95% CI 1.046-20.153; p = 0.043). Conclusions. The previously described HHcy in TA was confirmed in this study; however, it is not due to a higher frequency of SNP in genes encoding homocysteine metabolism enzymes and there was no association between HHcy and acute arterial ischemic events. TA was independently associated to HHcy, and among patients, hypertension was independently associated to HHcy. The higher homocysteine level observed in TA is not due to genetic factors and might be due to the burden of chronic arterial inflammation in TA and hypertension. Further studies are needed to unravel the pathogenesis of HHcy in TA and to assess potential benefit of homocysteine lowering therapies as well as the utility of HHcy as a biomarker of cardiovascular events.
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Citação
ZARUR, Eduarda Bonelli. Polimorfismos em genes relacionados ao metabolismo da homocisteína na arterite de Takayasu. 2024. 108 f. Tese (Doutorado em Reumatologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2024.