Assuntos
Trombose Intracraniana/genética , Mutação Puntual , Protrombina/genética , Adulto , Brasil/epidemiologia , Estudos de Casos e Controles , Fator V , Feminino , Humanos , Trombose Intracraniana/epidemiologia , Trombose Intracraniana/etiologia , Masculino , Epidemiologia Molecular , Fatores de Risco , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia , Trombose Venosa/genéticaRESUMO
BACKGROUND: Raloxifene therapy is associated with a three-fold increase in the risk for venous thromboembolism; however, its effects on the hemostatic system in postmenopausal women have not been well defined. OBJECTIVE: To determine the effects of raloxifene therapy on the levels of natural anticoagulant proteins in postmenopausal women. METHODS: Sixteen healthy postmenopausal women were enrolled in this prospective longitudinal study. The patients were treated with raloxifene hydrochloride (60 mg/day) for a period of 6 months. Antithrombin and protein C activities and protein S antigen levels were measured in all users at baseline, and after 1, 3 and 6 months of treatment. Statistical analysis included one-way analysis of variance (ANOVA) and the Bonferroni test for multiple comparisons among the study periods. RESULTS: Statistically significant 5.1% and 6.5% reductions of plasma antithrombin activity were observed at 3 and 6 months of therapy, respectively (p < 0.05). Compared with baseline, raloxifene did not significantly affect protein C activity or protein S level. CONCLUSIONS: The results of this prospective study show for the first time that raloxifene use is associated with a significant reduction in plasma antithrombin activity. This effect may contribute to a procoagulant state and partly explain the increased risk of venous thromboembolism in raloxifene users.
Assuntos
Antitrombinas/efeitos dos fármacos , Proteína C/efeitos dos fármacos , Proteína S/efeitos dos fármacos , Cloridrato de Raloxifeno/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Idoso , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Cloridrato de Raloxifeno/administração & dosagem , Cloridrato de Raloxifeno/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Trombose Venosa/induzido quimicamenteRESUMO
Fasting total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation were evaluated in 91 patients with venous thromboembolism and without acquired thrombophilia, and in 91 age-matched and sex-matched controls. Hyperhomocysteinemia was detected in 11 patients (12.1%) and in two controls (2.2%), yielding an odds ratio (OR) for venous thrombosis of 6.1 [95% confidence interval (CI), 1.3-28.4]. After excluding 21 patients and four controls with other known genetic risk factors for venous thrombosis, the OR was not substantially changed (7.0; 95% CI, 1.5-33.1). The prevalence of the MTHFR 677TT genotype was not significantly different in patients (9.9%) and in controls (5.5%), with an OR for venous thrombosis of 1.8 (95% CI, 0.6-5.8). Subjects with the MTHFR 677TT genotype showed higher levels of tHcy compared with the 677CC genotype in patients (P = 0.010) and in controls (P = 0.030). In conclusion, we found that fasting hyperhomocysteinemia is a risk factor for venous thrombosis in patients without known acquired thrombophilia and other genetic risk factors for venous thrombosis. Although tHcy levels are significantly higher in those homozygous for the MTHFR C677T mutation, this genotype does not increase the thrombotic risk in our study population.
Assuntos
Substituição de Aminoácidos , Hiper-Homocisteinemia/epidemiologia , Mutação de Sentido Incorreto , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Mutação Puntual , Trombofilia/epidemiologia , Trombose Venosa/epidemiologia , Regiões 3' não Traduzidas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Criança , Jejum/sangue , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Protrombina/genética , Fatores de Risco , Trombofilia/sangue , Trombofilia/genética , Trombose Venosa/etiologiaRESUMO
We have determined the prevalence of methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C in 71 children (< or = 15 years) with acute lymphoblastic leukaemia (ALL) and in 71 control subjects. Odds ratio (OR) for ALL linked to MTHFR C677T was 0.4 (95% CI 0.2-0.8); for heterozygotes it was 0.5 (95% CI 0.2-0.9) and for homozygotes it was 0.3 (95%CI 0.09-0.8). MTHFR A1298C yielded an overall OR for ALL of 1.3 (95% CI: 0.7-2.6); for heterozygotes it was 1.3 (95% CI: 0.7-7.6) and for homozygotes it was 2.8 (95% CI 0.5-15.6). In conclusion, MTHFR C677T was linked to a significant 2.4-fold decreased risk of developing childhood ALL, whereas MTHFR A1298C did not significantly affect the risk of ALL in our population.
Assuntos
Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Linfoma de Burkitt/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Homozigoto , Humanos , Lactente , Leucemia-Linfoma de Células T do Adulto/genética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Razão de Chances , Prevalência , RiscoRESUMO
BACKGROUND AND OBJECTIVES: Thrombin activatable fibrinolysis inhibitor (TAFI) plays an important role in hemostasis, functioning as a potent fibrinolysis inhibitor. TAFI gene variations may contribute to plasma TAFI levels and thrombotic risk. DESIGN AND METHODS: We sequenced a 2083-bp region of the 5'-regulatory region of the TAFI gene in 127 healthy subjects searching for variations, and correlated identified polymorphisms with plasma TAFI levels. TAFI polymorphisms were examined as risk factors for venous thrombosis by determining their prevalence in 388 patients with deep venous thrombosis (DVT) and in 388 controls. RESULTS: Seven novel polymorphisms were identified: -152 A/G, -438 A/G, -530 C/T, -1053 T/C, -1102 T/G, -1690 G/A, and -1925 T/C. -152 A/G, -530 C/T and -1925 T/C were found to be in strong linkage disequilibrium, as were the -438 A/G, -1053 T/C, -1102 T/G and -1690 G/A. Plasma TAFI levels were higher in -438GG/-1053CC/-1102GG/-1690AA homozygotes than in -438AG/-1053TC/-1102TG/-1690GA heterozygotes, and -438AA/-1053TT/-1102TT/-1690GG homozygotes had the lowest TAFI levels (p=0.0003). TAFI concentrations in -152AA/-530CC/-1925TT homozygotes were somewhat higher but not significantly different from levels observed for -152AG/-530CT/-1925TC heterozygotes. Taken in combination, -438AG/-1053TC/-1102TG/-1690GA and -438AA/-1053TT/-1102TT/-1690GG yielded an OR for DVT of 0.8 (95%CI: 0.6-1). In subjects aged <35 years the OR was 0.7 (95%CI: 0.5-1.1). The OR for -152AG/-530CT/-1925TC was 1 (95%CI: 0.5-2.2) in the whole group of patients and controls, whereas in subjects aged <35 years the OR was 0.1 (95%CI: 0.02-0.9). INTERPRETATION AND CONCLUSIONS: Polymorphisms in the TAFI promoter determine plasma antigen levels and may influence the risk of venous thrombophilia.
Assuntos
Regiões 5' não Traduzidas/genética , Carboxipeptidase B2/genética , Trombose Venosa/genética , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Carboxipeptidase B2/efeitos adversos , Carboxipeptidase B2/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Análise de Sequência de DNA , Trombose Venosa/epidemiologia , Trombose Venosa/etiologiaRESUMO
We investigated two genetic polymorphisms in the tumor necrosis factor locus (TNF-alpha -308 G-->A and LT-alpha +252 A-->G) as risk factors for coronary atherothrombotic disease (CAD) by determining its prevalence in 148 survivors of myocardial infarction (MI) with angiographically-proven severe CAD, and in 148 age-, gender- and race-matched controls. The odds ratio (OR) for MI related to the mutant TNF-alpha and LT-alpha alleles was 0.8 (CI95: 0.4-1.3) and 1. 3 (CI95: 0.8-2.0), respectively. We also sought interaction of smoking and metabolic risk factors for MI with each mutant genotype. Smokers not carrying the LT-alpha +252 A-->G mutation had a risk of MI of 2.7 (CI95: 1.4-5.4) whereas in smoking carriers the risk was 6. 9 (CI95: 3.4-14.1). An interactive effect of the LT-alpha mutation may also exist with dyslipidemia (OR for MI in non-carriers was 12 [CI95: 3.2-41.3] and in carriers the OR was 39, [CI95: 5.1-301] and with obesity (OR for MI was 2.7, [CI95: 1-7.2] in non-carriers and in carriers the OR was 6 [CI95: 2.1-16.8]). Lastly, the OR for MI in obese non-carriers of TNF-alpha -308 G-->A was 2.8 (CI95: 1.3-6) and in obese carriers the OR was 14.5 (CI95: 1.8-113). Although significant interactive effects could not be detected, the findings suggest that interaction of polymorphisms in the TNF locus with major risk factors for CAD may exist, and should be explored in larger studies.
Assuntos
Infarto do Miocárdio/etiologia , Fator de Necrose Tumoral alfa/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Heterozigoto , Humanos , Hiperlipidemias/genética , Linfotoxina-alfa/efeitos adversos , Linfotoxina-alfa/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Obesidade , Razão de Chances , Mutação Puntual , Polimorfismo Genético , Isoformas de Proteínas/genética , Fatores de Risco , Fumar/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversosRESUMO
A polymorphism in the coagulation factor XIII gene (FXIII Val34Leu) has been recently described to confer protection for arterial and venous thrombosis and to predispose to intracerebral hemorrhage. At present it is known that FXIII Val34Leu is prevalent in Caucasians, but information upon its distribution in different ethnic groups is scarce. We investigated the prevalence of FXIIIVal34Leu in 450 unrelated subjects of four ethnic groups: 97 Caucasians (Brazilians of European descent and Portuguese), 149 Blacks (Brazilians, and Africans from Cameroon, Zaire and Angola), 40 Asians (Japanese descendents) and 164 Amerindians from South America. PCR amplification of exon 2 of FXIII gene followed by MseI restriction-digestion was employed to define the genotypes. FXIIIVal34Leu was detected in 44.3% of the Caucasians, in 28.9% of the Blacks, in 2.5% of the Asians and in 51.2% of the Amerindians. These data confirm that FXIII Val34Leu is highly prevalent in Caucasians and indicate that it is rarer in populations of African origin. The very high frequency among Amerindians indicates that FXIII Val34Leu is not absent among Asians, and since it has a very low prevalence in Japanese, a heterogeneity in its distribution in Asia may be inferred. Taken together, our data showed that FXIII Val34Leu exhibits a significant ethnic heterogeneity, a finding that is relevant for studies relating this polymorphism with thrombotic and bleeding disorders.
Assuntos
Fator XIII/genética , Polimorfismo Genético , Grupos Raciais , Frequência do Gene , Humanos , Mutação Puntual , PrevalênciaRESUMO
Although iron can catalyze the production of free radicals involved in LDL lipid peroxidation, the contribution of iron overload to atherosclerosis remains controversial. The description of two mutations in the HFE gene (Cys282Tyr and His63Asp) related to hereditary hemochromatosis provides an opportunity to address the question of the association between iron overload and atherosclerosis. We investigated the prevalence of HFE mutations in 160 survivors of myocardial infarction with angiographically demonstrated severe coronary atherosclerotic disease, and in 160 age-, gender- and race-matched healthy control subjects. PCR amplification of genomic DNA followed by RsaI and BclI restriction enzyme digestion was used to determine the genotypes. The frequency of the mutant Cys282Tyr allele was identical among patients and controls (0.022; carrier frequency, 4.4%), whereas the mutant His63Asp allele had a frequency of 0.143 (carrier frequency, 27.5%) in controls and of 0.134 (carrier frequency, 24.5%) in patients. Compound heterozygotes were found in 2 of 160 (1.2%) controls and in 1 of 160 (0.6%) patients. The finding of a similar prevalence of Cys282Tyr and His63Asp mutations in the HFE gene among controls and patients with coronary atherothrombotic disease, indirectly questions the possibility of an association between hereditary hemochromatosis and atherosclerosis.
Assuntos
Doença da Artéria Coronariana/genética , Genes MHC Classe I/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana , Mutação , Adulto , Alelos , Feminino , Frequência do Gene , Hemocromatose/genética , Proteína da Hemocromatose , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Although iron can catalyze the production of free radicals involved in LDL lipid peroxidation, the contribution of iron overload to atherosclerosis remains controversial. The description of two mutations in the HFE gene (Cys282Tyr and His63Asp) related to hereditary hemochromatosis provides an opportunity to address the question of the association between iron overload and atherosclerosis. We investigated the prevalence of HFE mutations in 160 survivors of myocardial infarction with angiographically demonstrated severe coronary atherosclerotic disease, and in 160 age-, gender- and race-matched healthy control subjects. PCR amplification of genomic DNA followed by RsaI and BclI restriction enzyme digestion was used to determine the genotypes. The frequency of the mutant Cys282Tyr allele was identical among patients and controls (0.022; carrier frequency, 4.4 per cent), whereas the mutant His63Asp allele had a frequency of 0.143 (carrier frequency, 27.5 per cent) in controls and of 0.134 (carrier frequency, 24.5 per cent) in patients. Compound heterozygotes were found in 2 of 160 (1.2 per cent) controls and in 1 of 160 (0.6 per cent) patients. The finding of a similar prevalence of Cys282Tyr and His63Asp mutations in the HFE gene among controls and patients with coronary atherothrombotic disease, indirectly questions the possibility of an association between hereditary hemochromatosis and atherosclerosis.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Doença da Artéria Coronariana/genética , Genes MHC Classe I/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos HLA/genética , Mutação , Alelos , Frequência do Gene , Hemocromatose/genéticaRESUMO
It has been proposed that iron overload may adversely affect liver disease outcome. The recent identification of 2 mutations in the HFE gene related to hereditary haemochromatosis (Cys282Tyr and His63Asp) provided an opportunity to test whether they are associated with hepatic iron accumulation and the activity and severity of liver disease in hepatitis C virus (HCV) infection. We investigated the prevalence of HFE mutations in 135 male patients with chronic HCV hepatitis, and correlated genotype distribution with different parameters of iron status and the activity and severity of liver disease. Of these 135 patients, 6 (4.4%) carried Cys282Tyr and 32 (23.7%) carried His63Asp, frequencies which were similar to those observed in healthy controls. Serum iron levels and transferrin saturation (but not ferritin levels or liver iron content) were significantly higher in carriers than in non-carriers of HFE mutations. No difference was observed in serum ALT, AST and GGT levels between carriers and non-carriers. Finally, scores for necroinflammatory activity and fibrosis in the liver were significantly higher in HFE carriers than in non-carriers. Patients with chronic HCV infection carrying HFE mutations tend to present more evident body iron accumulation and a higher degree of necroinflammatory activity and fibrosis in the liver. HFE gene mutations might be an additional factor to be considered among those implicated in the determination of a worse prognosis of the liver disease in chronic HCV infection.