Asunto(s)
Aborto Habitual/epidemiología , Aborto Habitual/genética , Pruebas Genéticas/métodos , Polimorfismo de Nucleótido Simple/genética , Oclusión de la Vena Retiniana/epidemiología , Oclusión de la Vena Retiniana/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/estadística & datos numéricos , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
High plasma lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for atherosclerotic diseases. To date, no effective intervention strategies on reducing Lp(a) concentrations have been reported. The aim of the study was to evaluate the possible modulation of two polymorphisms of LPA gene (LPA 93C>T and LPA 121G>A) and nutritional habits on Lp(a) concentrations. We studied 647 healthy Italian subjects (260 M; 387 F) with a median age of 48 years (range: 19-78) enrolled in an epidemiological study conducted in Florence, Italy. A linear regression analysis showed a significant negative influence of fish intake (beta=-0.174+/-0.084; p=0.04) on Lp(a) concentrations, after adjustment for smoking habit, C-reactive protein serum concentrations, dietary habits and LDL-cholesterol concentrations. With regard to LPA polymorphisms, LPA 93C>T polymorphism resulted to significantly affect Lp(a) circulating concentrations in a dose-dependent manner, with lower concentrations shown by subjects carrying the T rare allele, whereas no significant influence of LPA 121G>A polymorphism on Lp(a) concentrations was observed. Moreover, by analyzing the possible interplay between LPA 93C>T and dietary fish intake, a significant interaction between these two determinants in lowering Lp(a) concentrations was reported. In addition, lower Lp(a) concentrations were observed in subjects carrying the T allele of the LPA 93C>T polymorphism and consuming a high intake of fish with respect to those being in the highest tertile of fish consumption but homozygotes for the common allele of the polymorphism. In conclusion, this study reported a significant interaction of daily fish intake and LPA 93C>T polymorphism in decreasing Lp(a) concentrations.
Asunto(s)
Lipoproteína(a)/sangre , Lipoproteína(a)/genética , Polimorfismo de Nucleótido Simple/genética , Alimentos Marinos , Adulto , Anciano , Dieta , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Lipoprotein(a) [Lp(a)] is a LDL-like particle containing a single copy of apolipoprotein B-100 (apoB-100), covalently attached to apolipoprotein(a) [apo(a)]. Apo(a) is encoded by LPA gene (6q26-27), and it has been hypothesized that LPA +93C>T and +121G>A polymorphisms in the 5' flanking region could influence the apolipoprotein(a) synthesis, so affecting Lp(a) levels. In order to permit a rapid detection of LPA polymorphisms, we performed an analysis protocol for the SNPs detection through Nanogen Technology with the Universal Reporting System, and we compared our results with those obtained with a more conventional method, such as PCR-RFLP assay. Our experiments evidenced that Nanogen Technology may be used as a high-throughput tool in LPA +93C>T and +121G>A polymorphisms analysis, minimizing the hands-on time and the costs for the SNPs detection. In particular, this Technology allows the analysis of polymorphisms at the LPA locus, able to modulate the levels of Lp(a), a relevant marker of atherosclerosis.
Asunto(s)
Apoproteína(a)/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Polimorfismo de Nucleótido Simple , Secuencia de Bases , Genotipo , Humanos , Datos de Secuencia Molecular , Fenotipo , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: An involvement of the renin angiotensin system in atrial fibrillation (AF) has been hypothesized, and ACE DD genotype has been suggested to influence the predisposition to AF. The aim of this study was to investigate the role of the ACE I/D polymorphism in relation to the different clinical forms of AF, lone and secondary nonvalvular atrial fibrillation (NVAF). METHODS: 510 consecutive patients with documented NVAF (106 patients had lone, and 404 secondary NVAF), and 520 controls with a negative history of cardiovascular disease have been studied. RESULTS: A significant difference in allele frequency between lone and secondary NVAF (p=0.002) has been found. The ACE D allele was associated with the predisposition to lone NVAF under a dominant, recessive and additive model, both at univariate and multivariate analysis, after adjustment for age and gender (multivariate analysis: dominant OR=2.87, p=0.02; recessive OR=2.01, p=0.003; additive OR=4.47, p<0.0001). ACE D allele was significantly associated with secondary NVAF at both univariate and multivariate analysis under a recessive and additive, but not dominant, model (multivariate analysis: recessive OR=1.89, p=0.001; additive OR=2.50, p<0.0001). CONCLUSIONS: This study highlights the role of ACE gene in predisposing to both lone and secondary NVAF, further contributing to penetrate the genetic mechanisms responsible for this complex disease. The clinical relevance of our results may be related to the possible characterization of subjects predisposed to NVAF in the absence of traditional risk factors, and to the use of ACE-inhibitors therapy able to improve the arrhythmogenic substrate.
Asunto(s)
Fibrilación Atrial/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Factores de RiesgoRESUMEN
AIM: Mink protein, a beta-subunit of I(ks) potassium channels modulate cardiac cellular electrophysiology, and experimental data demonstrated that NO is involved in cardiac vagal activity and in the inhibition of sympathetic activity. We evaluated the role of eNOS -786T>C, 894G>T, 4a/4b and of minK S38G polymorphisms as predisposing factors to non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: We studied 331 consecutive patients with documented NVAF and in 441 control subjects, comparable for age and gender. A significant difference in allele frequencies between patients and controls for minK S38G and eNOS -786T>C, but not for eNOS 894G>T and 4a/4b polymorphisms, was observed. The minK 38G allele was significantly associated with susceptibility to NVAF at both univariate and multivariable analysis, according to dominant and recessive genetic model (multivariable analysis, dominant: OR=1.73, P=0.004 and recessive: OR=1.59, P=0.006). The eNOS -786C allele weakly influenced NVAF at univariate analysis, according to the dominant model (OR=1.50, P=0.01). The contemporary presence of minK 38G and eNOS -786C alleles increased the predisposition to NVAF, after adjustment with cardiovascular risk factors (OR minK 38G*eNOS -786C=2.11, P<0.0001; OR=2.58, P=0.003; OR=3.08, P=0.002, according to dominant, recessive, and additive model, respectively). CONCLUSION: Our findings suggest a role for minK and eNOS genes as predisposing factors to NVAF.
Asunto(s)
Fibrilación Atrial/genética , Predisposición Genética a la Enfermedad/genética , Óxido Nítrico Sintasa de Tipo III/genética , Canales de Potasio con Entrada de Voltaje/genética , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Genético/genética , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
BACKGROUND AND PURPOSE: In patients with atrial fibrillation (AF), oral anticoagulant therapy (OAT) is effective in reducing stroke and embolism. However, despite OAT, ischemic events do occur in some patients. Studies specifically addressing the identification of risk factors for ischemic events during well-conducted OAT are not available. In this study, we prospectively investigated the role of classic risk factors and homocysteine levels in the occurrence of ischemic complications in 364 AF patients on OAT. METHODS: The quality of anticoagulation levels and the occurrence of bleeding and thrombotic events were recorded. RESULTS: During follow-up (859 patient years) 21 patients had ischemic complications (rate 2.4 x 100 patient-years). Homocysteine plasma levels were higher in these patients than in patients without ischemic complications during OAT (P<0.01), whereas no difference was observed in relation to the quality of OAT. The presence of a history of previous ischemic events, hypertension, and homocysteine plasma levels over the 90th percentile were all associated with an increased risk of ischemic events during OAT (odds ratio [OR]=7, 4.5, and 4.7, respectively). The coexistence of these risk factors markedly increased the risk (OR=13.1; 95% CI, 3.7 to 45.7; P=0.001). CONCLUSIONS: In conclusion, our results indicate that AF patients with multiple risk factors may not be sufficiently protected by OAT, even when this is well conducted.
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Fibrilación Atrial/tratamiento farmacológico , Homocisteína/química , Isquemia/prevención & control , Warfarina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacología , Fibrilación Atrial/patología , Ecocardiografía , Femenino , Estudios de Seguimiento , Homocisteína/sangre , Humanos , Isquemia/patología , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Análisis Multivariante , Oportunidad Relativa , Estudios Prospectivos , Análisis de Regresión , Proyectos de Investigación , Riesgo , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/prevención & control , Factores de Tiempo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Nitric oxide (NO) plays a relevant role in various events during atherogenesis. In vitro data suggest that NO may modulate homocysteine (Hcy) concentrations. The aim of this study was to investigate the role of endothelial nitric oxide synthase (eNOS) -786T>C, 894G>T, and 4a4b polymorphisms in influencing Hcy concentrations. METHODS: Blood samples were obtained from 1287 unrelated persons. Plasma Hcy was measured by fluorescence polarization immunoassay, folate and vitamin B(12) by RIA, vitamin B(6) by HPLC, and eNOS and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms by PCR with restriction fragment length polymorphism analysis. RESULTS: MTHFR 677C>T polymorphism significantly influenced Hcy concentrations after adjustment for all confounding variables (P <0.0001 for trend). Univariate analysis showed that the eNOS -786T>C polymorphism, but not 894G>T and 4a4b, was significantly associated with the risk of having Hcy in the third tertile [>13.4 micromol/L; odds ratio (OR) = 1.2; 95% confidence interval (CI), 1.02-1.5; P = 0.03]. After adjustment for all variables known to influence Hcy, the -786T>C polymorphism still influenced Hcy concentrations (OR = 1.9; 95% CI, 1.1-3.2; P = 0.01). By analyzing the influence of eNOS polymorphisms on plasma Hcy concentrations according to vitamin concentrations (folate, vitamin B(6), and vitamin B(12)), age, and smoking habits, we found a significant association between the eNOS -786T>C polymorphism and Hcy in nonsmokers, in persons with normal vitamin status, and in persons <60 years. CONCLUSION: The eNOS -786T>C polymorphism, but not 894G>T and 4a4b, influences plasma Hcy concentrations mildly but significantly and independently.
Asunto(s)
Óxido Nítrico Sintasa/genética , Polimorfismo Genético , Vitaminas/sangre , Adulto , Anciano , Femenino , Ácido Fólico/sangre , Genotipo , Homocisteína/sangre , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Óxido Nítrico Sintasa/sangre , Óxido Nítrico Sintasa de Tipo III , Vitamina B 12/sangre , Vitamina B 6/sangreRESUMEN
BACKGROUND: We previously demonstrated among renal-transplant recipients (RTRs) a high prevalence of hyperhomocysteinemia, which might account for their elevated cardiovascular risk. The purpose of our study was to document, in hyperhomocysteinemic RTRs, the effect of vitamin supplementation on carotid intima-media thickness (cIMT), which is an early sign of atherosclerosis. METHODS: A total of 56 stable hyperhomocysteinemic RTRs were randomly assigned to vitamin supplementation (folic acid 5 mg/day; vitamin B(6) 50 mg/day; vitamin B(12) 400 microg) (group A) or placebo treatment (group B) for 6 months. All subjects underwent cardiovascular risk-factor assessment, including fasting homocysteine (Hcy) levels assay, and high resolution B-mode ultrasound to measure the intima-media thickness of common carotid arteries, at time of enrollment and after 6 months. RESULTS: Fasting Hcy levels markedly decreased in group A after treatment (21.8 [15.5-76.6] micromol/L vs. 9.3 [5.8-13] micromol/L; P<0.0001), whereas no significant changes were observed in group B (20.5 [17-37.6] micromol/L vs. 20.7 [15-34] micromol/L; P=not significant). In group A, cIMT significantly decreased after treatment (0.95+/-0.20 mm vs. 0.64+/-0.17 mm; P<0.0001). All except one patient showed a reduction of cIMT and the mean percentage of cIMT decrease was -32.2+/-12.9%. Patients with methylenetetrahydrofolate reductase (MTHFR) C677T +/+ genotype, with higher Hcy levels, had the major percentage of decrease of Hcy with respect to the other genotypes (mean decrease: MTHFR +/+ 74.8+/-5.7%; MTHFR +/- 58.1+/-10%; MTHFR -/- 56.3+/-8.6%). In hyperhomocysteinemic patients without vitamin supplementation (group B) we documented a significant increase in cIMT after 6 months (0.71+/-0.16 mm vs. 0.87+/-0.19 mm; P<0.05). In 19 of 28 subjects we observed an increase in cIMT, and in 9 of 28 the cIMT was unmodified. The mean percentage of cIMT increase was + 23.3+/-21.1%. CONCLUSIONS: Our results demonstrate a beneficial effect of the treatment of hyperhomocysteinemia by vitamin supplementation on cIMT in a group of RTRs.