RESUMEN
Familial hypercholesterolemia (FH) is most frequently caused by LDLR or APOB mutations. Therefore, the aim of our study was to examine the genetic background of Slovak patients suspected of FH. Patients with clinical suspicion of FH (235 unrelated probands and 124 family relatives) were recruited throughout Slovakia during the years 2011-2015. The order of DNA analyses in probands was as follows: 1. APOB mutation p.Arg3527Gln by real-time PCR method, 2. direct sequencing of the LDLR gene 3. MLPA analysis of the LDLR gene. We have identified 14 probands and 2 relatives with an APOB mutation p.Arg3527Gln, and 89 probands and 75 relatives with 54 different LDLR mutations. Nine of LDLR mutations were novel (i.e. p.Asp90Glu, c.314-2A>G, p.Asp136Tyr, p.Ser177Pro, p.Lys225_Glu228delinsCysLys, p.Gly478Glu, p.Gly675Trpfs*42, p.Leu680Pro, p.Thr832Argfs*3). This is the first study on molecular genetics of FH in Slovakia encompassing the analysis of whole LDLR gene. Genetic etiology of FH was confirmed in 103 probands (43.8 %). Out of them, 86.4 % of probands carried the LDLR gene mutation and remaining 13.6 % probands carried the p.Arg3527Gln APOB mutation.
Asunto(s)
Encuestas Epidemiológicas , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , Adulto , Femenino , Encuestas Epidemiológicas/métodos , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Eslovaquia/epidemiología , Estadística como Asunto/métodos , Adulto JovenRESUMEN
Familial hypercholesterolemia (FH) is the world's most abundant and the most common heritable disorder of lipid metabolism. The prevalence of the disease in general population is 1:500. Therefore the approximate number of FH patients all over the world is 14 million. From the genetic point of view the disease originates as a result of mutations in genes affecting the processing of LDL particles from circulation, resulting in an increase in LDL cholesterol and hence total cholesterol. These are mutations in genes encoding LDL receptor, apolipoprotein B, proprotein convertase subtilisin/kexin 9 and LDL receptor adaptor protein 1. Cholesterol depositing in tissues and blood vessels of individuals creates tendon xanthoma, xanthelesma and arcus lipoides cornae. Due to the increased deposition of cholesterol in blood vessels, atherosclerosis process is accelerated, what leads to a significantly higher risk of premature cardiovascular diseases. Therefore, early clinical diagnosis confirmed by the DNA analysis, and effective treatment are crucial to reduce the mortality and high risk of premature atherosclerotic complications.
Asunto(s)
Apolipoproteína B-100/genética , Hiperlipoproteinemia Tipo I/genética , Mutación , Proproteína Convertasas/genética , Receptores de LDL/genética , Serina Endopeptidasas/genética , Anticolesterolemiantes/uso terapéutico , Apolipoproteína B-100/sangre , Biomarcadores/sangre , Colesterol/sangre , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Hiperlipoproteinemia Tipo I/epidemiología , Fenotipo , Valor Predictivo de las Pruebas , Prevalencia , Pronóstico , Proproteína Convertasa 9 , Proproteína Convertasas/sangre , Receptores de LDL/sangre , Factores de Riesgo , Serina Endopeptidasas/sangreRESUMEN
We assessed association between novel biomarkers of cardiovascular disease and conventional factors in 40 years old subjects (208 men and 266 women) from the general population of Slovakia. FER(HDL) (cholesterol esterification rate in HDL plasma), AIP--Atherogenic Index of Plasma [Log(TG/HDL-C)] as markers of lipoprotein particle size, and CILP2, FTO and MLXIPL polymorphisms, were examined in relation to biomarkers and conventional risk factors. Univariate analyses confirmed correlation between AIP, FER(HDL) and the most of measured parameters. Relations between AIP and CILP2, FTO and MLXIPL were not significant. However, CILP2 was significantly related to FER(HDL) in both genders. In multivariate analysis BMI was the strongest correlate of AIP levels. In multivariate model variability of FER(HDL) was best explained by AIP (R(2) = 0.55) in both genders with still significant effect of CILP2 SNP in men. In a model where AIP was omitted, TG levels explained 43 % of the FER(HDL) variability in men, while in women HDL-C was the major determinant (42 %). In conclusions, FER(HDL) and AIP related to the known markers of cardiovascular risk provide means to express their subtle interactions by one number. Our novel finding of association between CILP2 polymorphism and FER(HDL) supports its role in lipid metabolism.
Asunto(s)
HDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/genética , Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Pirofosfatasas/genética , Adulto , Enfermedad de la Arteria Coronaria/epidemiología , Esterificación , Femenino , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Prevalencia , Medición de Riesgo , Factores de Riesgo , Eslovaquia/epidemiología , Estadística como AsuntoRESUMEN
AIM: The aim of this trial was to evaluate the efficacy and safety of the combination of once-daily insulin detemir (IDet) and sitagliptin (SITA) versus SITA ± sulphonylurea (SU), both in combination with metformin (MET) in insulin-naive subjects. METHODS: In a 26-week, open-label, randomized, parallel-group study in type 2 diabetes, insulin-naive subjects concomitantly treated with MET ± second oral antidiabetic drug (OAD) were randomized 1 : 1 to IDet + SITA + MET or SITA + MET ± SU. All continued with MET treatment, and those treated with SU continued if randomized to SITA + MET ± SU. Efficacy endpoints included glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), 9-point self-measured plasma glucose (SMPG), weight, body mass index (BMI). Safety endpoints included adverse events (AEs) and hypoglycaemia. RESULTS: Significantly higher reductions in HbA1c, FPG and SMPG were achieved with IDet + SITA + MET compared with SITA + MET ± SU. Estimated HbA1c decreased by 1.44% in the IDet + SITA + MET group versus 0.89% in SITA + MET ± SU, p < 0.001. FPG decreased by 3.7 mmol/l (66.3 mg/dl) versus 1.2 mmol/l (22.2 mg/dl), p < 0.001, respectively. Small decreases in weight and BMI were observed in both arms, with no significant differences. AEs were mild or moderate and were more common in the SITA + MET ± SU arm than in the IDet + SITA + MET arm. There was no major hypoglycaemia. Observed rates of hypoglycaemia were very low (1.3/1.7 episodes/patient year) in both arms. The subgroup treated with MET and SUs prior to the trial achieved similar results. CONCLUSIONS: The combination of once-daily IDet with SITA showed a clinically and significantly better improvement in glycaemic control than SITA in combination with or without SUs. Both regimens were associated with a low rate of hypoglycaemia and slight weight reduction.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/análogos & derivados , Metformina/administración & dosificación , Pirazinas/administración & dosificación , Triazoles/administración & dosificación , Diabetes Mellitus Tipo 2/sangre , Esquema de Medicación , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/efectos de los fármacos , Humanos , Hipoglucemia/prevención & control , Hipoglucemiantes/farmacología , Insulina/administración & dosificación , Insulina/farmacología , Insulina Detemir , Insulina de Acción Prolongada , Masculino , Metformina/farmacología , Persona de Mediana Edad , Pirazinas/farmacología , Fosfato de Sitagliptina , Resultado del Tratamiento , Triazoles/farmacología , Pérdida de Peso/efectos de los fármacosRESUMEN
The aim of this study was to examine the effect of antioxidant supplementation on oxidative damage and chromosome stability in middle-aged men, smokers and non-smokers. A total of 124 men aged 48+/-6 years from Bratislava and from the rural population near Bratislava were investigated; 64 men (22 smokers and 42 non-smokers) were supplemented for 12 weeks with antioxidants, while 60 (25 smokers and 35 non-smokers) were given placebo. The daily antioxidant supplementation consisted of vitamin C (100 mg), vitamin E (100 mg), ss-carotene (6 mg), and selenium (50 microg). Samples of blood were taken on two occasions: At the beginning and at the end of the supplementation trial. Concentrations of dietary antioxidants, ferric reducing ability, malondialdehyde as an indicator of lipid peroxidation in plasma, micronuclei and chromosome aberrations in lymphocytes were measured. Antioxidant supplementation significantly increased the levels of vitamin C, ss-carotene, a-tocopherol and selenium in plasma. The overall antioxidant status of plasma measured as ferric reducing ability of plasma (FRAP) increased significantly (p<0.001) after antioxidant supplementation as well. The increase in antioxidant parameters after supplementation were consistently more pronounced in non-smokers than in smokers. There was a significant decrease of malondialdehyde concentration in the non-smokers, while in smokers the decrease of malondialdehyde concentration was not significant. Antioxidant supplementation did not affect the proportion of lymphocytes with micronuclei or the total number of micronuclei; however, there was a significant positive correlation (p<0.001) between the malondialdehyde concentration at the beginning of the supplementation trial and the difference in number of cells with micronuclei before and after the supplementation. The percent of cells with chromosome aberrations decreased significantly after antioxidant supplementation in smokers. These results indicate that a combined antioxidant supplementation (a) is effective even at very moderate doses; (b) significantly diminishes oxidative damage to lipids when it is high initially; and (c) is effective in decreasing chromosomal instability in lymphocytes of middle-aged men.
Asunto(s)
Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Suplementos Dietéticos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Antioxidantes/metabolismo , Biomarcadores , Recuento de Células Sanguíneas , Núcleo Celular/efectos de los fármacos , Aberraciones Cromosómicas/efectos de los fármacos , Humanos , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Oxidación-Reducción/efectos de los fármacos , FumarRESUMEN
This trial compared the efficacy and safety of basal-bolus therapy using either the soluble basal insulin analogue insulin detemir (IDet) in combination with meal-time rapid-acting analogue insulin aspart (IAsp), or NPH insulin (NPH) in combination with meal-time regular human insulin (HSI). This was a 22-week, multinational, open-labelled, symmetrically randomised, parallel group trial including 395 people with type 2 diabetes (IDet + IAsp: 195, NPH + HSI: 200). At 22 weeks, HbA1c was comparable between treatments (IDet + IAsp: 7.46%, NPH + HSI: 7.52%, P = 0.515) with decreases from baseline of 0.65% and 0.58%, respectively. Treatment with IDet + IAsp was associated with a significantly lower within-person variation in self-measured fasting plasma glucose (FPG) (SD:1.20 versus 1.54 mmol/L, p < 0.001), as well as a lower body weight gain (0.51 versus 1.13 kg, p = 0.038) than with NPH + HSI. The risk of nocturnal hypoglycaemia was 38% lower with IDet + IAsp than with NPH + HSI, but statistical significance was not attained (P = 0.14). The overall safety profile was similar between the two treatments. Basal-bolus treatment with IDet + IAsp is an effective and well tolerated insulin regimen in people with type 2 diabetes, resulting in glycaemic control comparable to that of NPH + HSI, but with the advantages of less weight gain and a lower day-to-day within-person variation in FPG.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/análogos & derivados , Insulina/uso terapéutico , Adulto , Anciano , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Ritmo Circadiano , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Ayuno/sangre , Femenino , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Insulina/administración & dosificación , Insulina/efectos adversos , Insulina/agonistas , Insulina Aspart , Insulina Detemir , Insulina de Acción Prolongada , MasculinoRESUMEN
Antioxidants and antioxidant enzymes protect living organisms against the attack of reactive oxygen species. An adequate daily intake of the individual antioxidants is therefore important to prevent the cells against oxidative damage. We investigated the effect of a modest dietary supplementation with a mixture of antioxidant nutrients (100 mg vitamin E, 100 mg vitamin C,6 mg beta-carotene and 50 microg of selenium per day) for 3 months on the plasma antioxidant capacity and indices of oxidative stress. Two groups of middle-age men were selected: group 1 with survivors of myocardial infarction (MI), and group 2 with clinically normal controls. The values of total antioxidant capacity of plasma (FRAP) significantly increased after supplementation with antioxidants in the both groups. Markers of in vivo lipid peroxidation, plasma malondialdehyde (MDA) and conjugated diene (CD) levels significantly decreased in the both supplemented groups. MDA and CD values were significantly higher at baseline in the group of survivors of myocardial infarction when compared with the group of healthy men. The results demonstrate that short-term and modest supplementation with a mixture of antioxidant nutrients improves antioxidative capacity and reduces products of lipid peroxidation in plasma. Since a more pronounced effect was observed within the group of survivors of myocardial infarction, a recommendation of antioxidant supplements seems appropriate for patients with a history of cardiovascular disease. (Fig. 1, Ref. 19.)
Asunto(s)
Antioxidantes/administración & dosificación , Suplementos Dietéticos , Peroxidación de Lípido , Antioxidantes/metabolismo , Humanos , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Infarto del Miocardio/sangreRESUMEN
We have investigated the effect of modest supplementation with alpha-tocopherol (100 mg/day), beta-carotene (6 mg/day), vitamin C (100 mg/day) and selenium (50 microg/day) on oxidative stress and chromosomal damage, and the influence of methylenetetrahydrofolate reductase (MTHFR) genotype on these end-points. Subjects were two groups of middle-aged men differing in cardiovascular risk; 46 survivors of myocardial infarction before age 50 and 60 healthy controls. They were randomly divided into equal groups to receive antioxidants or placebo for 12 weeks. Twenty-eight patients and 58 controls completed the intervention. Micronucleus levels in peripheral lymphocytes and changes seen after intervention were studied in relation to the MTHFR C677T genotype, basal homocysteine and plasma folate levels. Ferric reducing ability of plasma and concentration of malondialdehyde were measured to assess the antioxidant effect of supplementation. There was no association of micronuclei with folate, homocysteine or malondialdehyde levels before supplementation. Micronucleus frequencies and plasma folate levels did not vary significantly with MTHFR genotype. Homocysteine levels in subjects with the TT variant genotype were significantly higher compared with CT or CC (P = 0.001), especially in subjects with low folate (P = 0.012). In the placebo control group an increase in micronuclei (P = 0.04) was detected at the end of the intervention period. This effect was not seen in the supplemented group. In antioxidant-supplemented myocardial infarction survivors we found an increase in the ferric reducing ability of plasma (P < 0.001) and a decrease in malondialdehyde (P = 0.001). Micronucleus frequency showed a decrease, strongest in subjects with normal folate levels (P = 0.015). In subjects with low folate levels, a high correlation was found between micronuclei after supplementation and homocysteine, both before (r = 0.979, P = 0.002) and after supplementation (r = 0.922, P = 0.009). Thus, folate deficiency may amplify the effect of other risk factors such as elevated homocysteine levels or variant MTHFR genotype, as well as influencing the ability of antioxidant supplementation to protect against genetic damage.
Asunto(s)
Antioxidantes/farmacología , Enfermedades Cardiovasculares/prevención & control , Daño del ADN , Ácido Fólico/sangre , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/administración & dosificación , Antioxidantes/uso terapéutico , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/farmacología , Suplementos Dietéticos , Ácido Fólico/metabolismo , Deficiencia de Ácido Fólico/metabolismo , Genotipo , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Pruebas de Micronúcleos , Persona de Mediana Edad , Infarto del Miocardio/genética , Infarto del Miocardio/prevención & control , Selenio/administración & dosificación , Selenio/farmacología , alfa-Tocoferol/administración & dosificación , alfa-Tocoferol/farmacología , beta Caroteno/administración & dosificación , beta Caroteno/farmacologíaRESUMEN
The objective of this study was to examine plasma homocysteine levels and C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in two ethnic groups from Slovakia. The samples consisted of general Slovak-Romany population (68 men and 81 women) from Southwestern Slovakia and the Slovak-Caucasians (174 men and 177 women) who participated in the CINDI project. The homocysteine levels were examined by HPLC, the analysis of MTHFR genotypes was done by PCR. The Slovak-Romany men (12.0+/-5.6 (S.D.) micromol/l) and women (9.2+/-2.6 microol/l) have significantly lower plasma homocysteine levels (p<0.024 and p<0.00001) when compared to Caucasians (13.3+/-5.1 micromol/l in men and 11.3+/-4.3 micromol/l in women). The genetic equilibrium is assumed for the gene frequencies of the MTHFR polymorphism in both samples. The distribution of MTHFR genotypes did not differ between the two populations (TT 13 vs. 10.6 %; CT 46.6 vs. 41.7 %; CC 40.4 vs. 47.7 %, chí(2)2 = 2.315, df=2, ns). The effect of MTHFR genotypes on homocysteine levels was not confirmed in the Slovak-Romanies and TT homozygosity significantly increased plasma homocysteine levels only in Slovak-Caucasians (11.5+/-4.4 micromol/l, ns; vs. 14.8+/-4.8 micromol/l, p 0.002, respectively). To our knowledge, this is the first epidemiological study in the Romany population examining distribution of the MTHFR genotypes and their effect on homocysteine levels. Further studies are needed to establish the variety of cardiovascular risk factors among Romanies in order to evaluate the significance of particular factors.
Asunto(s)
Etnicidad/genética , Homocisteína/sangre , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo Genético/genética , Adulto , Estatura/etnología , Índice de Masa Corporal , Peso Corporal/etnología , Femenino , Frecuencia de los Genes/genética , Genotipo , Hematócrito , Homocisteína/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/fisiología , Romaní/genética , Factores Sexuales , Eslovaquia , Relación Cintura-Cadera , Población Blanca/genéticaRESUMEN
In order to investigate the effects of antioxidant supplementation on chromosome damage, a 3 month antioxidant supplementation trial was conducted on groups of 28 myocardial infarction survivors and 57 rural controls, all male. The supplement consisted of vitamin C (100 mg/day), vitamin E (100 mg/day), beta-carotene (6 mg/day) and selenium (50 microg/day). Dietary antioxidants in plasma were measured, as well as the ferric reducing ability of plasma (a measure of total plasma antioxidant status) and the concentration of malondialdehyde as an indicator of oxidative stress. Lymphocytes collected at the beginning and end of the supplementation period were stimulated to proliferate and metaphases accumulated for scoring of chromosome aberrations: per cent aberrant cells and chromatid and chromosome breaks. Supplementation with antioxidants was associated with a decrease in the percentage of cells with chromosome aberrations in the group of rural controls (0.63% before compared with 0.27% after supplementation; P = 0.03). The largest effect of supplementation was seen in smokers in this group (0.12% aberrant cells in supplemented compared with 0.81% in placebo group; P > 0.001). The results support the hypothesis that antioxidants decrease genetic damage.
Asunto(s)
Antioxidantes/farmacología , Aberraciones Cromosómicas/efectos de los fármacos , Suplementos Dietéticos , Adulto , Anciano , Daño del ADN/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacosRESUMEN
Dietary antioxidant levels in the blood depend on intake of fruits and vegetables and therefore might be expected to show seasonal variation. A group of healthy male subjects in Bratislava, Slovakia gave blood samples each month for 1 year. Vitamin C, alpha- and gamma-tocopherol and several carotenoids were measured in plasma, and concentrations of essential metals zinc, copper and selenium in serum. Oxidative DNA damage was assessed in lymphocytes using the comet assay. Seasonal variations in antioxidant levels did not follow a common pattern. beta-Cryptoxanthin was highest in the spring. Lycopene peaked in late summer. Lutein/zeaxanthin was higher in summer than in winter. The concentration of zinc in serum was higher in winter than in summer. DNA damage was lower in summer than in winter. Selenium as well as several antioxidants correlated negatively with indices of DNA damage, while zinc levels showed a positive correlation with DNA damage. These results provide some support for a link between consumption of antioxidants and protection against DNA oxidation.
Asunto(s)
Antioxidantes/administración & dosificación , Antioxidantes/análisis , Daño del ADN/efectos de los fármacos , Frutas , Verduras , Ácido Ascórbico/sangre , Carotenoides/sangre , Ensayo Cometa , Humanos , Masculino , Persona de Mediana Edad , Estaciones del Año , Selenio/sangre , Eslovaquia , Zinc/sangre , alfa-Tocoferol/sangre , gamma-Tocoferol/sangreRESUMEN
Glutathione S-transferase genotypes GSTT1, GSTM1, GSTP1 were characterised in 155 middle-aged men and compared with parameters of oxidative stress at the level of DNA and lipids, with antioxidant enzymes, and with plasma antioxidants in smokers and non-smokers. Smokers had on average significantly lower levels of Vitamin C, beta-carotene and beta-cryptoxanthin and higher amounts of oxidised purines and pyrimidines in lymphocyte DNA. The GSTM1 null genotype was associated with elevated glutathione as well as with higher Vitamin C concentration in plasma. Vitamin C was higher in GSTT1+ compared with GSTT1 null--as was glucose-6-phosphate dehydrogenase activity. The homozygous GSTP1 a/a genotype was associated with significantly higher levels of GST activity measured in lymphocytes, in comparison with the b/b genotype. Using multifactorial statistical analysis we found significant associations between smoking, GSTP1 genotype, plasma Vitamin C, and purine base damage in lymphocyte DNA. The difference in Vitamin C plasma levels between smokers and non-smokers was seen only with the GSTP1 b/b genotype. This group accounted also for most of the increase in purine oxidation in smokers. In contrast, the link between smoking and oxidised pyrimidines in DNA was seen only in the GSTT1 null group. It seems that polymorphisms in the phase II metabolising enzyme glutathione S-transferase may be important determinants of commonly measured biomarkers.
Asunto(s)
Antioxidantes/metabolismo , Daño del ADN , Glutatión Transferasa/genética , Infarto del Miocardio/genética , Polimorfismo Genético , Análisis de Varianza , Ácido Ascórbico/sangre , Estudios de Casos y Controles , Glutatión/sangre , Gutatión-S-Transferasa pi , Humanos , Isoenzimas/genética , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Pirimidinas/metabolismo , Salud Rural , FumarRESUMEN
In this study we compared several parameters characterizing differences in the lipoprotein profile between members of families with a positive or negative family history of coronary artery disease (CAD). In addition to regular parameters such as the body mass index (BMI), total plasma cholesterol (TC), low density (LDL-C) and high density (HDL-C) cholesterol and triglycerides (TG) we estimated the fractional esterification rate of cholesterol in apoB lipoprotein-depleted plasma (FER(HDL)) which reflects HDL and LDL particle size distribution. A prevalence of smaller particles for the atherogenic profile of plasma lipoproteins is typical. Log (TG/HDL-C) as a newly established atherogenic index of plasma (AIP) was calculated and correlated with other parameters. The cohort in the study consisted of 29 young (< 54 years old) male survivors of myocardial infarction (MI), their spouses and at least one offspring (MI group; n=116). The control group consisted of 29 apparently healthy men with no family history of premature CAD in three generations, their spouses and at least one offspring (control group; n=124). MI families had significantly higher BMI than the controls, with the exception of spouses. Plasma TC did not significantly differ between MI and the controls. MI spouses had significantly higher TG. Higher LDL-C had MI survivors only, while lower HDL-C had both MI survivors and their spouses compared to the controls. FER(HDL) was significantly higher in all the MI subgroups (probands 25.85+/-1.22, spouses 21.55+/-2.05, their daughters 16.93+/-1.18 and sons 19.05+/-1.33 %/h) compared to their respective controls (men 20.80+/-1.52, spouses 14.70+/-0.98, daughters 13.23+/-0.74, sons 15.7+/-0.76 %/h, p<0.01 to p<0.05). Log(TG/HDL-C) ranged from negative values in control subjects to positive values in MI probands. High correlation between FER(HDL) and Log (TG/HDL-C) (r=0.80, p<0.0001) confirmed close interactions among TG, HDL-C and cholesterol esterification rate. The finding of significantly higher values of FER(HDL) and Log (TG/HDL-C) indicate higher incidence of atherogenic lipoprotein phenotype in members of MI families. The possibility that, in addition to genetic factors, a shared environment likely contributes to the familial aggregation of CAD risk factors is supported by a significant correlation of the FER(HDL) values within spousal pairs (control pairs: r=0.51 p<0.01, MI pairs: r=0.41 p<0.05).
Asunto(s)
Arteriosclerosis/sangre , Lipoproteínas/sangre , Infarto del Miocardio/sangre , Adolescente , Adulto , Apolipoproteínas B/sangre , Arteriosclerosis/etiología , Arteriosclerosis/genética , Índice de Masa Corporal , Colesterol/sangre , Ésteres del Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Estudios de Cohortes , Enfermedad Coronaria/sangre , Enfermedad Coronaria/etiología , Enfermedad Coronaria/genética , Ambiente , Femenino , Humanos , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Infarto del Miocardio/genética , Tamaño de la Partícula , Triglicéridos/sangreRESUMEN
To explore the hypothesis that an interplay between genetic and environmental factors contributes to the development of coronary atherosclerosis, we compared the prevalence of risk factors for atherosclerosis among survivors of myocardial infarction (MI) and their spouses and apparently healthy men and women (spousal pairs) with no personal and family history of atherosclerosis in three generations. There were no significant differences in life-style and dietary habits between the groups. The daily vegetable and/or fruit intake was generally low and did not differ between the groups. Thirty percent and 25% of men and women did not consume any vegetables or fruits, respectively. All differences found in the male MI survivors and control men were also found between the female groups: MI survivors and their spouses were significantly more obese and had higher systolic and diastolic blood pressure and more pathologic plasma lipid levels compared with control males and females, respectively. Compared with the control men and women, MI survivors and spouses had higher plasma homocysteine (Hcgamma) levels (15.3 +/- 10.5, 11.9 +/- 4.0, 16.9 +/- 5.5, and 14.3 +/- 4.0, micromol/L, respectively, P = .01). The frequency of the homozygous C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism in MI survivors was twice that observed in their spouses and controls (12.1%, 4.8%, and 5.8%, respectively), but this difference did not reach statistical significance. A statistically significant association of the MTHFR genotype and Hcgamma concentration (multiple ANOVA) was shown. Neither the frequencies of apolipoprotein E (apoE) alleles nor Asp9Asn mutation of exon 2, Asn29lSer mutation of exon 6, and Ser447Ter of exon 9 of the lipoprotein lipase (LPL) gene varied significantly among the groups. A possible explanation for our findings is that individuals with a genetic predisposition for atherosclerosis and their spouses share a life-style that results in a higher body mass index (BMI) and waist to hip ratio (WHR). On the other hand, individuals with no family history of atherosclerosis, despite an unhealthy life-style similar to that in the affected families (diet and physical activity), had a lower BMI and WHR and more favorable metabolic parameters, including plasma Hcgamma. In conclusion, we have shown that a personal and/or family history of atherosclerosis corresponds to the prevalence and level of risk factors for atherosclerosis. A combination of life-style factors and inherited metabolic abnormalities, including high plasma Hcgamma, are the more likely explanation for our findings.
Asunto(s)
Arteriosclerosis/epidemiología , Infarto del Miocardio/complicaciones , Análisis de Varianza , Apolipoproteínas E/genética , Arteriosclerosis/etiología , Arteriosclerosis/genética , Estudios de Casos y Controles , Femenino , Homocisteína/sangre , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Infarto del Miocardio/genética , Polimorfismo Genético , Prevalencia , Factores de Riesgo , SobrevivientesRESUMEN
In subjects with Down's syndrome (DS) increased oxidative stress and consequent oxidative cell damage have been reported. The aim of this study was to assess whether the excessive production of free oxygen radicals in these subjects can affect the copper-induced lipid oxidation resistance measured in fresh whole serum. Since a significant elevation of serum uric acid levels, which is an efficient hydrophilic antioxidant, has been repeatedly reported in subjects with DS, we studied the association between increased serum uric acid levels and lipid resistance to oxidation measured directly in serum samples by monitoring the change in absorbance at 234 nm. The group of subjects with Down's syndrome consisted of 25 individuals (aged 18+/-5 years). Control group included brothers and sisters of subjects with DS (n = 25, aged 17+/-7 years). In subjects with DS, the serum lipid resistance to oxidation (lag time) was significantly higher than in controls (p<0.05) and a concomitant increase in serum uric acid levels was observed (p<0.001). A significant positive correlation between lag time and serum uric acid concentration was found in subjects with DS (r = 0.48, p<0.05), while the positive correlation in the control group was not significant. The results suggest that increased serum uric acid levels repeatedly observed in subjects with DS may be associated with an enhanced resistance of serum lipids to oxidation which is thought to play an important role in the atherogenic process.
Asunto(s)
Síndrome de Down/sangre , Lípidos/sangre , Ácido Úrico/sangre , Adolescente , Adulto , Femenino , Humanos , Metabolismo de los Lípidos , Masculino , Oxidación-Reducción , Valores de Referencia , Factores de TiempoRESUMEN
The effect of ciprofibrate therapy on plasma lipids and lipoproteins, HDL and LDL subfraction profile, fractional esterification rate of HDL cholesterol (FER(HDL)) and the resistance of LDL and serum lipids to oxidation was studied in 24 males with type 2 diabetes and atherogenic lipoprotein phenotype (ALP). We also examined the effect of ciprofibrate therapy on oxidative DNA damage in peripheral lymphocytes. No differences in glucose, HbA1C and BMI levels were found after three months of ciprofibrate therapy. Ciprofibrate significantly decreased total cholesterol and triglyceride levels by 5.5% and 50% (p = 0.05; 0.001, respectively) and increased HDL-cholesterol levels by 8.5% (p = 0.05). FER(HDL) and LDL subfraction profile were also favorably affected. However, no effect on HDL subclasses was found. There were no statistically significant differences in lipid resistance to oxidation measured in serum and in LDL (lag time and Vmax) before and after therapy. No significant effect of ciprofibrate was found on oxidative DNA damage. The evaluation of the relationship between oxidative damage of purines with lag time in LDL and maximal rate of serum lipid oxidation showed significant correlations after therapy (r = -0.58; 0.47, p = 0.01; 0.05, respectively), but only trends before starting ciprofibrate treatment. Type 2 diabetes mellitus represents a complex metabolic disorder expressed in glucose and lipoprotein disturbances and increased oxidative stress. Ciprofibrate therapy favorably affected major features of lipid abnormalities of diabetic patients, but the level of oxidative stress assessed by in vitro and in vivo methods was not changed. The evaluation of expected logical correlations between the parameters of lipoprotein metabolism, lipid resistance in serum and LDL, and oxidative DNA damage showed that those correlations were more relevant and significant after ciprofibrate treatment and were not related with glucose homeostasis.
Asunto(s)
Ácido Clofíbrico/farmacología , Diabetes Mellitus Tipo 2/sangre , Hipolipemiantes/farmacología , Lipoproteínas/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Colesterol/sangre , Ácido Clofíbrico/análogos & derivados , Ensayo Cometa , Daño del ADN , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Fíbricos , Hemoglobina Glucada/metabolismo , Humanos , Lipoproteínas/efectos de los fármacos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Estadísticas no Paramétricas , Triglicéridos/sangreRESUMEN
The objective of this study was to evaluate the effect of diet and 677 C-->T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene on plasma homocyst(e)ine concentrations in an adolescent population (113 males, age: 14.2+/-2.4 years; 202 females, age: 14.9+/-2.1 years) from a region characterized by high cardiovascular mortality. Homocyst(e)ine levels did not differ between males and females (9.4+/-3.5 and 8.9+/-3.1 micromol/l, respectively). The homozygosity for the 677 C-->T MTHFR mutation was found in 4.6 % of subjects. No differences in homocyst(e)ine levels were found between MTHFR genotypes. Analysis of the diet composition which was performed on a 24-hour daily recall basis and a food frequency questionnaire showed a low daily intake of vitamin B6 (males: 1.13 mg/66% RDA; females: 0.92 mg/61% RDA). Daily folic acid intake was 0.21 g/105% RDA in males and 0.23 g/115% RDA in females. The results of our study show that the high homocyst(e)ine levels in the adolescent population were not affected by the 677 C-->T MTHFR mutation. We conclude that an insufficient dietary intake of vitamin B6 and folic acid is responsible for this finding. This is in accord with the recommendation that the dietary allowances for folate should be reset to the originally prescribed levels of 0.4 g/day which should be sufficient to control the homocysteine levels.
Asunto(s)
Dieta , Genotipo , Homocisteína/sangre , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Adolescente , Enfermedades Cardiovasculares/mortalidad , Niño , Colesterol en la Dieta/administración & dosificación , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Ingestión de Energía , Femenino , Ácido Fólico/administración & dosificación , Humanos , Masculino , Mutación , Piridoxina/administración & dosificación , Factores de Riesgo , Eslovaquia/epidemiología , Encuestas y CuestionariosRESUMEN
The oxidative modification of low density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. LDL of subjects with atherogenic lipoprotein phenotype (ALP) is known to be more susceptible to oxidation. We studied the effect of the hypolipidaemic drug ciprofibrate on the susceptibility of LDL to in vitro oxidation. Nine patients with primary hypertriglyceridaemia and hypoalphalipoproteinaemia (mean plasma triglycerides 3.76 mmol.l-1 and HDL-cholesterol 0.74 mmol.l-1) were treated with ciprofibrate for 12 weeks. The susceptibility of LDL to in vitro Cu(2+)-mediated oxidation was assessed by measuring conjugated diene formation at 234 nm. Ciprofibrate therapy significantly prolonged the lag time (93 +/- 7 min vs. 102 +/- 11 min, P = 0.02). The maximal rate of diene production was 11% lower, but the decrease was not significant. A significant positive correlation was observed between maximal rate and maximal amount of dienes formed. Thiobarbituric acid reacting substances (TBARS) and lipid hydroperoxides (LPO) in oxidatively-modified LDL, isolated from the plasma of patients before and after drug treatment, were unchanged. The results suggest that ciprofibrate therapy has a favourable effect by increasing the in vitro resistance of LDL against oxidation.