RESUMEN
Gráficos com demonstração das curvas ângulo-tempo das articulações dos membros dos eqüinos foram avaliados por meio da análise de imagens digitalizadas tomadas de 10 cavalos e 13 éguas da raça Mangalarga Marchador. Foram utilizados marcadores reflexivos adesivos colocados em 19 pontos articulares dos eqüinos, procedendo-se à filmagem com freqüência de 250 quadros por segundo e utilizando-se o aplicativo Simi-motion 3D 6.0 para digitalização e análise das imagens. A utilização dos marcadores reflexivos adesivos constituiu boa metodologia para análise dos movimentos dos segmentos ósseos dos eqüinos. Os resultados observados indicam haver, durante a locomoção dos eqüinos marchadores brasileiros, comportamento similar das articulações quando comparados com eqüinos de sela europeus, apresentando mesmo padrão das curvas de ângulo-tempo e não havendo grandes diferenças entre os pontos máximos de flexão e extensão.
Images of 10 horses and 13 mares of Mangalarga Marchador breed were taken and digitalized to analyze the joint angle-time curves. Reflexives and adhesives markers were glued on 19 articulations points of the hindlimbs and forelimbs of the horses. The images were taken at 250 frames per second and the digitalization and analysis were made using a Simi-motion 3D 6.0 software. The results demonstrated that the methodology using reflexives and adhesives markers was efficient to make analyses of the bone segment movements of the horses. This study concluded that the Brazilian gaited horses have a similar angle-joint curve as the European warmblood horses and there are no great differences of the maximum extension and flexion points.
Asunto(s)
Articulaciones/metabolismo , Equidae , Locomoción/fisiología , Biomarcadores/análisis , Movimiento/fisiología , Películas Cinematográficas , Gráficos por Computador , Modalidades de MovimientoRESUMEN
Eight different single-nucleotide polymorphisms (SNPs) in six different genes were investigated for possible association with breast cancer. We used a case-control study design in two Caucasian populations, one from Tyrol, Austria, and the other from Prague, Czech Republic. Two SNPs showed an association with breast cancer: R72P inTP53 and P187S in NQO1. Six SNPs, Q356R and P871L in BRCA1, N372H in BRCA2, C112R (E4) and R158C (E2) in ApoE and C825T in GNB3, did not show any sign of association. The P187S polymorphism in NQO1 was associated with breast cancer in both populations from Tyrol and Prague with a higher risk for carriers of the 187S allele. Combining the results of the two populations, we observed a highly significant difference (P=0.0004) of genotype and allele frequencies (odds ratio (OR)=1.46; 95% confidence interval (CI) 1.16-1.85; P=0.001) and of the homozygote ratio (OR=3.8; 95% CI 1.73-8.34; P=0.0001). Combining the two 'candidate' SNPs (P187S and R72P) revealed an increased risk for breast cancer of double heterozygotes (P187S/R72P) of the NQO1 and TP53 genes (OR=1.88; 95% CI 1.13-3.15; P=0.011), suggesting a possible interaction of these two loci.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , NAD(P)H Deshidrogenasa (Quinona)/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Heterocigoto , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Factores de RiesgoAsunto(s)
Trastorno por Déficit de Atención con Hiperactividad/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Oxidorreductasas/genética , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Análisis Mutacional de ADN , Pruebas Genéticas , Humanos , Mutación , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
A clinical evaluation and Cx26 mutation analysis was performed in 92 consecutive patients with sensorineural hearing loss in order to delineate the spectrum of genetically caused hearing loss. Among patients of Austrian origin, 53% were classified with hereditary hearing loss. Cx26 mutations were found in 26% of NSHL patients (40% of familial vs 18% of sporadic cases). The mutation 35delG accounted for 52.8% of all presumed GJB2 disease alleles. The second most frequent mutation was L90P (16.7%) having been reported with a prevalence of 0.7-3.5% in other populations. Three novel mutations were found. The novel mutation, R143Q, was associated with dominant high-frequency hearing loss. Pseudodominant transmission of NSHL was seen in four families with Cx26 mutations. A mutation 35delG carrier rate of 0.9% was observed among 672 controls from West-Austria. Cx26 mutations were found associated with mild to profound, and with asymmetric hearing impairment.
Asunto(s)
Conexinas/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Austria , Conexina 26 , Femenino , Humanos , Masculino , LinajeRESUMEN
Smith-Lemli-Opitz syndrome/RSH (SLOS) is a multiple congenital anomaly syndrome caused by mutations in the gene for Delta7-sterol reductase (DHCR7) which catalyses the last step in the biosynthesis of cholesterol. SLOS is among the common recessive disorders in Europeans but almost absent in most other populations. More than 40 mutations in the DHCR7 gene some of which are frequent have been described in SLOS patients of various origins. Here we report mutation analysis of the DHCR7 gene in SLOS patients from Poland (n = 15), Germany/Austria (n = 22) and Great Britain (n = 22). Altogether 35 different mutations were identified and the two null mutations IVS8-1G > C and W151X were the most frequent in the total sample. In all three populations three mutations accounted for >0.5 of SLOS chromosomes. The mutational spectra were, however, significantly different across these populations with each of the common mutations showing an east-west gradient (W151X, V326L) or vice versa (IVS8-1G > C). W151X is the most frequent (0.33) mutation in Polish SLOS patients. It has an intermediate frequency in German/Austrian patients (0.18) and is rare among British patients (0.02). V326L shows the same distribution pattern (Poland 0.23, Germany/Austria 0.18, Britain 0.02). In contrast IVS8-1G > C is most frequent in Britain (0.34) intermediate in Germany/Austria (0.20) and rare in Poland (0.03). All analysed IVS8-1G > C and V326L alleles shared the same DHCR7 haplotype, whereas the W151X mutation occurred on different haplotypes. There is evidence for both recurrent mutations and founder effects. Together this suggests that the common SLOS mutations in Europe have different geographic and historic origins and spread across the continent in opposite directions.
Asunto(s)
Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Oxidorreductasas/genética , Síndrome de Smith-Lemli-Opitz/genética , Alelos , Austria , ADN/química , ADN/genética , Análisis Mutacional de ADN , Europa (Continente) , Frecuencia de los Genes , Alemania , Haplotipos , Humanos , Mutación , Polonia , Polimorfismo Conformacional Retorcido-Simple , Síndrome de Smith-Lemli-Opitz/patología , Reino UnidoRESUMEN
Patients with idiopathic Parkinson's disease (IPD) are described as having markedly decreased novelty seeking characteristics. Since recent publications suggest an association between the dopamine D4 receptor polymorphism and novelty seeking, we investigated this polymorphism in a group of 122 patients with IPD and 127 healthy control subjects. We found similar allele and genotype frequencies in both groups and no association with the age of onset of symptoms. Therefore, the dopamine D4 receptor polymorphism does not confer genetic susceptibility to IPD and cannot explain the decreased novelty seeking in IPD patients.
Asunto(s)
Enfermedad de Parkinson/genética , Polimorfismo Genético , Receptores de Dopamina D2/genética , Anciano , Femenino , Humanos , Masculino , Receptores de Dopamina D4RESUMEN
Lipoprotein(a) [Lp(a)] is a quantitative genetic trait in human plasma associated with atherothrombotic disease. The major determinant of Lp(a) concentration is the apolipoprotein(a) [apo(a)] gene locus. Variation in the number of kringle IV repeats (K-IV VNTR) in apo(a) has a direct effect on Lp(a) concentrations but explains only a fraction of the large intra- and inter-population variance in Lp(a) levels. Effects on Lp(a) of other intragenic polymorphisms including a pentanucleotide repeat (PNRP) in the promoter likely reflect allelic associations with as yet unidentified sequence variation in the apo(a) gene. We have studied a candidate C-->T transition in two European and two African populations. This polymorphism in the 5' region of the apo(a) gene creates an ATG start codon thereby reducing apo(a) translation in vitro by 60%. All samples were also analyzed for the K-IV VNTR and the PNRP to stratify for their effects and to consider allelic associations. Consistent with the in vitro effect the C-->T transition was associated with a significant reduction in Lp(a) levels in both African populations ( P < 0.0056). In Caucasians, however, the effect was not significant. This was explained by linkage disequilibrium of the +93 T with apo(a) alleles of intermediate length (K-24-K-34) and with nine PNRs. In Europeans these alleles are associated with low Lp(a) which makes any potential effect of the +93 T undetectable in the total sample. From our results we conclude (i) that the +93 C/T polymorphism is the second known intragenic apo(a) polymorphism which affects Lp(a) levels directly in vivo ; (ii) that allelic associations may mask the effect of a mutation; and (iii) that heterogeneity of an effect of a mutation across populations does not disprove causality.
Asunto(s)
Apolipoproteínas/genética , Población Negra/genética , Desequilibrio de Ligamiento , Lipoproteína(a)/sangre , Población Blanca/genética , Alelos , Apoproteína(a) , Austria , Codón/genética , Dinamarca , Etnicidad/genética , Heterogeneidad Genética , Humanos , Kringles/genética , Repeticiones de Minisatélite , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , SudáfricaRESUMEN
To elucidate how the apolipoprotein (apo) E polymorphism and modifiable factors interact in explaining plasma lipid and apolipoprotein levels, we studied 1448 young adults (18 to 26 years old), participating in the European Atherosclerosis Research Study (EARS). Venous blood was collected after an overnight fast. Modifiable factors, eg, body mass index (BMI), waist-to-hip ratio (WHR), tobacco and alcohol consumption, and physical activity, were determined by using standardized protocols. Associations of modifiable factors with apoE levels were homogeneous across apoE phenotypes. In contrast, correlations of BMI with total cholesterol and apoB levels, as well as correlations between WHR and apoB, were significantly (P < .05 to P < .01) stronger in E2 carriers than in subjects with other phenotypes. Total cholesterol and apoB levels were comparable in E2 carriers in the upper tertile of BMI or WHR to those in E3/3 subjects, suggesting that the lowering effect of the E2 allele was no longer present. The inverse association between the plasma cholesteryl linoleate-to-oleate ratio, a marker for the dietary polyunsaturated-to-saturated fatty acid ratio, and triglycerides was also stronger in E2 carriers (-0.33 versus -0.17 in E3/3 and -0.24 in E4 carriers). Associations with other modifiable factors were notably consistent across apoE phenotypes. Gender and modifiable factors explained three times more (31%) of the interindividual variation in apoB levels in E2 carriers than in E3/3 subjects (9%) or E4 carriers (14%), mainly due to a larger variance explained by BMI. Our results suggest that the apoE polymorphism acts in a relatively uniform manner, independently of lifestyle. However, the associations of adiposity to total cholesterol and apoB levels appear to be stronger in apoE2 carriers.
Asunto(s)
Apolipoproteínas E/genética , Apolipoproteínas/sangre , Estilo de Vida , Lípidos/sangre , Polimorfismo Genético/fisiología , Adolescente , Adulto , Apolipoproteína E4 , Apolipoproteínas B/sangre , Índice de Masa Corporal , Ésteres del Colesterol/sangre , Enfermedad de la Arteria Coronaria , Femenino , Heterocigoto , Humanos , Masculino , Factores de RiesgoRESUMEN
In type I (insulin-dependent) diabetic patients, peripheral hyperinsulinemia due to subcutaneous insulin treatment is associated with increased high-density lipoprotein (HDL) cholesterol, and also with an altered surface composition of HDL. Pancreas grafts also release insulin into the systemic rather than into the portal venous system, giving rise to pronounced peripheral hyperinsulinemia. We hypothesized that if peripheral hyperinsulinemia is responsible for high HDL cholesterol and/or altered surface composition of HDL in diabetic subjects, similar changes in the lipid profile should be present in pancreas-kidney transplant recipients (PKT-R). Using zonal ultracentrifugation, we isolated HDL2, HDL3, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) from fasting plasma of 14 type I diabetic PKT-R, eight nondiabetic kidney transplant recipients (KT-R), and 14 healthy control subjects and determined the level and composition of the above lipoproteins. HDL2 cholesterol was increased in PKT-R as compared with KT-R and healthy controls (both P < .05), whereas HDL3 cholesterol was unchanged. However, an altered lipoprotein surface composition was evident in PKT-R: HDL2, HDL3, and LDL were enriched in unesterified cholesterol ([UC] PKT-R v KT-R, P=.13, P < .005, and P < .05, respectively; PKT-R v controls, all P < .005); HDL2 was enriched in phospholipids; and LDL was depleted of phospholipid. KT-R, in contrast, showed no changes in lipoprotein surface composition but a substantial triglyceride enrichment of HDL2 as compared with PKT-R and healthy controls (both P < .05). LDL size as determined by gradient gel electrophoresis was increased in PKT-R compared with controls (P < .005). The plasma concentration of cholesteryl ester (CE) transfer protein (CETP), involved also in phospholipid transfer, was increased in both transplant groups compared with healthy controls (both P < .05). Insulin concentrations in fasting plasma were directly related to CETP levels and to the weight-percentage of UC in HDL3, and inversely to the weight-percentage of phospholipids in LDL (all P < .05). We explain the increase in HDL2 cholesterol and LDL size in PKT-R by their high lipoprotein lipase (LPL) activity conferring an excellent capacity to clear chylomicron triglycerides. Effective handling of postprandial triglycerides, high HDL2 cholesterol, and predominance of LDL pattern A, respectively, are established indicators of a low risk of atherosclerosis. However, it is presently unclear what effects the compositional changes on the surface of HDL and LDL may have on cardiovascular risk in clinically stable PKT-R.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/cirugía , Glicoproteínas , Lipoproteínas/sangre , Trasplante de Páncreas/fisiología , Adulto , Arteriosclerosis/etiología , Proteínas Portadoras/sangre , Estudios de Casos y Controles , Colesterol/sangre , Colesterol/química , Proteínas de Transferencia de Ésteres de Colesterol , Ésteres del Colesterol/sangre , HDL-Colesterol/sangre , HDL-Colesterol/química , LDL-Colesterol/sangre , LDL-Colesterol/química , VLDL-Colesterol/sangre , VLDL-Colesterol/química , Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/etiología , Femenino , Humanos , Trasplante de Riñón/fisiología , Lipoproteínas/química , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
In 17 patients with primary mixed hyperlipidemia we studied levels and composition of lipoproteins in fasting plasma, lipoprotein-modifying enzymes, and postprandial lipoprotein metabolism after an oral fat-tolerance test supplemented with vitamin A before, and 12 weeks after treatment with etophylline clofibrate. With treatment, fasting plasma cholesterol, triglycerides, and the levels of very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL) decreased significantly; high density lipoprotein (HDL) cholesterol increased significantly. Treatment caused also an increase in the protein content of IDL, a decrease in the triglyceride content of LDL, and an increase in the size of LDL as assessed by gradient gel electrophoresis. Concentrations of triglycerides, chylomicrons, and chylomicron remnants after an oral fat load supplemented with vitamin A decreased by 33%, 30% and 6%, respectively (P < 0.005; P < 0.01; and P < 0.05). The activity of lipoprotein lipase and hepatic lipase in postheparin plasma increased by 51% and 45%, respectively (P < 0.01; P < 0.05). We found a decrease in the mass concentration of cholesteryl ester transfer protein (P < 0.05). Stepwise multiple regression analysis showed that the triglyceride content of LDL is determined primarily by fasting triglycerides (r = + 0.53, P < 0.05;baseline) and cholesteryl ester transfer protein (r = + 0.49, P < 0.05; 12 weeks); in contrast, the triglyceride content of HDL3 is determined exclusively by accumulation of postprandial triglycerides (r = + 0.67; P < 0.05; baseline) and postprandial chylomicrons (r = +0.87; P < 0.005; 12 weeks). We conclude that hypolipidemic treatment with etophylline clofibrate favorably affects the cardiovascular risk factor profile in primary mixed hyperlipidemia.
Asunto(s)
Clofibrato/análogos & derivados , Glicoproteínas , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Lipoproteínas/sangre , Proteínas Portadoras/sangre , Proteínas de Transferencia de Ésteres de Colesterol , Quilomicrones/sangre , Clofibrato/uso terapéutico , Ingestión de Alimentos , Femenino , Humanos , Hiperlipidemias/sangre , Lipasa/sangre , Lipoproteína(a)/sangre , Masculino , Persona de Mediana Edad , Transaminasas/sangre , Triglicéridos/sangre , Vitamina A/administración & dosificaciónRESUMEN
In the European Atherosclerosis Research Study, genetic and environmental markers of risk of premature coronary heart disease were compared in offspring of men with and without myocardial infarction before the age of 55 years. Cases were 682 students with a paternal history of myocardial infarction, and control subjects were 1312 students without such a history. The students were enrolled in 14 universities in five European regions (Finland, Great Britain, and northern, middle, and southern Europe). Lipoprotein(a) [Lp(a)] concentrations were skewed towards lower concentrations in both cases (median, 7.3 mg/dL; 95% confidence interval, 6.3 to 8.1 mg/dL) and control subjects (median, 6.6 mg/dL; 95% confidence interval, 6.1 to 7.2 mg/dL) (P = .37). Significantly more northern European male cases than control subjects had Lp(a) levels exceeding 30 mg/dL (P = .040), but this did not pertain to females (P = .29), and overall, there was no difference between cases (16.5%) and control subjects (15.5%) in the frequency of Lp(a) concentrations above 30 mg/dL (P = .63). As expected, there was a significant (P < .01) inverse relationship between apo(a) molecular size and Lp(a) concentration. In Great Britain there was a significant difference in phenotype distribution between cases and control subjects (P = .035), due mainly to a high frequency of the apo(a) S2 isoform in cases. A similar but statistically insignificant tendency was seen in northern Europeans. In the three other regions, however, the distribution of apo(a) phenotypes among cases and controls was similar, and in the study population overall, the distribution of apo(a) phenotypes did not differ significantly (P = .74) between cases and control subjects.
Asunto(s)
Apolipoproteínas/genética , Arteriosclerosis/genética , Lipoproteína(a)/genética , Infarto del Miocardio/genética , Adulto , Apoproteína(a) , Western Blotting , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Europa (Continente) , Femenino , Frecuencia de los Genes , Geografía , Humanos , Masculino , FenotipoRESUMEN
We have developed a novel one-step pool screening PCR procedure which is based on the principles of amplification refractory mutation system (ARMS) and competitive oligonuleotide priming (COP) PCR. In addition to the usual primers, this approach uses two allele-specific competitive oligonucleotides, one of which is 3'-end labeled with a dideoxynucleotide and blocks amplification of the wild-type allele. An allele-specific product is generated only in the presence of the mutation. The introduction of an allele-specific competitive blocker oligonucleotide improves the specificity and robustness of ARMS-PCR. Further its sensitivity is dramatically increased, which allows detection of one mutant allele in a large excess of wild-type-bearing genomic DNA by electrophoresis in an ethidium bromide-stained agarose gel (up to 1 in 10(4) alleles). This makes the method ideal for nonradioactive pool screening. The successful application of the method has been demonstrated for four different point mutations, two in the apolipoprotein B gene (R3500Q, R3531C) which result in familial defective apolipoprotein B-100, one in the CFTR gene (R1162X), and one in the gene for lipoprotein lipase (G188E).
Asunto(s)
Alelos , Pruebas Genéticas/métodos , Reacción en Cadena de la Polimerasa/métodos , Secuencia de Bases , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Humanos , Lipoproteína Lipasa/genética , Datos de Secuencia Molecular , MutaciónRESUMEN
The genetic polymorphism of human apolipoprotein A-IV was investigated in Hungarian blood donors (n = 202) by isoelectric focusing (IEF) of plasma samples followed by immunoblotting. The frequency of apo A-IV alleles was f(A-IV1) = 0.95, f(A-IV2) = 0.039 and f(A-IV3) = 0.002. This frequency distribution is significantly different from other Caucasian populations (P < 0.05). The association of apo A-IV phenotypes with HDL-cholesterol concentration which was previously described for two other European populations was only of borderline significance (P = 0.08). Three previously undescribed apo A-IV variants, designated Budapest-1, Budapest-2 and Budapest-3, were detected by IEF. The mutant proteins are not associated with alterations in the lipid/lipoprotein concentrations in heterozygotes. DNA-sequencing revealed two point mutations (Arg285-->Cys and Thr347-->Ser) in exon 3 of apo A-IV-Budapest-1 and a Glu-->Lys substitution at position 24 in exon 2 of apo A-IV-Budapest-2.
Asunto(s)
Apolipoproteínas A/genética , Polimorfismo Genético , Adulto , Alelos , Apolipoproteínas A/sangre , Secuencia de Bases , Donantes de Sangre , ADN/genética , Femenino , Frecuencia de los Genes , Variación Genética , Humanos , Hungría , Lípidos/sangre , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación Puntual , Reacción en Cadena de la PolimerasaRESUMEN
The European Atherosclerosis Research Study was based on the comparison of offspring having a paternal history of premature myocardial infarction with age- and sex-matched control subjects. Case (n = 635) and control (n = 1259) subjects aged 18 through 26 years were recruited from 14 universities of 11 European countries. The allele distributions of apolipoprotein (apo) E polymorphism differed between populations, with a clear-cut gradient for allele epsilon 4 frequency decreasing from 0.18 in Finland to 0.11 in the south of Europe, following the gradient of coronary heart disease mortality rates. The association of apoE polymorphism with plasma total cholesterol, low-density lipoprotein cholesterol, apoB, and apoE levels was consistent with the now well-identified effects of epsilon 2 and epsilon 4 alleles on these traits. Both epsilon 2 and epsilon 4 alleles equally increased the level of triglycerides, and epsilon 2 had a lowering effect on lipoprotein(a) concentration. There were also weak effects of epsilon 2 and epsilon 4 on high-density lipoprotein cholesterol, apoA-I, and apoA-I-containing lipoprotein levels that paralleled those on apoE levels. The main finding of this study was the significant association of the apoE polymorphism with a paternal history of myocardial infarction. The association was consistent across regions, except in the south. When excluding this region, the population-adjusted odds ratios by reference to phenotype E3/3 were estimated as 0.23, 0.61, 0.78, 1.16, and 1.33 for E2/2, E3/2, E4/2, E4/3, and E4/4, respectively. The apoE locus largely explained the case/control difference of apoB level.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Apolipoproteínas E/genética , Enfermedad Coronaria/genética , Polimorfismo Genético , Adolescente , Adulto , Apolipoproteínas/sangre , Apolipoproteínas B/sangre , Estudios de Casos y Controles , Enfermedad Coronaria/epidemiología , Europa (Continente) , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lípidos/sangre , Masculino , Concentración Osmolar , Valores de Referencia , Factores de Riesgo , Triglicéridos/sangreRESUMEN
As a part of the EARS study we assessed the role of the common apo A-IV polymorphism in determining the hereditary predisposition to cardiovascular disease. The study population consisted of 1261 controls and 629 cases (students whose father had MI before 55 years) from five different European regions. The apo A-IV 1-1 phenotype accounted for 85% of the individuals. One per cent of subjects were homozygous for the apo A-IV2 allele. There was significant regional variation in the apo A-IV allele frequencies from North to South in Europe, with the lowest A-IV2 frequency in Finland. The distribution of the apo A-IV phenotypes was similar in cases and controls, as was the regional variation. The apo A-IV polymorphism did not affect HDL cholesterol. There was no correlation between apo A-IV alleles and the plasma concentration of apo A-IV. The plasma concentration of apo A-IV was lower in females than in males; furthermore, there was a significant difference in apo A-IV concentrations between oral contraceptive users and nonusers: users had the lowest values. As no strongly significant genetic difference could be demonstrated between plasma lipid concentration in cases and controls, and as the apo A-IV polymorphism did not significantly influence plasma lipid concentration, we conclude that the apo A-IV gene is not a major determinant of the risk for MI and/or CHD.
Asunto(s)
Apolipoproteínas A/genética , Lipoproteínas/sangre , Infarto del Miocardio/genética , Polimorfismo Genético , Adolescente , Adulto , Alelos , Europa (Continente) , Femenino , Humanos , Masculino , Infarto del Miocardio/sangre , FenotipoRESUMEN
The association between genetic polymorphisms and a multifactorial disease is generally investigated by case-control studies. However, inference about the genotype-disease association can also be drawn from studies comparing offspring having a parental history of disease with offspring having no parental history. In such studies, differences in genotype frequencies between the two groups of offspring will reflect a different transmission of alleles from affected and unaffected parents. We showed that in offspring studies, the odds ratios (ORs) associated with heterozygous and homozygous genotypes are related by the formula: OR(het) = (OR(hom) + 1)/2. These ORs depend only on the allele frequencies in affected and unaffected parents, and not on the pattern of genotype-disease association. Under simple patterns of association, it is possible to infer from the ORs observed among offspring, the expected ORs for the disease. The decrease of power of offspring studies by comparison with classical case-control studies is evaluated, and an application is given on the association between the apoE polymorphism and coronary heart disease.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Adulto , Apolipoproteínas E/genética , Estudios de Casos y Controles , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Infarto del Miocardio/genética , Polimorfismo Genético/genéticaRESUMEN
Lipoprotein(a) [Lp(a)] is a quantitative trait in human plasma. Lp(a) consists of a low-density lipoprotein and the plasminogen-related apolipoprotein(a) [apo(a)]. The apo(a) gene determines a size polymorphism of the protein, which is related to Lp(a) levels in plasma. In an attempt to gain a deeper insight into the genetic architecture of this risk factor for coronary heart disease, we have investigated the basis of the apo(a) size polymorphism by pulsed field gel electrophoresis of genomic DNA employing various restriction enzymes (SwaI, KpnI, KspI, SfiI, NotI) and an apo(a) kringle-IV-specific probe. All enzymes detected the same size polymorphism in the kringle IV repeat domain of apo(a). With KpnI, 26 different alleles were identified among 156 unrelated subjects; these alleles ranged in size from 32 kb to 189 kb and differed by increments of 5.6 kb, corresponding to one kringle IV unit. There was a perfect match between the size of the apo(a) DNA phenotypes and the size of apo(a) isoforms in plasma. The apo(a) DNA polymorphism was further used to estimate the magnitude of the apo(a) gene effect on Lp(a) levels by a sib-pair comparison approach based on 253 sib-pairs from 64 families. Intra-class correlation of log-transformed Lp(a) levels was high in sib-pairs sharing both parental alleles (r = 0.91), significant in those with one common allele (r = 0.31), and absent in those with no parental allele in common (r = 0.12). The data show that the intra-individual variability in Lp(a) levels is almost entirely explained by variation at the apo(a) locus but that only a fraction (46%) is explained by the DNA size polymorphism. This suggests further heterogeneity relating to Lp(a) levels in the apo(a) gene.
Asunto(s)
Apolipoproteínas A/genética , Lipoproteína(a)/sangre , Alelos , Secuencia de Bases , Mapeo Cromosómico , ADN , Desoxirribonucleasas de Localización Especificada Tipo II , Electroforesis en Gel de Campo Pulsado , Exones , Frecuencia de los Genes , Humanos , Intrones , Lipoproteína(a)/genética , Datos de Secuencia Molecular , Fragmentos de Péptidos/genética , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
The distribution of Lp(a) lipoprotein (Lp[a]) and genetic apolipoprotein(a) (apo[a]) isoforms in plasma samples from 29 healthy normolipidemic subjects of known apo(a) phenotype was evaluated by density gradient ultracentrifugation. The density of Lp(a) was directly related to the size of the apo(a) isoform, ranging from 1.043 g/ml for the LpF phenotype to 1.114 g/ml for the LpS4 phenotype. Heterozygotes had two distinct Lp(a) particles, each containing one of the respective isoforms in plasma. In each heterozygote, the concentration of the lighter Lp(a) species was higher than that of the denser Lp(a) population. These data suggest that apo(a) alleles determine the density and the metabolism and thereby also the concentrations of Lp(a) particles in plasma.
Asunto(s)
Alelos , Apolipoproteínas A/genética , Lipoproteínas/sangre , Apolipoproteínas A/metabolismo , Centrifugación por Gradiente de Densidad , Heterocigoto , Humanos , Immunoblotting , Lipoproteína(a) , Lipoproteínas/química , FenotipoRESUMEN
Application of uniform methods for measuring the apolipoprotein (apo) E polymorphism and plasma cholesterol levels in nine populations (Tyrolean, Sudanese, Indian, Chinese, Japanese, Hungarian, Icelandic, Finnish, and Malay) revealed significant heterogeneity among them in apo E type frequencies and mean cholesterol levels. The major apo E types in all populations were E3/2 (frequency range from 7.0% in Indians to 16.9% in Malays), E3/3 (frequency range from 39.8% in Sudanese to 72.1% in Japanese), and E3/4 (frequency range from 11.3% in Japanese to 35.9% in Sudanese). Mean cholesterol levels ranged from 144.2 mg/dl in the Sudanese to 228.5 mg/dl in the Icelandics. Two-way analysis of variance of the effect of population and apo E type on cholesterol levels showed no significantly interaction effect, indicating that the effects of apo E type on cholesterol levels do not differ significantly among the populations. The overall average excess for the epsilon 2 allele was -14.12 mg/dl (range -31.63 to -8.82 mg/dl); for the epsilon 3 allele, 0.04 mg/dl (range -1.87 to 1.58 mg/dl; and for the epsilon 4 allele, 8.14 mg/dl (range -1.71 to 13.31 mg/dl). Despite the apparent heterogeneity in these values, especially for the epsilon 4 allele, comparison of the average excesses by a method of repeated sampling with random permutations revealed no significant difference in effects among populations. These data indicate that a given apo E allele acts in a relatively uniform manner in different populations despite differences in genetic background and environmental factors.