Maria E. Armengod

Angiotensin II AT1 receptor gene polymorphism and microalbuminuria in essential hypertension

The objective of this study was to analyze the relationship of polymorphisms of the angiotensin II AT1 receptor gene with microalbuminuria in a group of young adults with essential hypertension. Essential hypertensives, less than 50 years old, never previously treated with antihypertensive drugs, and in absence of diabetes mellitus were included. Office blood pressure (BP), 24-h ambulatory BP monitoring, urinary albumin excretion (UAE) measurements, and DNA analysis were performed. Polymorphisms of the angiotensin II AT1-receptor gene (A1166C and C573T) were studied by polymerase chain reaction and single-strand conformation polymorphism techniques. One hundred eighty-three patients, 49 (27%) microalbuminurics, were included. Office and ambulatory BP values were significantly higher in the microalbuminuria group. No differences in the presence of microalbuminuria were observed among the genotypes of either A1166C or C573T polymorphisms of the angiotensin II receptor AT1 gene, or in the allele frequency of the A1166C or the C573T polymorphism. LogUAE was significantly different among genotypes of the C573T polymorphism [CC 1.30(1.15-1.45), CT 1.14(1.00-1.28), and TT 0.94(0.68-1.20), P < .05]. Both office and ambulatory blood pressure and the TT/C573T genotype were independently related to logUAE, and, at the same BP values, UAE was lower in subjects with this genotype. We have found that the C573T polymorphism is on linkage disequilibrium with A1166C, as the 573T allele is closely linked to the presence of the 1166A allele, but not vice versa. Haplotype analysis among subjects with the AA genotype for the A1166C polymorphism confirms the influence of the TT genotype of the C573T polymorphism on the UAE in hypertensives. The C573T polymorphism of the angiotensin II receptor AT1 gene seems to be a genetic protective factor for UAE in a population of essential hypertensives.

Influence of the I/D Polymorphism of the Angiotensin-Converting Enzyme Gene on the Outcome of Microalbuminuria in Essential Hypertension

The objective of the present study was to analyze the influence of the I/D polymorphism of the ACE gene on the outcome of microalbuminuria in essential hypertensive patients who were receiving antihypertensive treatment. One hundred thirty-six essential hypertensive patients who were <50 years old and had never previously received treatment with antihypertensive drugs were included in the study. During a 3-year period, patients received nonpharmacological treatment consisting of moderate salt restriction and a low-calorie diet they were obese, with or without a regimen of antihypertensive drugs based on beta-blockers or ACE inhibitors. Hydrochlorothiazide was added when necessary to maintain the blood pressure goal of <135/85 mm Hg. At the beginning of the study and at yearly intervals, systolic and diastolic blood pressures (SBP and DBP, respectively), 24-hour urinary albumin excretion (UAE), renal function, and biochemical profile measurements were made. The insertion/deletion (I/D) polymorphism of the ACE gene was determined through the use of polymerase chain reaction. The variables used in the statistical analysis were the measurements at the start of the study and the increase or decrease detected during the follow-up, estimated as individual specific regression line slope values. At baseline, no differences in blood pressure or UAE values were observed among genotypes. Likewise, the genotype or allele frequency was not significantly different between normoalbuminurics and microalbuminurics. After the 3 treatment years, significant reductions in SBP, DBP, and UAE were found (SBP 151.6+/-17.3 reduced to 137.2+/-14.3 mm Hg, P<0.001; DBP 96.6+/-8.9 reduced to 84.5+/-9.8 mm Hg, P<0.001; UAE 36.7+/-71.5 reduced to 28.3+/-78.6 mg/24 h, P<0. 05). The slopes of these parameters over time did not differ significantly among genotypes. The slope of SBP was the main factor related to the slope of logUAE (P<0.003). A significant positive correlation coefficient between the SBP and logUAE slopes was observed for the DD patients (r=0.57, P<0.0001) but was absent in patients carrying the I allele (II r=-0.03, P=NS; I/D r=0.01, P=NS). Follow-up studies should be used to achieve a better understanding of the impact of candidate gene polymorphisms on the development of hypertension-induced organ damage. Assessment of the I/D polymorphism of the ACE gene may identify subjects who require a greatly lowered blood pressure to prevent organ damage and to reduce hypertension-associated complications and death.

Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population

Few data are available on genotype–phenotype interactions among familial hypercholesterolemia (FH) patients in South European populations and there are no data about the influence of R3500Q mutation on lipoprotein phenotype compared to low-density lipoprotein receptor (LDLR) mutations. The objective of the study is to analyze the influence of mutations in the LDLR and apolipoprotein B (apoB) genes on lipoprotein phenotype among subjects clinically diagnosed of FH living in East Spain. In all, 113 FH index patients and 100 affected relatives were studied. Genetic diagnosis was carried out following a protocol based on Southern blot and PCR-SSCP analysis. A total of 118 FH subjects could be classified into three groups according to the type of LDLR mutations (null mutations, missense mutations affecting the ligand binding 3–5 repeat, and missense mutations outside this domain). In addition, the lipoprotein phenotype of these FH groups was compared with 19 heterozygous subjects with familial ligand-defective apoB (FDB), due to R3500Q mutation. FH patients carrying missense mutations affecting the ligand binding repeat 3–5 showed total and LDL cholesterol levels significantly higher than FH patients with missense mutations in other LDLR domains or FDB patients. FH subjects carrying null mutations showed lower high-density lipoprotein cholesterol plasma values compared to FH carrying missense mutations. FDB subjects showed the lowest total and LDL cholesterol plasma values. In conclusion, the type of LDLR gene mutation and R3500Q mutation influences the lipoprotein phenotype of FH population from East Spain.

Polimorfismos genéticos del sistema renina- angiotensina e hipertensión arterial esencial en la población española

Fundamento Analizar la asociacion entre los principales polimorfismos geneticos descritos en el sistema renina-angiotensina y la hipertension arterial (hta) esencial en una muestra de poblacion espanola. Pacientes y metodo Estudio de casos y controles con 185 hipertensos esenciales (edad [de] 39,6 [7,5] anos, 52% mujeres, presion arterial sistolica [pas] de 151,2 [17,4] mmhg, presion arterial diastolica [pad] de 96,0 [9,4] mmhg) y 350 controles normotensos apareados por edad y sexo de una muestra de poblacion general de la Comunidad Valenciana (edad 39,4 [8,0] anos, 51,7% mujeres, PAS de 116,0 [12,0] mmhg, pad de 69,6 [8,5] mmhg). Se realizo pcr para la determinacion de los polimorfismos i/d del gen de la enzima conversiva de la angiotensina (eca), a-6g y m235t del gen del angiotensinogeno y a1166c del gen del receptor at1 de la angiotensina ii. Resultados No hubo diferencias en las distribuciones genotipicas ni alelicas entre casos y controles. En hipertensos tampoco hubo diferencias al comparar genotipos y distribucion alelica segun terciles de valores de presion arterial o presencia/ausencia de antecedentes familiares de hta. Solo en mujeres se detecto un mayor riesgo de hipertension en las pacientes con haplotipos que contenian el alelo c del polimorfismo a1166c con los alelos a del polimorfismo a-6g(p = 0,007) o t del polimorfismo m235t (p = 0,007). Conclusiones No se hallo relacion entre la hta esencial y los polimorfismos i/d del gen de la eca, m235t y a-6g del gen del angiotensinogeno, ni a1166c del gen del receptor at1. En la poblacion de mujeres jovenes se observa un efecto epistatico entre polimorfismos del receptor at1 y del angiotensinogeno.

Polymorphism insertion/deletion of the ACE gene and ambulatory blood pressure circadian variability in essential hypertension.

Objective The objective of the present study was to analyze the influence of the insertion/deletion (I/D) polymorphism of the angiotensin‐converting enzyme on ambulatory blood pressure values and circadian variability in untreated patients with hypertension. Material and methods Ninety‐nine essential hypertensive patients, less than 50 years old (mean age 39.5 ± 7.0 years), previously untreated with antihypertensive drugs were included. Twenty‐four hour ambulatory blood pressure monitoring (ABPM) was performed with a Spacelabs (90202 and 90207) monitor, during a regular working day in unrestricted ambulatory conditions. The I/D polymorphism of the ACE was determined by PCR. Results The distributions of genotypes were in Hardy‐Weinberg equilibrium: I = 17 (17%), ID = 41 (41.5%), DD = 41 (41.5%). No significant differences were present among the groups in terms of age, sex, and biochemical and lipid profiles. The average of 24‐h ambulatory blood pressure was slightly higher in patients with the DD genotype as compared with patients with the II and ID genotypes. This was the result of higher nighttime blood pressure values, because no differences in blood pressure were observed during daytime. The systolic blood pressure (SBP) day : night ratio, as an estimate of circadian variability, was significantly lower in subjects homozygous for the D allele than it was in patients carrying the I allele (1.13 ± 0.09 vs. 1.17 ± 0.08, P  = 0.014). The subjects in the lowest tertile of the SBP day : night ratio, exhibited a higher frequency of the D allele when compared with those in the middle tertile (0.74 vs. 0.59, P  < 0.05) or with those in the highest tertile (0.74 vs. 0.54, P  < 0.01). By using two‐way ANOVA with repeated measures, significant differences in SBP variation over time were observed when comparing homozygous for the D allele with subjects carrying the I allele (F = 2.11, P  = 0.002). Conclusions Among the genotypes of the I/D polymorphism, subjects carrying DD genotype showed a blunted decline of the physiological nocturnal fall of blood pressure that was significant for SBP.

Identificación y caracterización del primer español con defecto homocigoto familiar de unión de la apolipoproteína B

Fundamento El defecto familiar de union de la apolipoproteina B-100 (DFB) es una enfermedad hereditaria autosomica dominante debida a mutaciones localizadas en el gen de la apolipoproteina B-100, clinicamente indistinguible de la hipercolesterolemia familiar. Describimos el primer homocigoto espanol para el DFB. Metodos Estudiamos por tecnica de PCR–SSCP la mutacion R3500Q en los familiares de primer y segundo grado de la familia con DFB previamente descrita por nuestro grupo. Ademas, analizamos la actividad del receptor de LDL en un ensayo con LDL conjugada con oro coloidal. Resultados El paciente presenta en ambos alelos la mutacion R3500Q causante de DFB. El estudio de la actividad del receptor de LDL es normal, lo que descarta que se trate de una hipercolesterolemia familiar. El grado de hipercolesterolemia es menor del esperado tratandose de un homocigoto (colesterol total, 415, y cLDL, 352 mg/dl), y presenta una buena respuesta terapeutica a estatinas y resins (descensos de hasta un 42% para el colesterol total y de un 51% para el cLDL). Conclusiones Hemos detectado y caracterizado el primer homocigoto espanol para el DFB (mutacion R3500Q), que presenta valores moderadamente elevados de colesterol total y cLDL a pesar de su situacion de homocigosis. Estos datos demuestran que el fenotipo lipoproteico de los homocigotos DFB es diferente de la situacion de homocigosis para la hipercolesterolemia familiar.

Influencia de las mutaciones HF Valencia 1 y 2 del gen del receptor de LDL sobre la respuesta terapéutica a simvastatina en sujetos con hipercolesterolemia familiar heterocigota caracterizada molecularmente

Fundamento Analizar si el diagnostico molecular de la hipercolesterolemia familiar (HF) ayuda apredecir la respuesta terapeutica a simvastatina, en una poblacion mediterranea del sur de Europa. Sujetos y metodo Hemos estudiado la respuesta terapeutica en 27 sujetos con diagnostico genetico de HF (11 varones) pertenecientes a 8 familias con HF, seleccionadas por muestreo aleatorio entre 30 familias con HF con diagnostico molecular, en un estudio de intervencion sin grupo control con 20 mg/dia de simvastatina. Comparamos las caracteristicas clinicobiologicas entre sujetos clasificados como HF mutaciones nulas ( HF Valencia 1 y Valencia 2 ; n = 11) o HF mutaciones no nulas (n = 16) en situacion basal y tras 6 semanas de tratamiento con simvastatina. Resultados Los sujetos con mutaciones nulas ( HF Valencia 1 y 2 ) que no expresan ARNmy, por tanto, no sintetizan rLDL a partir del alelo mutado, responden menos al tratamiento con simvastatina que los pacientes con HF con mutaciones no nulas. La media del porcentaje de reduccion del cLDL fue significativamente inferior en el grupo con mutaciones nulas (32,6% [9,5] frente a 42,8% [12,2], p = 0,03). Ademas, los valores plasmaticos del cHDL en situacion basal y postratamiento fueron menores en los sujetos con HF con mutaciones nulas. No encontramos diferencias estadisticamente significativas en los parametros clinicos y lipidicos en situacion basal ni tras tratamiento entre varones y mujeres. Conclusion La respuesta terapeutica a simvastatina en sujetos con HF molecularmente caracterizados es significativamente menor en los sujetos con HF con mutaciones nulas (HF Valencia1 y 2). La aplicacion de estos resultados ayudara a predecir la respuesta al tratamiento con estatinas y permitira disenar terapeuticas individualizadas en este grupo de sujetos con alto riesgo cardiovascular.

Asociación de factores lipídicos, genotipo de APOE y tipos de mutación del gen del receptor de LDL con el infarto agudo de miocardio en sujetos con hipercolesterolemia familiar heterocigota

Fundamento Evaluar la relacion de los lipidos, del genotipo de APOE y del tipo de mutacion delgen del receptor de LDL, clasificandolas en nulas y no nulas, sobre la prevalencia de infartoagudo de miocardio (IAM) en individuos heterocigotos con hipercolesterolemia familiar (HF) delsur de Europa, donde existen pocos datos al respecto. Pacientes y metodo Se trata de un estudio transversal que compara individuos con HF e IAM(n = 32) y a individuos con HF sin IAM (n = 76) mayores de 35 anos (41 varones y 67 mujeres).En 88 sujetos se establecio el diagnostico genetico, siendo divididos en portadores de mutacionesnulas o no nulas del gen del receptor de LDL. Se han comparado los factores clasicosde riesgo cardiovascular, concentraciones plasmaticas de lipidos y lipoproteinas, tipo de mutaciondel receptor de LDL y genotipo de APOE entre individuos con HF e IAM y sin IAM. Resultados Las variables relacionadas con el IAM fueron, en el analisis univariante, la edad, lapresencia de xantomas tendinosos o arco corneal, las concentraciones plasmaticas de colesteroltotal (CT) y colesterol unido a lipoproteinas de baja densidad (cLDL), el cociente CT/cHDL > de 5,3 y genotipo e4 de la APOE. Las odds ratio (OR) bipareadas para IAM fueron: la presenciade xantomas o arco corneal, 1,36 (intervalo de confianza [IC] del 95%, 1,08–1,71; p = 0,01);la edad > 54 anos (percentil 50 del total de individuos con HF) 1,56 (IC del 95%, 1,19–2,04;p = 0,001), y las concentraciones plasmaticas de CT > 332 mg/dl (percentil 50 del total de individuoscon HF), 1,34 (IC del 95%, 1,05–1,71; p = 0,019). En el analisis multivariante solola edad (p = 0,002) y el CT (p = 0,032) permanecieron en el modelo. Conclusiones El IAM en individuos con HF mayores de 35 anos de una poblacion del sur deEuropa se relaciona de forma univariante con la edad y las concentraciones plasmaticas de CTy cLDL, el cociente CT/cHDL y genotipo e4. El IAM se relaciona de forma independiente con laedad y las concentraciones plasmaticas de CT.