Revista Colombiana de Cardiología (Jan 2006)
Bases genéticas de la hipertensión arterial esencial en Colombia: avances en nueve años de estudio Genetic basis of essential arterial hypertension in Colombia: advances in nine years of work
Abstract
Las enfermedades cardiovasculares se han consolidado como las principales causas de enfermedad y muerte no violenta en Colombia. La hipertensión arterial es el desorden cardiovascular más frecuente en nuestra nación, con una prevalencia que oscila entre 13% y 23% (1, 2). Por la alta frecuencia en la población adulta, la hipertensión arterial es un factor de riesgo mayor para el desarrollo de enfermedad coronaria así como de enfermedad cerebrovascular y renal. Por más de cincuenta años se han investigado las causas de la hipertensión arterial y se ha descubierto que existen factores ambientales y genéticos que afectan la respuesta de órganos como el riñón o el cerebro y del sistema cardiovascular, que además provocan alteraciones en el control de la presión arterial y la hipertensión crónica. Algunos factores ambientales como exceso de calorías y sal en la dieta, sobrepeso, estrés sicosocial y consumo significativo de alcohol elevan la presión arterial (3), lo cual se ha corroborado en nuestra población (4). Sin embargo, poco se sabe acerca de qué factores genéticos participan en el desarrollo de la hipertensión. En la actualidad, se considera que el componente genético, aun no clarificado, determina un 30% a 50% de los niveles de presión arterial en las poblaciones (5). Para iniciar el estudio genético se tomó una población colombiana de tamaño mediano. De un total de 5.720 personas entre 18 y 65 años, se evaluaron 3.000, de donde se excluyeron individuos con primer grado de consanguinidad (1.998 sujetos). Se obtuvo la curva de distribución de la presión arterial con 1.002 individuos sin parentesco en quienes se estudiaron varios genes candidatos para hipertensión (6-22). Se ha encontrado que genes candidatos como el gen del angiotensinógeno (AGT) regulan la función renal y provocan retención de sal y vasoconstricción sistémica (23, 24). Otros genes están implicados en el trasporte molecular de sodio en el riñón, como el WNK1 y el GNB3 (25-28), o poseen acción en la vasculatura, como el gen del receptor beta 2 adrenérgico (29). Inicialmente, se diseñó un estudio de casos y controles para comparar los percentiles 10 y 90 de la curva de distribución de presión arterial. Se analizaron los haplotipos de las variantes M235T en el exón 2 y dos variantes moleculares de la región promotora del gen AGT (A-6G; A-20C). Se genotipificaron 191 personas con la técnica de reacción en cadena de la polimerasa (ARMS-PCR). Al comparar los diferentes genotipos para A-20C se demostró asociación genética entre la presencia de hipertensión con la variante -20AA del gen AGT (X2 = 4,26; p Cardiovascular diseases are the main causes of disease and non-violent death in Colombia. Arterial hypertension is the most common cardiovascular disorder in our country, with a prevalence oscillating between 13% and 23% (1, 2). Given its high frequency in the adult population, arterial hypertension is a mayor risk for the development of coronary disease, as well as for cerebro-vascular and renal diseases. The causes of arterial hypertension have been investigated for more than fifty years and it has been stated that there are environmental and genetic factors that affect the response of organs such as the kidney, the brain and the cardiovascular system, which in turn provoke alterations in the arterial pressure control and chronic hypertension. Some environmental factors like excessive caloric and salt intake, overweight, psycho-social stress and significant alcohol intake raise the arterial pressure (3), which has been corroborated in our population (4). Nevertheless, little is known regarding the genetic factors implicated in the development of hypertension. Currently, the not yet clarified genetic component determines 30% to 50% of the blood pressure levels in the population (5). In order to initiate the genetic study, a medium size population was chosen. From a total of 5.720 people with ages between 18 and 65 years, 3.000 were evaluated, excluding relatives with first degree of consanguinity (1.998 subjects). A distribution curve of the arterial pressure was obtained with 1.002 non-related individuals in whom many candidate genes for hypertension were studied (6-22). It has been found that candidate genes like the angiotensinogen gene (AGT) regulates kidney function, provokes salt retention and systemic vasoconstriction (23, 24). Other genes are implicated in the molecular sodium transport in the kidney, like the WNK1 and the GNB3 (25, 28), or act in the vasculature as the beta 2 adrenergic receptor gene (29). Initially, a case control study was designed in order to compare the 10 and 90 percentiles from the arterial pressure distribution curve. The haplotypes of the M235T in the exon and two molecular variants of the promoter region of the AGT gene (A-6G; A-20C) were analyzed. 191 people were genotyped by means of the polymerase chain reaction technique (ARMS-PCR). When comparing the different genotypes for A-20C, a genetic association between the presence of hypertension with the -20AA variant of the AGT gene was found (X2; = 4,26; p < 0,05). Later, an association of the GNB3 gene that controls the sodium transport by the renal tubules was found. It showed an independent genetic effect in the presence of hypertension in obese individuals, carriers of the 825T allele of the GNB3 gene. In these individuals hypertension would develop through vascular volume expansion due to changes in the renal salt excretion. Finally, the gene of the beta 2 adrenergic receptor did not show genetic association with hypertension, but had a high frequency in our population; for this reason, its hemodynamic effect was evaluated. The presence of homozygocity in the nucleotides that determine the amino acid in the 16 gene position modifies the hemodynamic state through significant changes in the cardiac output at rest, under postural stimulation in the tilt table or under the effect of an agonist of the beta 2 receptor. After nine years exploring the genetic basis of essential hypertension in Colombia, the presence of subgroups of individuals with phenotypic differences through certain genotypes is demonstrated. Theses results open new ways in order to understand the pathophysiology of this condition in our population and are the start point for a better characterization of hypertension with preventive and therapeutic aims.
