Hypertension and the roles of the 9p21.3 risk locus: Classic findings and new association data.

BACKGROUND: The band 9p21.3 contains an established genomic risk zone for cardiovascular disease (CVD). Since the initial 2007 Wellcome Trust Case Control Consortium study (WTCCC), the increased CVD risk associated with 9p21.3 has been confirmed by multiple studies in different continents. However, many years later there was still no confirmed report of a corresponding association of 9p21.3 with hypertension, a major CV risk factor, nor with blood pressure (BP). THEORY: In this contribution, we review the bipartite haplotype structure of the 9p21.3 risk locus: one block is devoid of protein-coding genes but contains the lead CVD risk SNPs, while the other block contains the first exon and regulatory DNA of the gene for the cell cycle inhibitor p15. We consider how findings from molecular biology offer possibilities of an involvement of p15 in hypertension etiology, with expression of the p15 gene modulated by genetic variation from within the 9p21.3 risk locus. RESULTS: We present original results from a Colombian study revealing moderate but persistent association signals for BP and hypertension within the classic 9p21.3 CVD risk locus. These SNPs are mostly confined to a 'hypertension island' that spans less than 60 kb and coincides with the p15 haplotype block. We find confirmation in data originating from much larger, recent European BP studies, albeit with opposite effect directions. CONCLUSION: Although more work will be needed to elucidate possible mechanisms, previous findings and new data prompt reconsidering the question of how variation in 9p21.3 might influence hypertension components of cardiovascular risk.

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

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 porciento y 23 porciento (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 porciento a 50 porciento 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...

The atrial natriuretic peptide gene and essential hypertension in African-Caribbeans from St. Vincent and the Grenadines

Atrial natriuretic peptide (ANP) which alters sodium balance, blood volume and vascular tone represents an important candidate for investigating the genetic basis of essential hypertension (EH). Accordingly, we have studied Bg11 and Xho1 restriction fragment length polymorphisms (RFLPs) of the ANP gene in 147 hypertensive, 141 normotensive and 67 population-based control subjects from a homogenous population of West African origin from St Vincent and the Grenadines. We found no association of either Bg11 and Xho1 RFLPs with EH. This study suggests that the ANP locus may not exert a major gene effect on EH amongst the black people of St. Vincent and the Grenadines.(AU)

Linkage of the angiotensin gene locus to human essential hypertension in African Caribbeans

The renin-angiotensin system regulates blood pressure and sodium balance. The angiotensinogen gene which encodes the key substrate within the system has been linked to essential hypertension in white Europeans. It has been suggested that people of West African ancestry may have a different genetic basis for hypertension. In this study we have tested whether there is linkage of the angiotensinogen to essential hypertension in African Caribbeans from St. Vincent and the Grenadines. DNA from 63 affected sibling pairs with hypertension was tested for linkage by analyzing whether there was excess allele sharing among sibling genotyped using an angiotensingogen dinucleotide repeat sequence. There was significant support for linkage (T = 3.07, P = 0.001) and association of this locus to hypertension (Xý = 50.2, 12 degrees of freedom, P ó 0.001). A DNA polymorphism which alters methionine to threonine at position 235 (M235T) within the angiotensinogen peptide has been associated previously with hypertension. However, we found no association of this variant with hypertension in this study. These findings provide support for linkage and association of the angiotensinogen locus to hypertension in African Caribbeans and suggest some similarities in the genetic basis of essential hypertension in populations of different ethnicity (AU)

Investigation of the renin gene as a putative locus for essential hypertension (EH) in Vincentian African Caribbeans

Epidemiological studies have consistently reported a higher prevalence of essential hypertension in black people. Other data indicate that black people may have salt regulatory systems with low reserves which are unable to cope with moderate quantities of salt and respond to salt loading by increasing their blood pressures. Black people are therefore susceptible to the deleterious effects of salt. As some forms of EH may be related to defects in salt regulatory systems, we investigated association of the renin gene locus (the rate limiting enzyme in an important salt regulatory system) with EH in an ethnically homogenous group of black people of African origin (Summary)