Genetics of arterial hypertension and hypotension

Abstract

Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

“…La unión de la dopamina a DRD1 lleva a una inhibición de la reabsorción de sodio, al promover la internalización de las Na+/K+ ATPasas; este mecanismo requiere la formación de vesículas revestidas de clatrina, para lo cual la participación de las proteínas de citoesqueleto aduccinas es clave (94). Se ha observado que en presencia de mutaciones en ADD1 no se no lleva a cabo la endocitosis de las Na+/K+ ATPasas, a pesar del estímulo por la dopamina, y por lo tanto, no se produce la inhibición esperada de la reabsorción de Na+ (39,94).…”

“…De este modo, se ha observado interacción funcional de las ATP2Bs con proteínas dependientes de la calmodulina como las sintasas de óxido nítrico endotelial, (eNOS) y neuronal (nNOS), y la cinasa de serina dependiente de calcio (CASK), entre otras (43,44,94,95). Por lo anterior, es posible que esta enzima se encuentre también modulando la función de las aduccinas, ya que estas proteínas dependen de la acción de la calmodulina (39).…”

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

“…The genotypes Gly16 and Glu27 are frequent in whites (approximately 50%), but a somewhat different prevalence may exist in other ethnicities (Table 1) (Hawkins et al, 2006;Lima et al, 2006;Wu et al, 2006). Genotype-phenotype association studies for the frequent R16G and Q27E variants have largely remained inconclusive with regard to arterial hypertension and other cardiovascular diseases (Hahntow et al, 2006;Rosskopf et al, 2007). Neither of the variants in position 16 or 27 is associated with major alterations in ligand affinity or in vitro signaling potency.…”

Single Nucleotide Polymorphisms in G Protein Signaling Pathway Genes in Preeclampsia

“…17,18 The subtype RGS2 negatively regulates G protein signaling initiated by vasoconstrictor ligands, such as Ang II, 18 and several observations point to a role for RGS2 in the control of blood pressure. 18,19 Recently, the 3′UTR C1114G polymorphism in RGS2 (rs4606), has been associated with hypertension and reduced RGS2 expression. 20 To our knowledge, the rs4606 in RGS2 has not previously been studied in preeclampsia.…”