Genes and hypertension.
The combination of investigation of rare Mendelian forms of hypertension, candidate gene studies, comparative mapping and genome-wide screening in both animal models and man has led to significant progress in determining new mechanisms of blood pressure control. In this review, the newly discovered blood pressure/cardiovascular genes, WNK kinases and angiotensin converting enzyme 2 and the development of a new anti-hypertensive agent PST2238 are discussed. Major genes causing essential hypertension have yet to be discovered, however, there are now over 20 published genome-wide screens for blood pressure controlling genes. Several regions demonstrate suggestive linkage to the trait and there is some overlap of regions between the different studies. It is hoped that new blood pressure genes will ultimately be discovered using this method. Pharmacogenetic studies in hypertension have only been initiated recently, some are described in this paper. Small studies upon single candidate genes, suggest that the contribution of genetics to the inter-individual variation in blood pressure response to anti-hypertensive therapy, is small, approximately 3-5%. Recently micro-arrays with multiple polymorphisms in multiple genes have been used. After accounting for the additive affects of multiple blood pressure loci, an individual's genetic profile appeared to explain up to 50% of the variation in blood pressure response to therapy. Knowledge of the genetic variants that cause hypertension and influence response to anti-hypertensive therapy will ultimately provide a greater understanding of the molecular mechanisms underlying blood pressure control.
Garcia
E A
EA
Clinical Pharmacology and the Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, London, UK.
Newhouse
S
S
Caulfield
M J
MJ
Munroe
P B
PB
D000732:Androstanols / Q000494:pharmacology / Q000627:therapeutic use; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000235:genetics*; D002148:Calmodulin-Binding Proteins / Q000494:pharmacology / Q000627:therapeutic use; D002268:Carboxypeptidases / Q000235:genetics; D023281:Genomics / Q000639:trends; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D020411:Oligonucleotide Array Sequence Analysis; D007703:Peptidyl-Dipeptidase A; D010597:Pharmacogenetics / Q000639:trends; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099291:Adducins
D000732:Androstanols; D000085962:Angiotensin-Converting Enzyme 2; D000959:Antihypertensive Agents; D002148:Calmodulin-Binding Proteins; D002268:Carboxypeptidases; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D007703:Peptidyl-Dipeptidase A; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099291:Adducins; C498743:WNK1 protein, human; C433806:WNK4 protein, human; C000705307:ACE2 protein, human; C106263:rostafuroxin