title: Personalized Therapy of Hypertension: the Past and the Future.
abstract: During the past 20 years, the studies on genetics or pharmacogenomics of primary hypertension provided interesting results supporting the role of genetics, but no actionable finding ready to be translated into personalized medicine. Two types of approaches have been applied: a "hypothesis-driven" approach on the candidate genes, coding for proteins involved in the biochemical machinery underlying the regulation of BP, and an "unbiased hypothesis-free" approach with GWAS, based on the randomness principles of frequentist statistics. During the past 10-15 years, the application of the latter has overtaken the application of the former leading to an enlargement of the number of previously unknown candidate loci or genes but without any actionable result for the therapy of hypertension. In the present review, we summarize the results of our hypothesis-driven approach based on studies carried out in rats with genetic hypertension and in humans with essential hypertension at the pre-hypertensive and early hypertensive stages. These studies led to the identification of mutant adducin and endogenous ouabain as candidate genetic-molecular mechanisms in both species. Rostafuroxin has been developed for its ability to selectively correct Na(+) pump abnormalities sustained by the two abovementioned mechanisms and to selectively reduce BP in rats and in humans carrying the gene variants underlying the mutant adducin and endogenous ouabain (EO) effects. A clinical trial is ongoing to substantiate these findings. Future studies should apply both the candidate gene and GWAS approaches to fully exploit the potential of genetics in optimizing the personalized therapy.
authors.affiliation: Università Vita Salute San Raffaele, Chair of Nephrology; IRCCS San Raffaele Scientific Institute, Genomics of Renal Disease and Hypertension Unit, Via Olgettina 60, 20132, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
authors.affiliation: CVie Therapeutics Limited, Taipei, Taiwan.
authors.forename: Mara
authors.initials: M
authors.lastname: Ferrandi
authors.affiliation: Italian National Centre of Research, Institute of Biomedical Technologies, Segrate, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: CVie Therapeutics Limited, Taipei, Taiwan.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
authors.affiliation: Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.|R&D Group VitaK, Maastricht University, Maastricht, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Staessen
authors.affiliation: Università Vita Salute San Raffaele, Chair of Nephrology; IRCCS San Raffaele Scientific Institute, Genomics of Renal Disease and Hypertension Unit, Via Olgettina 60, 20132, Milan, Italy. bianchi.giuseppe@hsr.it.|CVie Therapeutics Limited, Taipei, Taiwan. bianchi.giuseppe@hsr.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D005820:Genetic Testing; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D057285:Precision Medicine; D012964:Sodium / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D012964:Sodium
keywords: Adducin; Candidate gene; Endogenous ouabain; GWAS; Genetics; Hypertension; Kidney cross-transplantation; Personalized therapy; Pharmacogenomics; Rostafuroxin