Genetics of primary hypertension: The clinical impact of adducin polymorphisms

Lorena Citterio, Chiara Lanzani, Paolo Manunta, Giuseppe Bianchi

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The usefulness of the results so far published on genetics of primary hypertension for establishing the clinical impact of candidate gene polymorphisms is weakened by the scanty information regarding: a) the functional effect of the gene variants of interest in humans; b) the regulatory genetic network (RGN) where the gene is operating with all the interacting environmental-biological factors and the respective hierarchical organization; c) the consistency between the natural history of the established pathophysiological mechanisms underlying hypertension and the new molecular mechanism detected with genetics; d) the limitations regarding the translation of animal data to human due to the differences among species of the genetic molecular mechanisms underlying similar organ function changes in the different species. Of course, not all these information are available for adducin polymorphisms. In this review, being aware of their importance, the evaluation of the clinical impact of adducin has been focused on data obtained together with the interacting genetic-environmental or biological factors. Adducin polymorphisms and endogenous ouabain (EO) were detected by a top-down approach in rodents after having demonstrated, at cellular and kidney level, that an increase in tubular Na reabsorption could underlies the transition from normotension to hypertension both in rodents and humans. Therefore, we hypothesized that adducin polymorphisms and EO may operate within the triggering RGN that initiates the increase in blood pressure in both species. The distinction between triggering RGN and the secondary RGN is important both to limit the level of genetic complexity arising from secondary changes, and to detect the molecular target to develop tailored therapeutic approach. The pharmacogenomic approach, both in rodents or humans, with newly discovered and never treated hypertension, may be useful to strengthen the "causation" of genetic mechanism. Mutant adducin increases tubular reabsorption: diuretics, because of their effect on overall tubular reabsorption, or rostafuroxin, because of its selective inhibition of the adducin and ouabain effects, may be used for this purpose. Indeed the pharmacogenomic approach with both drugs have provided data consistent with the role of adducin and EO. Taken together, all these findings indicate a clear impact of adducin polymorphism and EO in a subset of patients when the appropriate environmental, biological or genetic context is taken into account. The size of this impact is variable and affected by the context.

Original languageEnglish
Pages (from-to)1285-1298
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1802
Issue number12
DOIs
Publication statusPublished - Dec 2010

Fingerprint

Hypertension
Ouabain
Rodentia
Pharmacogenetics
Biological Factors
adducin
Gene Regulatory Networks
Natural History
Diuretics
Causality
Genes
Molecular Biology
Blood Pressure
Kidney
Pharmaceutical Preparations

Keywords

  • Complex disease
  • Hypertension phase
  • Network
  • Polymorphism

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

Genetics of primary hypertension : The clinical impact of adducin polymorphisms. / Citterio, Lorena; Lanzani, Chiara; Manunta, Paolo; Bianchi, Giuseppe.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1802, No. 12, 12.2010, p. 1285-1298.

Research output: Contribution to journalArticle

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