Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

Abstract

The definition of the most appropriate strategy to demonstrate causation of a given genetic-molecular mechanism in a complex multifactorial polygenic disease like hypertension is hampered by the underestimation of the complexity arising from the genetic and environmental interactions. To disentangle this complexity, we developed a strategy based on six steps: 1) isolation of a rodent model of hypertension (Milan hypertensive strain and Milan normotensive strain) that shares some pathophysiological abnormalities with human primary hypertension; 2) definition in the model of the sequence of events linking these abnormalities to a genetic molecular mechanism; 3) determination of the polymorphism of the three adducin genes discovered in the model both in rats and in humans; 4) comparison at biochemical and physiological levels between the rodent models and the hypertensive carriers of the “mutated” gene variants; 5) evaluation of the impact of the adducin genes in hypertension and its organ complications with association and linkage studies in humans, also considering the genetic and environmental interactions; and 6) development of a pharmacogenomic approach aimed at establishing the therapeutic benefit of a drug interfering with the sequence of events triggered by adducin and their effect's size. The bulk of data obtained demonstrates the importance of a multidisciplinary approach considering a variety of genetic and environmental interactions. Adducin functions within the cells as a heterodimer composed of a combination of three subunits. Each of these subunits is coded by genes mapping to different chromosomes. Therefore, the interaction among these genes, taken together with the interactions with other modulatory genes or with the environment, is indispensable to establish the adducin clinical impact. The hypothesis that adducin polymorphism favors the development of hypertension via an increased tubular sodium reabsorption is well supported by a series of consistent experimental and clinical data. Many mechanistic aspects, underlying the link between these genes and clinical symptoms, need to be clarified. The clinical effect size of adducin must be established also with the contribution of pharmacogenomics with a drug that selectively interferes with the sequence of events triggered by the mutated adducin.