Adducin, Renal Intermediate Phenotypes, and Hypertension

Genetics of hypertension with its disappointing results may evoke reactions ranging from enthusiasm and hope to suspicion and skepticism. A variety of reasons may account for these contrasting results1 that cannot be discussed here. However, in our opinion, 2 of these reasons are the most important ones: First, there is clear contradiction between the well established notion of the enormous heterogeneity of hypertension (in terms of molecular, biological, and clinical mechanisms) and the demand that a gene variant must be active across different populations, race, age, gender, etc. Second, the probability models of frequentist statistics, based on randomness, trivialize the ordered complexity of biological systems based on natural laws.2 In fact, all the available statistical genetic guidelines for defining causation of a single gene in a complex disease, like hypertension, are unable to fully account for genetic or environmental interactions.3 More than 50 years of pathophysiological, clinical, and epidemiological studies have clearly shown that these interactions are of paramount importance for the elevation of blood pressure. In fact, it is highly unlikely that the same molecular mechanism may account for a disease that affects up to 40% of the adult population of the industrialized countries. Interactions among these factor varieties can only be inferred from empirical observations and not from deductive mathematical logic.3,4 Along this line, studies trying to correlate genotypes with intermediate phenotypes, that are along biologically plausible pathways linking the genes of interest to blood pressure, may reduce this complexity and, therefore, provide more consistent data across the different studies.4 Intermediate phenotypes are also indispensable to dissect the heterogeneity of this human condition …