From genetics to mechanism of disease liability

The molecular basis of single-gene Mendelian disorders resulting from gain or loss of function is being clarified at a rapid pace. Progress in the genetics of common disease, by contrast, has been frustratingly limited, as we discuss by reference to essential hypertension (EH). The application of standard genetic paradigms to hypertension research has yielded remarkable findings. Arterial pressure (AP) variation in laboratory rats has been correlated with various genes. Likewise, rare Mendelian hypertension syndromes are increasingly understood in molecular terms. The implications of these findings for EH have proven to be modest, however. Genetic methods have been applied to investigate directly essential hypertension in humans, with mixed results. The power of such methods to identify genetic determinants of EH has been questioned. The issues confronting the genetic analysis of EH are discussed by drawing from our ongoing work along the hypothesis that molecular variants of the angiotensinogen gene may constitute inherited predispositions to the condition. Simply establishing correlation is already a daunting task. Far more challenging yet is to establish causation for a physiological phenotype, that is, to understand the mechanism by which a genetic factor may predispose to essential hypertension. Susceptibility imparted by genetic variation, modest and quantitative, modulates response to environmental exposure over time. The product of the gene under examination may be highly pleiotropic, being involved with multiple physiological processes in multiple tissues. Finally, as physiological phenotypes are defined at the level of the entire organism, ultimate demonstration of genetic determination may require specific genetic manipulations in entire organisms.