Molecular Genetics of Polygenic Hypertension

Abstract

Essential hypertension is one of the most damaging health risk factors; however, its underlying mechanisms of pathogeneses continue to be undeciphered. To assist this endeavour, investigations utilising human populations and rodent models have revealed numerous genetic building blocks known as quantitative trait loci (QTLs) for blood pressure (BP). Although BP is a quantitatively measured trait manifesting in a continuous variation in heterogeneous populations, each QTL governing it appears to functionally behave as an independent and ‘monogenic’ Mendelian determinant. Mechanistically, multiple QTLs are functionally modularised by epistasis that implies a common pathway or cascade among them, whereas others belong to parallel epistatic modules/pathways. These insights suggest that similar genetic mechanisms probably shepherd the genetic architectures in physiological functions for essential hypertension. Translations of gene discovery to therapeutic targets and diagnostic tools will require biology‐based function validations of specific genes constituting BP QTLs in appropriate animal models. Key Concepts There is a regulatory hierarchy in the genetic architecture governing the functional biology of BP determination. When a master control is removed, modularity and epistatic hierarchy, not a cumulation of minuscule effects, determine the functionality of multiple QTLs on BP. Mechanistically, separate epistatic modules integrating BP QTLs are best explained by independent pathways, each consisting of multiple components that act in sequential cascades in a pathway. As there are fewer pathways than the components comprising them, a defective protein product per se encoded by a mutated QTL, either qualitatively or quantitatively, can lead to a deficient BP‐regulating pathway of pathogenesis and does not have to directly act on BP as a physiological agent.