Genetic Programming of Hypertension

Abstract

The heritability of hypertension (HTN) is widely recognized and as a result, extensive studies ranging from genetic linkage analyses to genome-wide association studies are actively ongoing to elucidate the etiology of both monogenic and polygenic forms of HTN. Due to the complex nature of essential HTN, however, single genes affecting blood pressure (BP) variability remain difficult to isolate and identify and have rendered the development of single-gene targeted therapies challenging. The roles of other causative factors in modulating BP, such as gene-environment interactions and epigenetic factors, are increasingly being brought to the forefront. In this review, we discuss the various monogenic HTN syndromes and corresponding pathophysiologic mechanisms, the different methodologies employed in genetic studies of essential HTN, the mechanisms for epigenetic modulation of essential HTN, pharmacogenomics and HTN, and finally, recent advances in genetic studies of essential HTN in the pediatric population.

Keywords: children; epigenetics; genetics; hypertension; pediatrics; pharmacogenomics.

Figure 1

Molecular mechanisms involved in the different types of monogenic hypertension (HTN). Liddle syndrome: gain-of-function mutation in the gene encoding the apical epithelial sodium channel (ENaC) causes increased sodium absorption and subsequent HTN. Gordon syndrome: WNK1 normally inhibits WNK4, which in turn inhibits the Na–Cl cotransporter (NCC). WNK1 gain-of-function and WNK4 loss-of-function mutation increases the activity of the NCC leading to increased salt and water retention. AME: 11 β-hydroxysteroid dehydrogenase type II enzyme deficiency results in reduced cortisol conversion to cortisone (inactive form). Cortisol binds to the mineralocorticoid receptor and leads to signs of mineralocorticoid excess. GRA: a chimeric gene leads to excess aldosterone production, which acts on mineralocorticoid receptors. 11β HSD type II, 11 β-hydroxysteroid dehydrogenase type II enzyme; AME, apparent mineralocorticoid excess; GRA, glucocorticoid-remediable aldosteronism; Activation, green arrows; Inhibition, red lines with barheads. [Adapted from Simonetti et al. (18)].