Unraveling Hypertension: Epigenomics Comes of Age

Abstract

Shifting paradigms in hypertension research Early recognition of a significant familial aggregation of high blood pressure [2] held promises that gene discovery would offer significant insights into disease pathophysiology and open avenues for the development of novel therapeutic modalities. In the past decade, genome-wide linkage strategies have successfully identified genes for several rare forms of hypertension, in each of which a single gene imparts large effects on blood pressure in affected individuals [3]. However, the population-wide attributable risk for hypertension of each of these rare gene variants is minimal, and the contribution of common variants of these genes to susceptibility to high blood pressure remains largely unverified. Despite considerable efforts [4], application of linkage mapping strategies to the common form(s) of hypertension has failed to yield significant progress in identifying disease genes, indicating that genes of large effects are unlikely to underlie susceptibility to high blood pressure in the population-at-large. In an attempt to detect susceptibility genes of small-to-moderate effects, research efforts are now shifting toward linkage disequilibrium strategies that assess the association of disease phenotypes with single nucleotide polymorphisms (SNPs) distributed over the whole genome. These studies are made possible by advances in the identification and characterization of patterns of sequence variation in human populations, coupled with the development of large-scale cost-effective genotyping technologies. Yet, limitations of these ‘genotype-centric’ strategies are predicted by the growing recognition that susceptibility to common chronic diseases such as hypertension, is shaped by the dynamic and adaptive responses of physiological and regulatory networks – at the levels of individual cells, tissues, organs or whole organisms – to genetic variation and variation in environmental exposures indexed over time and space [5,6]. Hence, comprehensive research approaches that efficiently integrate genomic and epigenomic information are required to fully understand susceptibility to disease such as hypertension.