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  • Review Article
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The genetic dissection of essential hypertension

Nature Reviews Genetics volume 7, pages 829–840 (2006)Cite this article

Key Points

  • Arterial pressure is determined by the complex interactions of cardiovascular haemodynamics, kidney function and neural, endocrine and paracrine factors. The function of the kidneys in regulating fluid and electrolyte balance has been shown to be the most important long-term determinant of blood pressure. Essential hypertension represents an imbalance of one or more of these determinants of arterial pressure and is the most common cardiovascular disease, being one of the main risk factors for stroke, heart disease and end-stage kidney disease.

  • Defining the genetic basis of susceptibility to hypertension is challenging because of the complex polygenic nature of arterial blood pressure, which is a quantitative trait that is influenced by multiple variants, gene–gene interactions and environmental factors.

  • Genetic sequence variations within families that are affected by Mendelian forms of hypertension have been identified, but these rare alleles account for less than 1% of human hypertension. However, all of these mutations were found to affect renal tubular electrolyte transport functions, confirming the importance of the kidney in the regulation of blood pressure.

  • Linkage studies using single polymorphic markers that were previously known to participate in a biological pathway of interest (candidate gene markers) have not shown strong linkage with hypertension, and replication between populations has been limited.

  • Genome-scanning linkage studies using microsatellite markers or SNPs have become the method of choice in hypertension research, and have identified many QTLs across the genome. These QTLs have not yet been mapped to the level of individual genetic variants, but attention to precise phenotyping and ecogenetic context is likely to be critically important in this respect.

  • Isolated founder populations show reduced genetic and environmental heterogeneity and provide greater power for QTL mapping because of longer linkage disequilibrium intervals. Studies in such populations have allowed the mapping of QTLs that underlie both arterial pressure per se and intermediate phenotypes that contribute to blood pressure variation.

  • Several candidate-gene association studies for hypertension have been carried out with normotensive (control) and hypertensive (case) subjects. Such approaches are providing fruitful results in other complex diseases. Furthermore, to identify variants across the genome in an unbiased manner, the large numbers of SNPs that have been identified and characterized by efforts such as the HapMap project provide the basis for future genome-wide association studies for hypertension.

  • Rodent models overcome many of the confounding issues that are related to the genetic and environmental heterogeneity that is present in human populations. The rat enables the production of large numbers of informative progeny, invasive measurements and mechanistic studies, which are important not only for phenotyping for the initial ascertainment of QTL, but even more so for narrowing QTL regions.

  • A number of inbred rat strains have been developed that mimic various aspects of human essential hypertension. Comparative mapping to conserved regions in the human genome, and confirmation of linkage across species, seems to be a promising approach for narrowing the regions of interest.

  • Linkage data from rat intercross studies have identified many blood pressure QTLs on a range of chromosomes. These linkage studies confirm the polygenic nature of hypertension and, as found in human linkage studies, dense clusters of blood-pressure-related QTLs are present on a subset of chromosomes.

  • Chromosomal substitution techniques between inbred rats with homogeneous genetic backgrounds provide powerful tools to confirm and narrow down QTL regions in the form of inbred consomic and congenic strains.

  • Microarrays are now being used to identify gene expression differences between normotensive and hypertensive strains. These techniques are beginning to define the molecular, biochemical and physiological pathways that are involved in hypertension and could point to candidate genes. However, to assess causal relationships it is important to carry out serial studies that can properly identify those genes with a relevant temporal response.

  • Genomic regions that are identified as important in regulating blood pressure in rat models of hypertension could provide useful guides in the discovery of functionally related conserved genomic regions in human populations. These model systems will also be essential for determining the functions of newly discovered human candidate genes, through invasive phenotyping and transgenesis.

Abstract

QTL mapping in humans and rats has identified hundreds of blood-pressure-related phenotypes and genomic regions; the next daunting task is gene identification and validation. The development of novel rat model systems that mimic many elements of the human disease, coupled with advances in the genomic and informatic infrastructure for rats, promise to revolutionize the hunt for genes that determine susceptibility to hypertension. Furthermore, methods are evolving that should enable the identification of candidate genes in human populations. Together with the computational reconstruction of regulatory networks, these methods provide opportunities to significantly advance our understanding of the underlying aetiology of hypertension.

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Figure 1: Mechanisms of arterial blood pressure regulation.
Figure 2: Hypertension QTLs in the human genome.
Figure 3: Derivation of a consomic strain.
Figure 4: Comparative mapping of blood pressure QTLs in human and rats.

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Acknowledgements

The ideas represented in this overview of the genetics of hypertension have evolved over more than a decade of collaborations with a research team of dedicated and highly interactive geneticists, physiologists and computational biologists working at the Medical College of Wisconsin (MCW). These include H. Jacob, R. Roman, A. Greene, A. Kwitek, M. Olivier, M. Michalkiewicz, M. Liang, J. Lombard, D. Mattson, H. Forster, C. Moreno-Quinn, P. Tonellato, D. Beard and M. Kaldunski. The clinical collaborators responsible for the human hypertension studies in our group are T. Kotchen and U. Broeckel at MCW and P. Hamet at the University of Montreal. We acknowledge the National Heart Lung and Blood Institute and the National Human Genome Institute for support of this research.

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  1. Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, 53226, Wisconsin, USA

    Allen W. Cowley Jr

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DATABASE

OMIM

Apparent mineralocorticoid excess

GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM

LIDDLE SYNDROME

Pseudohypoaldosteronism type II

Type 2 diabetes

FURTHER INFORMATION

MCW Department of Physiology web site

PhysGen physiological genomics database

The Complex Trait Consortium

The International HapMap Project

The Rat Genome Database

NIH Mammalian Gene Collection

Rat Resource & Research Center

Glossary

Compliance

The ratio of the increase in the intraluminal volume relative to an increase in pressure within a blood vessel.

Glomerular filtration

The production of plasma ultrafiltrate by glomeruli

Linkage studies

Studies that are designed to identify the co-segregation of marker alleles and disease within pedigrees.

Renin–angiotensin–aldosterone system

The renin–angiotensin system (RAS) and aldosterone hormone systems have a crucial role in sodium and blood-volume homeostasis, and in the long-term regulation of arterial pressure.

Pleiotropy

Describes situations in which one gene contributes to many phenotypic expressions.

Penetrance

The proportion of individuals with a specific genotype who manifest that genotype at the phenotypic level.

Founder population

The small founding population of a new location that subsequently grows and populates the region; the offspring of these founders can be used in genetic studies to reduce variation due to heterogeneity.

Linkage disequilibrium

The non-random associations of alleles. For example, if the proportion of double homozygotes is greater than predicted from normal Mendelian segregation, then there is linkage disequilibrium between the two alleles. This can arise from epistatic selection, and might indicate a functional interaction between loci that is associated with a phenotype of interest.

Metabolic syndrome

A cluster of conditions that often occur together, including obesity, high blood glucose, high blood pressure and high triglyceride levels, which can lead to cardiovascular disease.

Gene association studies

Population-based genetic studies that examine whether an allele or marker segregates with a phenotype or disease at a significantly higher rate than predicted by chance alone. This is ascertained by genotyping variants in both affected and unaffected individuals.

Genome-wide association studies

The scanning of genomes with genetic markers at regular intervals to identify chromosomal regions with elevated levels of marker similarity in normotensive compared with hypertensive subjects.

Consomic strain

An animal strain that is produced by transferring a single, full-length chromosome from one inbred strain (the donor) into the genetic background of a host strain (the recipient) by repeated backcrossing.

Congenic strain

A congenic strain is produced by transferring a part of a chromosome from one inbred strain into the genetic background of a host strain.

Marker-assisted selection

The use of genetic markers for the selection of a linked characteristic, trait or disease-associated gene.

Dimension reduction

A computational technique that is widely used in informatics science for the mining and visualization of large-scale data sets.

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Cowley, A. The genetic dissection of essential hypertension. Nat Rev Genet 7, 829–840 (2006). https://doi.org/10.1038/nrg1967

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