How does genetics play a role in hypertension?

Human essential hypertension is now considered the most critical public health challenge of the world, with hundreds of millions of people affected. It actually represents a very complex, multifactorial, and polygenic disease that plays an important role in the pathogenesis and development of cardiovascular disease. Despite numerous effective treatments available for hypertension, the genetic basis for this disease has yet to be unraveled even after centuries of research. Further elucidation of the genetics underlying EH may therefore provide a means toward more effective therapies and preventive measures.

Hypertension Genetics: A Complex Problem

Hypertension is often classified broadly into two groups: those with a known cause (secondary hypertension) and those for which no cause is known, termed essential hypertension (EH). Although several mutations that cause Mendelian forms of hypertension—that is, forms in which a mutation at a single gene causes the disease—have been identified, the quest for genes involved in EH has been less rewarding.

As pointed out by Luft, 2004, the question remains: do we know the genes causing EH?

Maybe the answer is in the methodologies and species we use to find them.

Genome-wide scans and the candidate gene approach have been the two main strategies pursued in the search for genes involved in hypertension. Genome-wide scans, which search the entire genome for QTLs, represent an approach that will provide a list of chromosomal regions bearing genes that may control a particular phenotype, such as BP. Such searches are fraught with ambiguity because associations between genotype and phenotype for complex traits such as EH are very weak and obscured by environmental influences. Thus, many such studies often confront the problem of false positives and negatives, further complicating identification of the causative genes.

In the last couple of years, two major genome-wide scans, the Family Blood Pressure Programme and the British Genetics of Hypertension study, have been undertaken to identify hypertension-linked regions in the genome. The FBPP did not report any significant genome-wide linkages except for a region on chromosome 1q associated with diastolic BP. Indeed, the BRIGHT provided evidence for a significant locus on chromosome 6q for hypertension and suggestive evidence of linkage on chromosomes 2q, 5q, and 9q. However, studies of EH using genome-wide scans have yielded variable success because of variation in study design, markers, and inheritance patterns; hence, allowing it to be very challenging for interpretation, making it difficult to find genes related to EH.

Candidate Gene Approach: Limited Success

This approach has, however yielded modest results as any other candidate gene approach that associates EH with variations in genes of known pathophysiological relevance. The difficulty with this approach is to identify candidates for further verification in functional studies. Several factors have been identified that contribute to the limited success of this approach: inadequate phenotyping, hidden population stratification, and lack of statistical power. Ioannidis et al. 2001 proposed criteria for high-quality association studies: the P-values should be significant and survive corrections for multiple testing, the sample sizes should be large, biologic plausibility and functional significance should be demonstrated, and replication should exist across different populations. In human studies, it is quite challenging to fulfill all these criteria.

Animal Models: An Emerging Road

Of the genetic and environmental complexities of human studies, one promising avenue is the use of animal models. Inbred rat strains with inherited hypertension, such as spontaneously hypertensive rats (SHRs) and Dahl salt-sensitive rats, have long been utilized to identify genes of EH. By developing congenic and consomic rat strains, researchers are able to exclude genetic variability found within a heterogeneous population, thereby more easily pinpointing QTLs for hypertension.

Congenic strains are produced by backcrossing a chromosomal region from one strain onto another, while consomic strains represent the transfer of entire chromosomes. Using such strategies, researchers have mapped at least one QTL for BP to almost every chromosome in the rat genome, emphasizing the polygenic nature of hypertension. In many instances, however, this reduction of QTLs to more usefully smaller sizes and positional identification of the responsible genes often remains a challenging task. In fact, on congenic mapping, up till now, there is only one successful cloning of the gene responsible for hypertension (Cicila et al., 2001).

In addition to congenic mapping, other genetic approaches including knockout, knockin and transgenic models and RNA interference can determine the individual contribution of a gene to hypertension. Though these approaches have not as yet been utilised fully in hypertension research, their development may herald major advances in our knowledge of the disease.

The Use of Microarray Technology in Hypertension Research

Recent advances in technology in molecular biology have made possible the analysis of large-scale gene expression with the help of microarray technology. This allows the measure of expression levels of almost all genes (mRNA or proteins) in any given sample. The availability has increased, and a growing number of investigators have applied this technology to hypertension research using animal models.

The integration of microarray technology with congenic mapping has flourished in the identification of glutathione S-transferase µ-type 1 as a potential contributor to hypertension (McBride et al., 2003). In human studies, however, the application of microarray technology remains technically challenging by the need for tissue biopsies from the relevant organs, but these obstacles are likely to be surmounted in the near future.

The Future of Hypertension Genetics

Human and animal studies continue to emphasize the complexity of hypertension as a polygenic disorder. There is no consensus for the number and identity of genes involved, and genome screens indicate that no genes with major effects on BP exist. More likely, multiple genes with modest effects are being sought, each contributing incrementally to the overall risk of hypertension.

The confirmation of the linkage peaks from human and animal studies, and the identification of the disease-predisposing variants is the challenge for future research. Most importantly, the post-genome era, studying the interaction between genes and environmental factors, holds great promise for the future of EH research. Integration of new resources including SNP haplotyping may enable the breakthroughs in the identification of genetic determinants of hypertension.

A Call for Collaborative Research

Though EH disease development mechanisms and their respective treatments are becoming more and more understood, a lot of gaps in our genetic knowledge are yet to be filled. In this regard, it is essential that collaboration exists between scientists from a variety of disciplines to try and bridge these gaps. Joint collaboration will facilitate an accelerated pace in discovering the responsible genes in hypertension so that we can subsequently provide better treatment to patients all over the world…

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