Genetic influences in human hypertension

Hypertension is a common problem in the Western world and its treatment is responsible for much of the overall drug expenditure. Estimates for the prevalence of hypertension within the general population vary according to the definition of high blood pressure. However, it is likely that approximately 25% of the adult population in Western nations are hypertensive and thus are placed at increased risk of coronary artery disease and stroke. Screening for hypertension can take place in either the secondary care ‘end-organ damage’ clinic, the primary care clinic (in a patient presenting with symptoms of vascular disease or other pathology) or in a population screening setting, such as the ‘well-person’ initiative. Finding hypertensive patients in these different ways has become part of established clinical practice and forms a major part of initiatives such as the UK National Service Framework for Coronary Artery Disease. However, finding and confirming high blood pressure, especially in asymptomatic individuals, can lead to clinical uncertainties. Perhaps the two commonest questions asked in the clinic when discussing the need for treatment of high blood pressure are: (i) ‘why must I start drug treatment – I feel well, what are the benefits?’ and (ii) ‘why have I got high blood pressure anyway?' It is the second question which is the most difficult to answer for an individual patient. Accordingly, this has stimulated further research into the pathophysiology of hypertension. The clinician managing the individual hypertensive patient is aware of the multitude of proposed pathophysiological mechanisms, the relationship of environmental factors such as diet and the simple clinical observation that the hypertensive patient is often aware of other family members with raised blood pressure. The latter clinical observation has stimulated much interest over the years as the genetic basis of hypertension has been explored. In this issue of the journal Chien et al. [1] examine this topic once again in a novel study population. Why is there so much interest in the genetic basis of hypertension? Several factors are important to consider: (i) Underlying pathophysiological mechanisms could be elucidated. (ii) The Human Genome Project is providing additional knowledge and could allow more focused research. (iii) Determining which genetic influences are important in human hypertension could allow more targeted drug therapy (i.e. pharmacogenomics). (iv) Screening for future hypertension could begin at an early stage, before blood pressure rises. Patients could be warned of any future risk, and environmental factors such as obesity and high salt intake could be avoided. The arguments regarding the genetic basis of hypertension have been debated for many years following publications by Platt [2] and Pickering [3]. Whilst Platt proposed a major gene, Pickering's compelling arguments regarding blood pressure as a multigenic trait fashioned modern opinion. Each gene has a small effect on a trait (intermediate phenotype) that contributes to increased blood pressure, and each trait effect adds to others to determine blood pressure levels. Figure 1 demonstrates a model that describes the combination of individual major genes, polygenes and environment in determining blood pressure.Fig. 1: A model demonstrating how human essential hypertension (shaded area) could result from an interaction of the combined effects of individual major genes, polygenes and the environment.Chien et al. [1] have contributed to this debate by performing a cross-sectional family study in a Chinese population. Whilst studies in both Caucasian and Afro-Caribbean subjects have been performed [4], the literature in Chinese patients is relatively sparse. Chien et al. [1] employed complex genetic analyses in adult patients presenting for health screening purposes. The authors conclude that major gene effects are present in these Chinese patients, confirming the results of previous studies in other racial groups. However, although these data offer confirmatory evidence, they also serve as an example for a general analysis of the problems (present and future) facing genetic studies in hypertension. The natural history of hypertension A major problem in studies examining population risk and the epidemiology of hypertension is that hypertension develops with age and thus is defined by rather arbitrary means. Therefore, the study by Chien et al. [1], similar to many other studies including patients who are relatively young, is at risk of potential misclassification. Furthermore, the definition of which level of blood pressure is regarded as being truly hypertensive will affect the analysis. Clearly, if readily identifiable intermediate phenotypes were available then this would allow those subjects who are at risk of hypertension to be included at a time when they were at this stage, before blood pressure has risen to the defined levels. This is an analogous situation to that of type 2 diabetes mellitus in the phase of impaired glucose tolerance. Another potential problem in this area concerns the definition of family history of hypertension and coronary artery disease. Relying on history alone is not ideal, but direct measurement of first-degree relatives is often practically impossible. There is increasing awareness of the important differences in the natural history of hypertension and its impact upon cardiovascular risk. Thus, diastolic, isolated systolic, combined systolic–diastolic hypertension and the hypertensive patient with a wide pulse pressure may have different underlying pathophysiological mechanisms and therefore genetic influences. Once again, this is observed in type 2 diabetes, another multifactorial disease. Relative importance of genes and environment The model described above of multiple susceptibility genes interacting with the environment is also observed in coronary artery disease, diabetes and asthma. It is useful to examine the relative importance of genes versus environment. The degree of genetic influence on a trait such as hypertension can be expressed in terms of heritability (i.e. the fraction of total inter-individual variance due to genes). Therefore, a comparison (as in this study) is made between pairs of subjects with different familial connections and thus genetic similarity. There are differences observed between different populations around the world as described in the study by Chien et al. [1]. However, their study has confirmed in a previously unstudied population, the Chinese, which similar levels of heritability are observed. Another way of considering the genetic contribution is the relative risk for a sibling (i.e. the proportion of siblings who are hypertensive compared to the general population). This ratio, λs, is approximately 3.5 for hypertension [5], which is small compared to a single gene disorder such as cystic fibrosis (λs = 500) but is comparable with that of coronary artery disease (λs = 2). However, it cannot simply be concluded that the remainder of the variance in blood pressure is due to the environment. Using current techniques, it is impossible to resolve gene–environment interactions. The major task, as identified in the study by Chien et al. [1], is to identify the multiple susceptibility genes and their molecular variants that modulate blood pressure. Monogenic hypertension Some of the greatest advances in recent years have been in families in whom hypertension is inherited as a simple Mendelian characteristic. Index cases are often highlighted because of biochemical intermediate phenotypes, such as hypokalaemia or low plasma renin. For example, the very rare Liddles syndrome is inherited in an autosomal dominant fashion and has been found to be inherited on chromosome 16p, with the gene product being the amiloride-sensitive sodium channel in the distal nephron (ENaC) [6]. This is the type of candidate gene that could be responsible for the genetic basis of essential hypertension, as suggested by the study of Chien et al. [1]. However, there is conflicting evidence for the role of functional mutations in ENaC subunits. Interestingly, there is greater evidence for the role of mutations in EnaC in certain racial groups. Thus, one study demonstrated that the T594M mutation of the β subunit in African-Americans conferred a greater risk of hypertension (odds ratio = 4.17, P = 0.029) [7]. Furthermore, a study examining seven amino acid changes including the T594M variant found that they were more frequent in subjects of African origin (44%) compared to Caucasians (1%) [8]. An Australian study [9] identified a linkage between systolic blood pressure and microsatellite markers close to the genes encoding the β and γ subunits of EnaC. The monogenic gene studies are interesting, and suggest possible candidate genes for more detailed analysis in large populations in essential hypertension. Chien et al. [1] demonstrate that genetic influences are important in different racial groups, but also suggests that linkage studies will need to be repeated across these different groups before any final conclusions are made. ENaC mutations appear to be more relevant in African-Americans while, in Chinese populations, other variants in other genes may be more important. Family linkage and association studies The study by Chien et al. [1] is an example of a family linkage study in which it is important to achieve accurate dichotomous phenotype definition. As discussed above, this can be difficult in the case of hypertension. Using the affected sibling pair method, it is possible to avoid such false negatives. This is the rationale used in the current study, although it should be noted that most of the pairs were unrelated spouse pairs. Ultimately, risk needs to be defined in unrelated individuals and genetic markers must be examined in unrelated individuals rather than in families. This type of case–control study is an important and necessary step to assess the utility of potential markers defined in linkage studies. In the future, more chromosomal regions will be identified using linkage analysis from genome wide scans and candidate gene association studies will be increasingly important. It will be necessary to demonstrate that the markers are truly causal, but it is also important to remember that certain mutations may only be significant in certain environments which also vary between different racial populations. Racial differences It has long been observed that there are racial differences in the prevalence of hypertension among human populations. There is plentiful epidemiological evidence demonstrating that hypertension is both more prevalent and severe in African-Americans. To explain this observation requires a consideration of: (i) the important genes and variants leading to susceptibility to hypertension and (ii) an understanding of the genetic basis of race. This subject has been reviewed recently [10]. Furthermore, the complication of environmental factors, which also vary systematically between populations, should not be overlooked. Data in Chinese populations are relatively scarce. However, one study [11] used rural sibling pairs with extreme blood pressure and identified a locus on chromosome 15q which is likely to be involved in regulation of diastolic blood pressure. Further work is required to identify the gene(s) involved and its functional variants. The work by Chien et al. [1] confirms that genetic factors are important in Chinese subjects and that such studies are worthwhile. The future The literature concerning genetic influences in human essential hypertension suggests that a number of candidate genes and genomic regions are involved. However, the results are often inconsistent and difficult to replicate and new strategies are needed. Because hypertension is a heterogeneous problem with delayed penetrance, the identification of robust intermediate phenotypes with greater heritability and early penetrance would be desirable. It would then be possible to map quantitative trait loci in sibling pairs, while simultaneously testing for an association using intermediate phenotypes. Second, comparative genomics utilizing the results from rodent models of hypertension may uncover additional genes to examine. Third, chip-based technology and public gene databases would allow large-scale testing to examine potential loci. Many pathways mediate blood pressure regulation and there are many population/racial divisions and environmental changes. Hypertension is regarded as a disease of the Western world, made more prevalent by modern lifestyle and diet. However, it is also important to consider that: (i) as life expectancy has increased, hypertension manifests itself to a greater degree; (ii) the lifestyles and diets of today were not prevalent in the past when certain genetic traits had survival advantage; and (iii) treatment for hypertension means that patients survive and are able to transmit deleterious genes for hypertension, or predisposition to end-organ damage, to the next generation. These concepts emphasize the importance of both genes and the environment and their interaction in modulating blood pressure. Chien et al. [1] have shown that, in the Chinese population, genetic influences on blood pressure are significant and these require further investigation in future studies.