Genetic Basis Of Hypertension Research Articles

Multi-Trait Genetic Analysis Reveals Clinically Interpretable Hypertension Subtypes.

Hypertension comprises a heterogeneous range of phenotypes. We asked whether underlying genetic structure could explain a part of this heterogeneity. Our study sample comprised N=198 148 FinnGen participants (56% women, mean age 58 years) and N=21 168 well-phenotyped FINRISK participants (53% women, mean age 50 years). First, we identified genetic hypertension components with an unsupervised Bayesian non-negative matrix factorization algorithm using public genome-wide association data for 144 genetic hypertension variants and 16 clinical traits. For these components, we computed their (1) cross-sectional associations with clinical traits in FINRISK using linear regression and (2) longitudinal associations with incident adverse outcomes in FinnGen using Cox regression. We observed 4 genetic hypertension components corresponding to recognizable clinical phenotypes: obesity (high body mass index), dyslipidemia (low high-density lipoprotein cholesterol and high triglycerides), hypolipidemia (low low-density lipoprotein cholesterol and low total cholesterol), and short stature. In FINRISK, all hypertension components had robust associations with their respective clinical characteristics. In FinnGen, the Obesity component was associated with increased diabetes risk (hazard ratio per 1 SD increase 1.08 [Bonferroni corrected CI, 1.05-1.10]) and the Hypolipidemia component with increased autoimmune disease risk (hazard ratio per 1 SD increase 1.05 [Bonferroni corrected CI, 1.03-1.07]). In addition, all hypertension components were related to both hypertension and cardiovascular disease. Our unsupervised analysis demonstrates that the genetic basis of hypertension can be understood as a mixture of 4 broad, clinically interpretable components capturing disease heterogeneity. These components could be used to stratify individuals into specific genetic subtypes and, therefore, to benefit personalized health care and pharmaceutical research.

The AGT epistasis pattern proposed a novel role for ZBED9 in regulating blood pressure: Tehran Cardiometabolic genetic study (TCGS)

IntroductionHigh blood pressure is widely regarded as the most important risk factor for cardiovascular diseases. Epistasis analysis may provide additional insight into the genetic basis of hypertension. MethodsA nested case-control design was used on 4214 unrelated Tehran Cardiometabolic Genetic Study (TCGS) adults to evaluate 65 SNPs of previously associated genes, including ZBED9, AGT, and TNXB. The integrated effect of each gene was determined using the Sequence-based Kernel Association Test (SKAT). We used model-based multifactor dimension reduction (Mb-MDR) and entropy-based gene-gene interaction (IGENT) methods to determine interaction and epistasis patterns. ResultsThe integrated effect of each gene has a statistically significant association with blood pressure traits (P-value < 0.05). The single-locus analysis identified two missense variants in ZBED9 (rs450630) and AGT (rs4762) associated with hypertension. In the ZBED9 gene, significant local interactions were discovered. The G allele in rs450630 showed an antagonistic effect on hypertension, but interestingly, IGENT analysis revealed significant epistasis effects for different combinations of ZBED9, AGT, and TNXB loci. ConclusionWe discovered a novel interaction effect between a significant variant in an essential gene for hypertension (AGT) and a missense variant in ZBED9, which has shifted our focus to ZBED9′s role in blood pressure regulation.

Rare mutations in renal sodium and potassium transporter genes exhibit impaired transport function

Recent efforts to explore the genetic underpinnings of hypertension revealed rare mutations in kidney salt transport genes contribute to blood pressure (BP) variation and hypertension susceptibility in the general population. The current review focuses on these latest findings, highlighting a discussion about the rare mutations and how they affect the transport function. Rare mutations that confer a low BP trait and resistance to hypertension have recently been extensively studied. Physiological and biochemical analyses of the affected renal salt transport molecules [NKCC2 (SLC12A1), ROMK (KCNJ1), and NCC (SLC12A3)] revealed that most of the mutations do, in fact, cause a loss of transport function. The mutations disrupt the transport by many different mechanisms, including altering biosynthetic processing, trafficking, ion transport, and regulation. New insights into the genetic basis of hypertension have recently emerged, supporting a major role of rare, rather than common, gene variants. Many different rare mutations have been found to affect the functions of different salt transporter genes by different mechanisms, yet all confer the same BP phenotype. These studies reinforce the critical roles of the kidney, and renal salt transport in BP regulation and hypertension.

Genetics of Hypertension and Cardiovascular Disease

With the force something like a tsunami wave, a surge of genome-wide association studies (GWASs) in common complex diseases has flooded the recent literature and left us awash with data regarding the identification of causative genetic risk factors for cardiovascular disease such as hypertension. Nevertheless, the more slowly moving tide of the classical candidate gene approach also makes steady progress to clarify the interaction between gene function and pathogenesis of hypertension. Like most other common conditions the estimated effects of each genetic variant on blood pressure and the predisposition to hypertension is quite small, yet the delineation of genetic contribution could reveal new targets for risk reduction in cardiovascular disease. The main focus of this special issue is to highlight the genetic basis of hypertension and cardiovascular disease and outline recent progress in genomics. In addition, several successful investigations in common diseases are introduced as good examples of the potential for better understanding of hypertension using genomic approaches. In the first part of this issue, two papers provide clear reviews of the recent progress in the GWAS approach for hypertension and coronary artery disease. These papers elucidate not only the common findings in studies that, to a certain extent, disparate but also interprete these findings in the context of the advantages and limitations of GWAS. This context includes the contrast between the very strong (genome-wide) significance of associations and the relatively small phenotypic effects of each SNP. In terms of discovery potential, unexpected candidate genes obtained from GWAS provide fresh perspectives in hypertension research. But the genomic picture is for more complex than isolated SNPs. It involves the ways in which the sophisticated organization of the operational elements of the genome interdigitates to provide tissue and development stage-specific regulation and integration of gene expression. It also aligns these factors with phenotypic changes that can result. Two subsequent review articles illustrate these principles by showcasing a new cutting edge of cardiovascular research in the form of microRNAs (miRNAs) and scavenger receptors. Both papers disclose the potentials of these newcomers as therapeutic targets of cardiovascular disease. In a more focused review of candidate genes, the next 2 papers focus on gene polymorphisms of adrenergic receptors. K. Masuo examines the critical role of beta2- and beta3-adrenoceptors gene polymorphisms on hypertension or metabolic syndrome unequivocally. K. B. Bostrom et al. report that a polymorphism (Arg389Gly) of beta1-adrenoceptor gene is significantly associated with increased risk of obstructive sleep apnea (OSA) with hypertension. In the research using candidate gene approach, precise and appropriate phenotyping is important to identify small but significant genetic effect. G. D. Kitsios and E. Zintzaras reveal the protective effect of a haplotype of endothelial nitric oxide synthase gene (NOS3) for predisposition to hypertension. K. Sugimoto et al. point out that a polymorphism in the promoter region of regulator of G protein signaling-2 (RGS2) gene affects the difference of antihypertensive medication in a clinical trial. The last two papers extend the consideration of novel and unexpected concepts for cardiovascular research. A recent topic is the awareness of shared physiological mechanisms between osteoporosis and cardiovascular disease. F. Marini and M. L. Brandi elegantly review the genetic aspects of osteoporosis and touch on the shared mechanisms. The last manuscript by G. Mertens offers a unique perspective on these issues by zooming out to take an evolutionary view. To consider the underlying mechanisms of atherosclerosis, we have to take a larger view without becoming lost in details of the immediate. We hope that this special issue is useful for your research and is conducive to the incorporation of new concepts and methods in your own laboratory. Tomohiro Katsuya Stephen B. Harrap Toshio Ogihara

Genetic Analysis of Blood Pressure in 8 Mouse Intercross Populations

The genetic basis of hypertension is well established, yet very few genes that cause common forms of hypertension are known. Quantitative trait locus (QTL) analyses in rodent models can guide the search for human hypertension genes, but the excellent genetic resources for mice have been underused in this regard. To address this issue, we surveyed blood pressure variation in mice from 37 inbred strains and generated 2577 mice in 8 intercross populations to perform QTL analyses of blood pressure. We identified 14 blood pressure QTL in these populations, including > or =7 regions of the mouse genome not linked previously to blood pressure. Many QTL were detected in multiple crosses, either within our study or in studies published previously, which facilitates the use of bioinformatics methods to narrow the QTL and focus the search for candidate genes. The regions of the human genome that correspond to all but 1 of the 14 blood pressure QTL in mice are linked to blood pressure in humans, suggesting that these regions contain causal genes with a conserved role in blood pressure control. These results greatly expand our knowledge of the genomic regions underlying blood pressure regulation in mice and support future studies to identify the causal genes within these QTL intervals.

Cardiorespiratory Fitness, BMI, and Risk of Hypertension

Cardiorespiratory fitness and regular physical activity are inversely associated with the risk of hypertension, and exercise training has been shown to lower elevated blood pressure (BP). Genetic factors contribute significantly to the interindividual differences in endurance training-induced changes in BP. However, similar data on the genotype-by-fitness interactions on the risk of hypertension are scarce. In 2000, we started a systematic collection of blood samples from all consenting subjects of the Aerobics Center Longitudinal Study (ACLS) with a goal to generate a resource for studies addressing genotype-by-fitness interaction effects on various health-related end points. Here, we introduce the rationale and design of the first study based on the ACLS genetics resource focusing on hypertension as the health outcome (HYPGENE study), and we report the associations of cardiorespiratory fitness and body mass index (BMI) with the risk of hypertension. All HYPGENE subjects (N = 1234) were healthy and normotensive at their first clinic visit. Cases (N = 629) developed hypertension during the follow-up period (mean 8.7 yr), whereas controls (N = 605) remained normotensive (mean follow-up 10.1 yr). Cardiorespiratory fitness was the strongest predictor of the hypertension risk, with each maximal metabolic equivalent unit being associated with a 19% lower risk (95% confidence interval [95% CI], 12-24%). Each baseline BMI unit was associated with a 9% higher hypertension risk (95% CI, 4-13%). However, the association of BMI was greatly attenuated (odds ratio 1.04 [95% CI, 0.99-1.09]) when fitness also was included in the model. The HYPGENE study will provide an excellent resource to address hypotheses regarding the genetic basis of hypertension while taking cardiorespiratory fitness level into account.

Functional genomics in hypertension

Essential hypertension is a complex polygenetic disease with a major impact on health worldwide. Despite earlier detection of promising candidate genes, only recent advances in genotyping technology and new approaches to examining gene and protein function have provided the tools to unravel the genetic basis of hypertension. In humans, genome-wide scans resulted in the identification of several chromosomal loci that are linked to hypertension. These regions still contain a large number of potential candidate genes, but high-throughput genotyping methods will facilitate the detection and analysis of single-nucleotide polymorphisms within these genes. The focus will be on animal models of hypertension, specifically rats. Congenic strains facilitate the identification of genetic determinants of hypertension, and new technologies such as RNA interference (which silences the expression of target genes) and transgenic rescue models will help us to analyse the relationship between genes and function. Analysis of conserved synteny (preserved order of genes) between species allows translation of findings from rodent models to essential hypertension in humans. Recent discoveries and approaches beyond genomics will also be discussed, including the regulatory role of microRNA and the concept of proteomics. The genetic basis of hypertension is complex, and the examination of the functional consequences of genetic variants in particular is still challenging. A number of tools are now available with which to examine gene-function relationships, and these will provide an improved understanding of cardiovascular genomics. This will eventually lead to targeted prevention and treatment strategies in patients with hypertension and other cardiovascular diseases.

Transgenesis and Gene Targeting in the Mouse: Tools for Studying Genetic Determinants of Hypertension

As more effort is made to identify genes responsible for hypertension in human populations and genetically hypertensive animal models, the need for experimental systems in which the functional significance of genes, gene variants, and quantitative trait loci (QTL) can be determined is becoming increasingly important. Over the past five years, transgenic and gene-targeting technology has been utilized to study the cardiovascular effects of over-expression or ablation of genes which have been considered candidates in the genetic basis of hypertension. This review focuses on the most recent major advances in this area, and how this technology aids in our understanding of the molecular mechanisms by which newly discovered genes or gene variants affect blood pressure in the whole organism. We also discuss the potential use of transgenic models in refining the location of a QTL, and discuss some of the limitations and potential pitfalls in the application of these tools to the field of hypertension research. The coupling of genetic manipulations afforded by transgenesis and gene targeting, along with advances in our ability to assess the cardiovascular phenotype in the mouse, provides us with a powerful system for examining the genes responsible for causing essential hypertension.

Angiotensinogen in human essential hypertension.

The candidacy of angiotensinogen for a role in the genetic basis of hypertension is supported by the observation that plasma angiotensinogen levels track with raised blood pressure through families. In addition, transgenic mice with overexpression of a rat angiotensinogen gene develop hypertension, and knockout mice with a disrupted gene and absent angiotensinogen production develop low blood pressure. There are now two studies in populations of white European origin and one in African Caribbeans providing support for a role of the angiotensinogen gene locus in human essential hypertension.

The genetics of hypertension

In the past few years, a number of key insights have been made concerning the genetic basis of hypertension and blood pressure regulation. The genes responsible for two Mendelian forms of hypertension, glucocorticoid-remediable aldosteronism and Liddle's syndrome, were identified. In addition, research into the role of the renin—angiotension system in blood pressure regulation has further implicated the angiotensinogen and angiotensin-converting enzyme loci in hypertension and its complications, such as myocardial infarction. Finally, several new candidate genes for hypertension have been identified through the use of genome scanning and contemporary gene expression assays in model organisms.

The genetic basis of hypertension

Genetic approaches are setting the stage for a new understanding of the biological mechanisms underlying blood pressure regulation and hypertension. Recently, substantial progress has been made in elucidating the molecular mechanisms that cause several rare forms of hypertension, including hypertension arising from mutations in the 11 beta-hydroxylase gene, Liddle's syndrome, and glucocorticoid-suppressible aldosteronism. New results have been obtained on the possible role of the angiotensinogen gene, and other candidate genes, such as the angiotensin II receptor Type I gene and the Sa gene, in human hypertension. Investigation of experimental models of hereditary hypertension have also been important in unravelling the genetic complexity of the disease.

Kidney disease and hypertension in blacks.

Black Americans have relatively more hypertension and hypertensive renal disease than white Americans. The reasons for these differences are not clear and are under investigation. The genetic basis of hypertension may be different between blacks and whites. The response to systemic hypertension may also be different. Hypertensive black patients appear to develop renal arterial fibroplasia and renal insufficiency at an earlier age than white patients. Adequate control of blood pressure appears to be more effective in slowing the rate of decline in renal function among whites than among blacks. However, the available data are not sufficient. More information is needed to identify risk factors for the development of end-stage renal disease and to guide the management of hypertension in blacks.

Genetic basis of hypertension.

Recent advances in the genetics of hypertension include studies on localizations of many loci involved in blood pressure regulation in the rat, elucidation of the molecular mechanisms underlying monogenetic forms of hypertension, and studies of candidate genes in primary hypertension. Evidence that the angiotensinogen gene is involved in primary hypertension has been found by linkage in affected sibling pairs, and by the demonstration of increased risk of disease associated with DNA variants of the gene. Similar evidence of linkage and association has been found in preeclampsia, which suggests that the two diseases share at least one common factor of genetic susceptibility.