Genetic basis of hypertension for the development of tailored medicine (original) (raw)
Related papers
The Genetic Basis of Hypertension: An Overview
Avicenna Journal of Pharmaceutical Research
In light of the widespread recognition of the heritability of hypertension (HTN), numerous studies have been conducted to better understand the pathogenesis of different variants of HTN and their interactions. The complexity of crucial HTN makes it difficult to segregate and identify particular genes that influence blood pressure (BP) fluctuation, making the development of single-gene targeted treatments tough. Therefore, finding HTN susceptibility genes will contribute to the understanding of the biology behind the disease. Apart from its potential impact on antihypertensive drug therapy selection, genomic information may also contribute to identifying persons at risk of developing the condition, resulting in new preventative strategies. It is necessary to conduct more replication studies in other populations to confirm that there is a link between certain genetic variations and the varying response to these frequently used antihypertensive medications. Moreover, antihypertensive m...
Advances in the Genetics of Hypertension: The Effect of Rare Variants
International Journal of Molecular Sciences
Worldwide, hypertension still represents a serious health burden with nine million people dying as a consequence of hypertension-related complications. Essential hypertension is a complex trait supported by multifactorial genetic inheritance together with environmental factors. The heritability of blood pressure (BP) is estimated to be 30-50%. A great effort was made to find genetic variants affecting BP levels through Genome-Wide Association Studies (GWAS). This approach relies on the "common disease-common variant" hypothesis and led to the identification of multiple genetic variants which explain, in aggregate, only 2-3% of the genetic variance of hypertension. Part of the missing genetic information could be caused by variants too rare to be detected by GWAS. The use of exome chips and Next-Generation Sequencing facilitated the discovery of causative variants. Here, we report the advances in the detection of novel rare variants, genes, and/or pathways through the most promising approaches, and the recent statistical tests that have emerged to handle rare variants. We also discuss the need to further support rare novel variants with replication studies within larger consortia and with deeper functional studies to better understand how new genes might improve patient care and the stratification of the response to antihypertensive treatments.
Genetics of hypertension: From experimental animals to humans
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2010
Essential hypertension affects 20 to 30% of the population worldwide and contributes significantly to cardiovascular mortality and morbidity. Heridability of blood pressure is around 15 to 40% but there are also substantial environmental factors affecting blood pressure variability. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Animal models of hypertension, particularly in the rat, have led to the discovery of quantitative trait loci harbouring one or several hypertension related genes, but translation of these findings into human essential hypertension remains challenging. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models.
Genetic and molecular aspects of hypertension
Circulation research, 2015
Until recently, significant advances in our understanding of the mechanisms of blood pressure regulation arose from studies of monogenic forms of hypertension and hypotension, which identified rare variants that primarily alter renal salt handling. Genome-wide association and exome sequencing studies over the past 6 years have resulted in an unparalleled burst of discovery in the genetics of blood pressure regulation and hypertension. More importantly, genome-wide association studies, while expanding the list of common genetic variants associated with blood pressure and hypertension, are also uncovering novel pathways of blood pressure regulation that augur a new era of novel drug development, repurposing, and stratification in the management of hypertension. In this review, we describe the current state of the art of the genetic and molecular basis of blood pressure and hypertension.
Hypertension genomics and cardiovascular prevention
Annals of translational medicine, 2018
Hypertension continues to be a major risk factor for global mortality, and recent genome-wide association studies (GWAS) have expanded in size, leading to the identification of further genetic loci influencing blood pressure. In light of the new knowledge from the largest cardiovascular GWAS to date, we review the potential impact of genomics on discovering potential drug targets, risk stratification with genetic risk scores, drug selection with pharmacogenetics, and exploring insights provided by gene-environment interactions.
Genetics of hypertension: discoveries from the bench to human populations
AJP: Renal Physiology, 2014
Franceschini N, Le TH. Genetics of hypertension: discoveries from the bench to human populations. Hypertension is a complex trait that is influenced by both heritable and environmental factors. The search for genes accounting for the susceptibility to hypertension has driven parallel efforts in human research and in research using experimental animals in controlled environmental settings. Evidence from rodent models of genetic hypertension and human Mendelian forms of hypertension and hypotension have yielded mechanistic insights into the pathways that are perturbed in blood pressure homeostasis, most of which converge at the level of renal sodium reabsorption. However, the bridging of evidence from these very diverse approaches to identify mechanisms underlying hypertension susceptibility and the translation of these findings to human populations and public health remain a challenge. Furthermore, findings from genome-wide association studies still require functional validation in experimental models. In this review, we highlight results and implications from key studies in experimental and clinical hypertension to date.
Genetic Predisposition to Hypertension and Cardiovascular Disease
Progress in Experimental Cardiology, 2003
Sehool if Medicine Summary. Essential hypertension occurs in individuals with a genetic predisposition who respond abnormally to environmental changes. A complex interplay of a number of genetic alterations and environmental factors is involved in the pathogenesis of hypertension. Therefore, hypertension does not follow a clear pattern of inheritance but exhibits familial aggregation of cases. Areverse genetic approach, which examines genetic factors underlying the root of pathogenesis first, is a powerful tool to clarify the complex interplay. To clarify the role of gene polymorphisms in hypertension, we have carried out case-control studies using a candidate gene approach. We mainly focused on gene components of the renin-angiotensin system as candidates, and obtained some suggestive positive results in the association with hypertension, but the estimated relative risk for hypertension was less than 2.0. These results led us to recognize the importance of investigation using a general population with a sufficient number of subjects. We collaborated in two large epidemiological cohort studies and examined the association between genetic factors and the participants' health status in each of them. To deal with a large number of sampies, we established the TaqMan peR method to save time and cost of genotyping. Our investigations revealed a small but significant effect of gene polymorphisms in increasing the risk for hypertension, and suggested interactions with environmental factors such as aging, sex, and salt intake. In this review, we discuss the consensus and controversy of genetic investigations for identification of hypertensive genes and consider the future of tailor-made medicine.
Hypertension Research, 2008
A multiple candidate-gene approach was used to investigate not only candidate genes, but also candidate pathways involved in the regulation of blood pressure. We evaluated 307 single nucleotide polymorphisms (SNPs) in 307 genes and performed an association study between 758 cases and 726 controls. Genes were selected from among those encoding components of signal transduction pathways, including receptors, soluble carrier proteins, binding proteins, channels, enzymes, and G-proteins, that are potentially related to blood pressure regulation. In total, 38 SNPs were positively (p <0.05) associated with hypertension. Replication of the findings and possible polygenic interaction was evaluated in five G-protein-related positive genes (GNI2, GNA14, RGS2, RGS19, RGS20) in a large cohort population (total n =9,700, 3,305 hypertensives and 3,827 normotensive controls). In RGS20 and GNA14, dominant models for the minor allele were significantly associated with hypertension. Multiple dimension reduction (MDR) analysis revealed the presence of gene-gene interaction between GNA14 and RGS20. The MDR-proved combination of two genotypes showed a significant association with hypertension ( 2 = 9.93, p = 0.0016) with an odds ratio of the high-risk genotype of 1.168 (95% confidence interval [CI] [1.061-1.287]). After correction for all possible confounding parameters, the MDR-proved high-risk genotype was still a risk for hypertension ( p = 0.0052). Furthermore, the highrisk genotype was associated with a significantly higher systolic blood pressure (133.not only hypertension-susceptibility genes but also hypertension-susceptibility pathways in which related genes may synergistically collaborate through gene-gene interactions to predispose to hypertension.
Dissecting complex traits: recent advances in hypertension genomics
Genome Medicine, 2009
Genome-wide association scans are beginning to identify risk alleles for a number of complex diseases and traits. Essential hypertension looked as though it would be an exception to this trend after the Wellcome Trust Case Control Consortium data were published in 2007. However, more recent scans and meta-analyses have reversed the fortunes of essential hypertension. A number of loci have been identified, including a new antihypertensive drug target in the guise of the serine/threonine kinase SPAK. This kinase forms part of a novel kinase cascade that regulates the NCCT (Na + /Clco-transporter; SLC12A3) in the kidney and is defective in a rare Mendelian hypertension syndrome (Gordon's syndrome). Genome-wide scans are also being used to look for alleles to predict individual response to antihypertensive drugs and their risk of causing side-effects. The results of these are expected in the near future and may finally deliver the long-awaited goal of personalized drug therapy for hypertensive patients.