Monogenic Forms Of Hypertension Research Articles

#4127 MODULATION OF BLOOD PRESSURE THROUGH MICROBIOME EXCHANGE BETWEEN MILAN NORMOTENSIVE AND HYPERTENSIVE STRAINS OF RATS

Abstract Background and Aims Hypertension is one of the major health problems contributing to the development of cardiovascular diseases. In contrast to essential hypertension, which often displays complex pathogenesis due to multifactorial aetiology, several monogenic forms of hypertension are caused by mutations in genes associated with renal salt handling. Thus, studies on monogenic forms of hypertension could hold potential for novel therapeutic approaches for essential hypertension. Recently, increasing numbers of studies have demonstrated the alteration of the gut microbiome in pathological states including hypertension. These observations suggest the involvement of the intestinal microbiome in the development and/or maintenance of hypertension. A reciprocal congenic strain of Milan hypertensive rat (NA rat), harbouring a missense mutation in the gene encoding the alpha subunit of the membrane-skeletal protein adducin (Add1), develops hypertension starting from 3 months after birth. Preliminary studies on NA rats and its littermate Milan normotensive (MN) rats showed diverse expression patterns of renal sodium transporters/ion channels in two strains of rats, indicating a putative role of altered renal salt handling on the enhanced blood pressure in NA rats (unpublished data). Based on this background, the aim of this study was to investigate a possible connection between the gut microbiome and blood pressure phenotypes in these two strains. Furthermore, we evaluated whether the exchange of faeces between the two strains could transfer the phenotypes through the gut microbiome. Finally, mechanisms underlying the altered phenotype after microbiome exchange were investigated. Method Hypertensive NA rats and normotensive MN rats were subjected to ‘homogenization (HOM)’ of the microbiome after birth, which consisted of the exchange of bedding containing faeces from either strain, followed by co-housing of MN and NA rats in the same cage (MN-HOM and NA-HOM groups). For the baseline (BSL) condition, rats were homogenized within the same strain (MN-BSL and NA-BSL). At the age of 5 months, blood pressure measurement was performed using a non-invasive tail-cuff BP-2000 Blood Pressure Analysis system. Faeces from each rat were collected for microbiota metataxonomic analysis using next generation sequencing of 16S ribosome encoding DNA. At the end of the treatment, rats were sacrificed for the collections of blood and organs to assess the expressions of genes involved in renal salt reabsorption. Results Systolic blood pressure (SBP) in MN-BSL was averaged at 143.6 mmHg, while NA-BSL showed average SBP 163.3 mmHg, confirming the hypertensive phenotype in NA rats at baseline (P<0.001). Interestingly, MN-HOM showed a significantly enhanced SBP compared to MN-BSL, reaching 153.5 mmHg (P = 0.005). On the other hand, the average SBP of NA-HOM was163.7 mmHg, indicating that homogenization did not significantly impact blood pressure in NA rats. Although the MN-HOM group showed significantly increased SBP compared with MN-BSL group, the average SBP of MN-HOM was still significantly lower than both the NA-BSL and NA-HOM groups. Different gut microbiota compositions were observed in the two strains of rats at baseline, and HOM altered both. Conclusion We have demonstrated that the hypertensive phenotype in NA rats was transferred to normotensive MN rats through the exchange of gut microbiota, indicating that the intestinal microbiota and/or metabolites derived therefrom could eventually modulate blood pressure. Further studies including immunoblotting as well as uremic toxin analyses are required to unveil the molecular mechanisms by which the gut microbiome modulates blood pressure.

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension.

BackgroundLiddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, β, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family.MethodsDNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism.ResultsWe identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome.Conclusionc.1691_1693delinsG, a novel frame-shift mutation in the β subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

Моногенные причины вторичной артериальной гипертензии (лекция)

За последние десятилетия обнаружены особые моногенные формы артериальной гипертензии (АГ), вызванные специфическими путями, обусловленными нарушенными редкими мутациями в отдельных генах, что приводит к раннему и тяжелому фенотипу АГ. На сегодняшний день известно о не менее 37 генах, нарушение функции которых четко сопровождается нарушением регуляции артериального давления (АД), что улучшает наше понимание как механизмов развития, так и лечения АГ. Генетические причины вторичной гипертензии, как правило, обусловлены нарушением одного гена. Открытие генов, ответственных за моногенные формы АГ, раскрыло важную роль почек и надпочечников в регуляции уровня АД. Большинство из этих синдромов обусловлены мутациями, которые приводят к усилению или потере функции, которые, в свою очередь, приводят к изменению содержания минералокортикоидов, глюкокортикоидов или активации симпатических путей. Моногенные формы АГ часто приводят к тяжелым формам гипертензии, электролитным и гормональным нарушениям, сопровождающимся резистентностью к препаратам, а также часто к большему риску сердечно-сосудистых событий и преждевременной смерти. В лекции даны рекомендации по генетическому тестированию при АГ, алгоритм диагностического обследования пациента с подозрением на моногенную форму АГ, а также приведены особенности клинического течения и лечения основных известных форм моногенных АГ.

Current knowledge in hypertension genetics: mosaic theory, candidate genes and genome-wide association studies

The article reviews monogenic forms of hypertension, data on the role of heredity of essential hypertension and candidate genes, as well as genome-wide association studies. Modern approach for the role of genetics is driven by implementation of new technologies and their productivity. High performance speed of new technologies like genome-wide association studies provide data for better knowledge of genetic markers of hypertension. The major goal nowadays for research is to reveal molecular pathways of blood pressure regulation, which can help to move from populational to individual level of understanding of pathogenesis and treatment targets.

Genomics of hypertension: the road to precision medicine.

The known genetic architecture of blood pressure now comprises >30 genes, with rare variants resulting in monogenic forms of hypertension or hypotension and >1,477 common single-nucleotide polymorphisms (SNPs) being associated with the blood pressure phenotype. Monogenic blood pressure syndromes predominantly involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, with a smaller fraction caused by neuroendocrine tumours of the sympathetic and parasympathetic nervous systems. The SNPs identified in genome-wide association studies (GWAS) as being associated with the blood pressure phenotype explain only approximately 27% of the 30-50% estimated heritability of blood pressure, and the effect of each SNP on the blood pressure phenotype is small. A paucity of SNPs from GWAS are mapped to known genes causing monogenic blood pressure syndromes. For example, a GWAS signal mapped to the gene encoding uromodulin has been shown to affect blood pressure by influencing sodium homeostasis, and the effects of another GWAS signal were mediated by endothelin. However, the majority of blood pressure-associated SNPs show pleiotropic associations. Unravelling these associations can potentially help us to understand the underlying biological pathways. In this Review, we appraise the current knowledge of blood pressure genomics, explore the causal pathways for hypertension identified in Mendelian randomization studies and highlight the opportunities for drug repurposing and pharmacogenomics for the treatment ofhypertension.

Liddle\u2019s-like syndrome associated with nephrotic syndrome secondary to membranous nephropathy: the first case report

BackgroundLiddle’s syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel (ENaC) β or γ subunits. Patients with this syndrome present with early onset of hypertension, hypokalemia, metabolic alkalosis, hyporeninemia and hypoaldosteronism, and a potassium-sparing diuretics (triamterene or amiloride) can drastically improves the disease condition. Although elderly patients having these characteristics were considered to have Liddle’s syndrome or Liddle’s-like syndrome, no previous report has indicated that Liddle’s-like syndrome could be caused by nephrotic syndrome of primary glomerular disease, which is characterized by urinary excretion of > 3 g of protein/day plus edema and hypoalbuminemia, or has explained how the activity function of ENaC could be affected in the setting of high proteinuria.Case presentationA 65-year-old Japanese man presented with nephrotic syndrome. He had no remarkable family history, but had a medical history of hypertension and hyperlipidemia. On admission, hypertension, spironolactone-resistant hypokalemia (2.43 mEq/l), hyporeninemic hypoaldosteronism, and metabolic alkalosis, which suggested Liddle’s syndrome, were observed. Treatment with triamterene together with a steroid for nephrotic syndrome resulted in rapid and remarkable effective on improvements of hypertension, hypokalemia, and edema of the lower extremities. Renal biopsy revealed membranous nephropathy (MN) as the cause of nephrotic syndrome, and advanced gastric cancer was identified on screening examination for cancers that could be associated with the development of MN. After total gastrectomy, triamterene was not required and proteinuria decreased. A mutation in the β or γ subunits of the ENaC gene was not identified.ConclusionWe reported for the first time a case of Liddle’s-like syndrome associated with nephrotic syndrome secondary to MN. Aberrant activation of ENaC was suggested transient during the period of high proteinuria, and the activation was reversible with a decrease in proteinuria.

Monogenic Hypertension in Children: A Review With Emphasis on Genetics.

Hypertension (HT) is a public health problem in children particularly related to the epidemic of overweight and obesity. Monogenic forms of HT are important in the differential diagnosis in children presenting with severe or refractory HT, who have a family history of early-onset HT, unusual physical examination findings, and/or characteristic hormonal and biochemical abnormalities. Most genetic defects in these disorders ultimately result in increased sodium transport in the distal nephron resulting in volume expansion and HT. Genetic testing, which is increasingly available, has diagnostic, therapeutic, and predictive implications for families affected by these rare conditions.

GW26-e2433 Prevalence of Liddle syndrome among young hypertension patients of undetermined cause in a Chinese population

Liddle syndrome, an autosomal dominant form of monogenic hypertension, has been regarded as a rare disorder, which leads to many Liddle syndrome patients being misdiagnosed and suffering from severe complications at an early age. Little is known about the prevalence of Liddle syndrome. Therefore, we

Autoinhibition and Salt Sensing are Linked in the WNK1 Kinase

This research focuses on a 230kDa serine/threonine protein kinase known as WNK1 (With No lysine {K}), isoforms of which have been associated with a monogenic form of hypertension. Structural analysis of the autoinhibitory (AI) domain from WNK1 by NMR indicates that the RFXV binding site from the PASK/FRAY homology 2 (PF2) domain is conserved in the WNK1 AI domain. Titration data shows that incubation of RFXV peptides display extensive chemical shift perturbation as assessed by 1H, 15N‐HSQC. Size exclusion chromatography of the tethered construct of the AI and kinase domains show substantial conformational changes when dialyzed from high to low [NaCl]. Differential scanning fluorimetry conducted on the kinase domain shows that the domain undergoes a substantial increase in stabilization as the concentration of salt is increased. Further analysis of this phenomena points toward evidence of anion sensing. To corroborate this, the crystal structure of the activated WNK1 kinase domain was solved in low salt conditions. The kinase displays disorder of many key structural elements such as αC which is unsurprising given the DSF data. The coupling of the information gathered points to a mechanism of salt sensing and self‐contained signaling control in the WNK1 kinase.

A Hypertension Gene: Are We There Yet?

Cardiovascular diseases are the leading cause of death worldwide. Essential hypertension is a major risk factor for the development of other cardiovascular diseases and is caused by a combination of environmental and genetic factors, with up to 50% of blood pressure variance currently attributed to an individual's genetic makeup. By studying genes that cause monogenic forms of hypertension and pathways relevant to blood pressure control, a number of polymorphisms have been identified that increase an individual's risk of developing high blood pressure. We report on candidate gene association studies and genome-wide association studies that have been performed to date in the field of hypertension research. It is becoming clear that for the majority of people there is no single gene polymorphism that causes hypertension, but rather a number of common genetic variants, each having a small effect. Using pharmacogenomics to personalize the treatment of hypertension holds promise for achieving and sustaining normotensive pressures quickly, while minimizing the risk of adverse reactions and unwanted side-effects. This will decrease the risk of stroke and myocardial infarction in individuals and lead to a reduced burden of disease upon society as a whole.

Monogenic forms of hypertension

Arterial hypertension in childhood is less frequent as compared to adulthood but is more likely to be secondary to an underlying disorder. After ruling out more obvious causes, some patients still present with strongly suspected secondary hypertension of yet unknown etiology. A number of these children have hypertension due to single gene mutations inherited in an autosomal dominant or recessive fashion. The finding of abnormal potassium levels (low or high) in the presence of suppressed renin secretion, and metabolic alkalosis or acidosis should prompt consideration of these familial diseases. However, mild hypertension and the absence of electrolyte abnormalities do not exclude hereditary conditions. In monogenic hypertensive disorders, three distinct mechanisms leading to the common final pathway of increased sodium reabsorption, volume expansion, and low plasma renin activity are documented. The first mechanism relates to gain-of-function mutations with a subsequent hyperactivity of renal sodium and chloride reabsorption leading to plasma volume expansion (e.g., Liddle's syndrome, Gordon's syndrome). The second mechanism involves deficiencies of enzymes that regulate adrenal steroid hormone synthesis and deactivation (e.g., subtypes of congenital adrenal hyperplasia, apparent mineralocorticoid excess (AME)). The third mechanism is characterized by excessive aldosterone synthesis that escapes normal regulatory mechanisms and leading to volume-dependent hypertension in the presence of suppressed renin release (glucocorticoid remediable aldosteronism). Hormonal studies coupled with genetic testing can help in the early diagnosis of these disorders.

BK channels and a new form of hypertension

Large, Ca-activated K channels (BK) are comprised of an α pore (BKα) and one of four β subunits (BKβ1-4). When the gene for BKβ1 is knocked out (BKβ1-KO), the result is increased myogenic tone of vascular smooth muscle and hypertension. We reexamined whether the hypertension is entirely due to increased vascular tone, because most monogenic forms of hypertension have renal origins and BKβ1 resides in renal connecting tubule (CNT) cells. Moreover, BKβ1 is localized in the adrenal glands, where it may control production of aldosterone. This review will summarize our report that a majority of the hypertension of BKβ1-KO is the result of insufficient handling of dietary K, resulting in increased plasma K and hyperaldosteronism, the latter promoting Na and fluid retention. The fluid retention and hypertension are exacerbated by a high-K diet and reduced by eplerenone, an aldosterone receptor inhibitor. Genetic knockout of BKβ4 (BKβ4-KO), which resides in intercalated cells, also exhibits deficient K excretion, fluid retention, and mild hypertension that is not exacerbated when animals are treated with a high-K diet. These results show that the hypertension associated with BKβ1-KO occurs because of enhanced fluid retention, as well as because of the previously described vascular dysfunction.

G Protein–Coupled Receptor Kinase 4

Nearly 30% of middle-aged Americans have hypertension, but the prevalence is higher in non-Hispanic blacks and individuals >60 years of age (65%).1 There is a direct and quantitative relationship between higher blood pressure values and mortality. Although 30% to 50% is thought to be heritable, the genetic cause(s) of essential hypertension has been difficult to identify. More than 1 gene is undoubtedly involved, because Mendelian dominant and recessive traits are not readily discernible in hypertensive subjects, except in those with monogenic forms of hypertension. Moreover, in any hypertensive individual, risk-predisposing genes are engaged in a complex network of gene-gene and gene-environment interactions.2,3 The kidney plays a major role in the long-term regulation of blood pressure, and abnormal sodium chloride metabolism is frequently encountered in hypertension. Therefore, many studies have focused on the abnormal renal handling of sodium chloride in the pathogenesis of essential hypertension.2,4 Approximately 50% of subjects with essential hypertension are sodium chloride sensitive.5 Indeed, humans with salt-sensitive hypertension have increased sodium transport in the renal proximal tubule and medullary thick ascending limb, although distal tubular mechanisms may also be involved.6 The sodium retention in hypertension is because of enhanced sodium transport, per se, and/or a failure to respond appropriately to signals that decrease sodium transport. Sodium transport is regulated by natriuretic and antinatriuretic hormones and humoral agents, such as dopamine and angiotensin, which exert their effects via G protein–coupled receptors (GPCRs). Activation of certain postjunctional dopamine receptor subtypes (D1R, D3R, D4R, and D5R) and the angiotensin type 2 receptor inhibit, whereas activation of the postjunctional D2R and angiotensin type 1 receptor (AT1R) increase sodium transport.2,7 The GPCR kinases (GRKs) are a 7-member family of serine/threonine protein kinases characterized by their …

Genetic information in the diagnosis and treatment of hypertension

Advancement in cardiovascular science should be measured by a number of new diagnostic and therapeutic options applied in clinical practice as a result of translational research. Hypertension genetics is a good example of such a successful transfer of knowledge from bench to bedside. There are genetic methods currently used as diagnostic tools in patients presenting with secondary forms of hypertension, including primary hyperaldosteronism, Cushing's syndrome, pheochromocytoma, and chronic kidney disease. Directed treatment that corrects pathophysiologic abnormalities is available for several monogenic forms of hypertension as a result of uncovering their underlying genetic mechanisms. Progress in hypertension pharmacogenetics and pharmacogenomics brings closer a perspective of personalized antihypertensive treatment and gene transfer strategies, which, although still considered as innovative approaches, may soon become options to treat, control, and, possibly, cure hypertension.

Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p.

Essential (primary) hypertension is an important risk factor for cardiovascular morbidity and mortality. Blood pressure is largely heritable; however, the genetic factors contributing to essential hypertension are mostly unknown. We examined a large Chinese kindred (n=387) and selected a subset of 94 individuals for genotyping. An additional 32 Chinese nuclear families with essential hypertension were also recruited. Genome-wide parametric linkage analysis identified a new locus for primary hypertension on chromosome 12p (parametric LOD score 3.44). This locus overlaps with the assigned locus that causes severe autosomal-dominant hypertension and brachydactyly, the only form of monogenic hypertension known to date that resembles primary hypertension. We suggest that this genomic region, spanning 18 annotated genes, will be of great relevance in elucidating new mechanisms for primary hypertension.

Epithelial Na+ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin.

Liddle's syndrome is a monogenic form of hypertension caused by mutations in the PY motif of the COOH terminus of beta- and gamma-epithelial Na+ channel (ENaC) subunits. These mutations lead to retention of active channels at the cell surface. Because of the critical role of this PY motif in the stability of ENaCs at the cell surface, we have investigated its contribution to the ENaC response to aldosterone and vasopressin. Mutants of the PY motif in beta- and gamma-ENaC subunits (beta-Y618A, beta-P616L, beta-R564stop, and gamma-K570stop) were stably expressed by retroviral gene transfer in a renal cortical collecting duct cell line (mpkCCDcl4), and transepithelial Na+ transport was assessed by measurements of the benzamil-sensitive short-circuit current (Isc). Cells that express ENaC mutants of the PY motif showed a five- to sixfold higher basal Isc compared with control cells and responded to stimulation by aldosterone (10(-6) M) or vasopressin (10(-9) M) with a further increase in Isc. The rates of the initial increases in Isc after aldosterone or vasopressin stimulation were comparable in cells transduced with wild-type and mutant ENaCs, but reversal of the effects of aldosterone and vasopressin was slower in cells that expressed the ENaC mutants. The conserved sensitivity of ENaC mutants to stimulation by aldosterone and vasopressin together with the prolonged activity at the cell surface likely contribute to the increased Na+ absorption in the distal nephron of patients with Liddle's syndrome.

Serum potassium is not associated with blood pressure tracking in the Framingham heart study

Background Abnormal potassium homeostasis accompanies many secondary forms of hypertension as well as uncommon inherited, monogenic forms of hypertension. We hypothesized that serum potassium may be associated with longitudinal tracking of blood pressure (BP) and development of hypertension. Methods A total of 2358 participants (1292 women, 1066 men) in the Framingham Heart Study who were free of hypertension, were not taking drugs affecting potassium homeostasis, and had serum potassium measured in 1979 to 1983 were followed for longitudinal tracking of BP and development of hypertension at examination 4 years later. Progression of BP stage was defined as an increment of one or more BP category, as defined by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI), between baseline and follow-up examinations. Results At baseline, there were no differences in systolic or diastolic BP across serum potassium quartiles. Over 4 years of follow up, 37% (457 women, 412 men) of subjects progressed by one or more JNC-VI BP category. In a logistic regression model adjusting for multiple confounders, serum potassium quartile was not associated with risk of BP progression. During follow-up, 14% (162 women, 175 men) of subjects progressed to hypertension. After adjustment for multiple confounders, there was no significant association between serum potassium quartile and risk for progression to hypertension. Conclusions In our community-based study sample, serum potassium was not associated with current BP, longitudinal BP tracking, or progression to hypertension.

The genetics of human hypertension

Human hypertension is a common and complex disease and is associated with diabetes, cardiovascular, and renal disease. Therefore, it is important to understand the genetic basis of this disease. Specific genetic mutations leading to monogenic forms of hypertension have been identified in Liddle's syndrome and glucocorticoid-remediable hypertension and in some syndromes in which blood pressure is lowered. Because essential hypertension is a polygenic disease, elucidating a genotype that is causally related to essential hypertension will be difficult. To date, no genotype has been conclusively linked to essential hypertension except in certain populations. However, there has been progress in finding genetic variations that are associated with hypertension in patients with components of the metabolic syndrome (or Syndrome X). Future discoveries in this area should enhance our ability to intervene earlier and more effectively and therefore lessen the complications of this common disease.

A mineralocorticoid receptor mutation causing human hypertension.

In recent years, the study of monogenic forms of hypertension has added greatly to our understanding of the regulatory mechanisms affecting blood pressure. Recently, a novel such form of human hypertension caused by gain-of-function mutation in the mineralocorticoid receptor, the mediator of aldosterone-induced sodium transport in the distal nephron, has been described, with the notable finding being that pregnancy causes a severe worsening of blood pressure. In this review, the mechanism by which the mutation causes hypertension, and the implications these findings have for improved understanding of cardiovascular physiology and mineralocorticoid receptor biology, are discussed.

Hypertension in children and adolescents: definition, pathophysiology, risk factors, and long-term sequelae

Background: Awareness of hypertension as an adult public health issue has increased dramatically during the past 3 decades, leading to substantial decreases in morbidity and mortality related to stroke and coronary artery disease. Awareness of blood pressure issues in the pediatric population also has increased, leading to conceptual changes in the diagnosis and treatment of childhood hypertension. The current focus has shifted to early identification of mild to moderate hypertension in asymptomatic, otherwise healthy children and adolescents. Objective: The purpose of this article was to define hypertension in the pediatric population and describe the secondary causes of childhood hypertension, risk factors and potential pathophysiology of essential hypertension in childhood, and the long-term sequelae for individuals with hypertension identified during childhood. Methods: Information regarding pediatric hypertension was identified through a MEDLINE ® search of the literature from 1985 to 2000. Results: Definitions of pediatric hypertension have been carefully refined over the past 30 years, and normative data are available for children and adolescents, based on age, sex, and height. Childhood hypertension may be identified during evaluation of an acutely ill child, but is increasingly identified during routine blood pressure screening, particularly in adolescents. Although, historically, most pediatric hypertension was believed to be secondary in origin (related to an identifiable underlying disorder), recent data suggest that almost 90% of hypertensive adolescents have essential hypertension. The proposed factors that may be involved in the pathophysiology of essential hypertension include familial and genetic influences, race, and salt sensitivity. Although an essential hypertension gene has not yet been identified, several monogenic forms of hypertension have been described, which may account for a minority of individuals with presumed essential hypertension. In addition, a number of candidate genes that may be involved in the complex genetic susceptibility to hypertension have been described. There is growing evidence concerning adverse long-term consequences of hypertension identified in childhood and adolescence, including increased incidence of cardiovascular and coronary heart disease. Conclusions: Based on the generally accepted concept that essential hypertension begins in childhood, early optimization of blood pressure control in childhood may reduce an individual's lifetime risk of cardiovascular morbidity and mortality. In addition, aggressive treatment of cardiovascular risk factors during childhood and adolescence may have a major impact on the prevalence of adult cardiovascular disease.