Treatment usually consists of mineralocorticoid receptor antagonists spironolactone and eplerenone , epithelial Na channel blockers amiloride , and thiazides for hypercalciuria with potassium supplementation as needed Geller syndrome, otherwise known as HTN exacerbated by pregnancy, is another mineralocorticoid excess syndrome caused by an activating mineralocorticoid receptor gene mutation.

As a result of this mutation, the mineralocorticoid receptor loses its specificity for aldosterone and is activated by both aldosterone and progesterone. Inherited in an autosomal dominant manner, Geller syndrome leads to early HTN, which is exacerbated during pregnancy due to activation of the mineralocorticoid receptors by progesterone.

Clinical features include normal serum potassium levels in the setting of low serum renin and aldosterone levels Congenital adrenal hyperplasia results from defects in enzymes involved in cortisol synthesis In type IV CAH due to 11 β-hydroxylase deficiency and type V CAH due to 17 α-hydroxylase deficiency , the loss of cortisol feedback inhibition on the pituitary results in increased ACTH production and adrenal hyperplasia.

This in turn leads to the accumulation of cortisol precursors, which cause increased salt and water uptake and subsequent HTN via activation of mineralocorticoid receptors.

As a result, aldosterone production is suppressed Characteristic features of type IV CAH are precocious puberty, virilization due to excess sex hormone production with androgenic action, and early onset HTN Type IV CAH is treated with steroids and mineralocorticoid receptor antagonists such as spironolactone for HTN.

Type V CAH has features opposite to type IV CAH due to sex hormone synthesis blockade, which manifests as delayed sexual development in girls and ambiguous genitalia in boys. Type V CAH is treated with steroids and sex hormones, in addition to mineralocorticoid receptor antagonists for HTN This mutation causes an inability of ENaC to be removed from cell surfaces of the cortical collecting tubules, leading to increased sodium reabsorption and subsequent HTN Patients with Liddle syndrome typically present with hypokalemia, metabolic alkalosis, low renin and aldosterone levels, and early onset HTN.

Treatment includes a low salt diet and ENaC inhibitors, such as amiloride and triamterene Gordon syndrome is characterized by autosomal dominant inheritance of serine—threonine kinase gene WNK1 and 4 mutations.

Normally, WNK1 inhibits the function of WNK4, while WNK4 inhibits the expression of the Na—Cl cotransporter NCC Therefore, a gain-of-function mutation in WNK1 and loss-of-function mutation in WNK4 collectively result in increased NCC expression and activity in the distal convoluted tubule This leads to salt and water retention, followed by HTN The increased salt reabsorption reduces sodium delivery to the cortical collecting duct, facilitating increased potassium absorption and hyperkalemia, which is typical of Gordon syndrome.

ROMK channels, which aid in potassium excretion, can also be inhibited by the WNK4 mutation, further causing hyperkalemia 8. Other metabolic abnormalities in Gordon syndrome include mild hyperchloremic metabolic acidosis, hypercalciuria, low urinary sodium excretion 26 , low serum renin, and varying aldosterone levels.

Metabolic abnormalities tend to occur earlier than HTN, which tends to present in adolescence or adulthood Treatment of Gordon syndrome consists of low dose thiazide diuretics. Hypertension with brachydactyly is caused by a mutation in the PDE3A gene which encodes phosphodiesterase 3A Patients affected by this syndrome have severe salt-independent HTN with short phalanges and metacarpals The mechanism for HTN in this syndrome remains unknown, although it has been suggested that vascular smooth muscle cell hyperplasia and increased vascular resistance may play a role Traditional pedigree-based analyses are not very effective in genetic studies of essential HTN due to its complex nature.

Therefore, other methodologies have been used to study the genetic epidemiology of essential HTN. The following section contains a brief description of the different study designs that have been employed in investigating the genetics of HTN, with a special focus on genome-wide association studies GWAS 7.

Linkage refers to the tendency of two genes to be inherited together when they are in close physical proximity to each other on a chromosome Based on this phenomenon, linkage analysis aims to locate the approximate position of a disease gene by using the location of a known marker gene 29 , The marker gene refers to a DNA sequence that has a known physical location and has a detectable phenotype.

By investigating whether markers and disease traits co-segregate, linkage analysis can approximate the location of the disease gene Non-parametric linkage analysis or model-free analysis is used when details regarding the disease, such as the genetic mode of inheritance, are not known This method is particularly useful in studying complex diseases, such as essential HTN, where the mode of inheritance is unknown.

Non-parametric linkage analysis of affected sibling pairs can provide significant insights into a particular HTN phenotype 7. However, a limitation of this method is that many affected sibling pairs are often required to achieve adequate power to detect statistically significant differences.

Discordant sibling pair analysis is a type of genetic linkage analysis that traces quantitative genetic trait loci. In this method, the square of the BP difference is measured as a function of the number of alleles that a sibling pair shares at known marker loci If siblings with very discordant BPs are identified, then their genetic variation can be studied.

The disadvantage of this method is that the process of identifying siblings with significant BP discordance can be quite challenging 7. These studies aim to determine whether an association is present between the particular allele and a disease trait Association studies can be family-based or population-based comprising unrelated individuals and may use a case—control or cohort approach.

Population-based studies are more widely used than family-based studies, since fewer resources are required to enroll cohorts than family-based studies. Population-based studies may also require less genotyping One advantage of family-based association studies, however, includes protection against population substructure-related bias.

This is a selection bias that occurs when study subjects come from population subgroups with different ancestries In family-based association studies, study subjects within each family come from the same source population, minimizing selection bias.

Another advantage of family-based association studies is the higher likelihood of true linkage and association when significant findings are identified Based on the concept of linkage disequilibrium at the population level, GWAS attempt to identify the association between genetic variants or single-nucleotide polymorphisms SNPs , and common disease traits in populations SNPs are located in particular genetic loci and refer to variations in single nucleotides 14 , The Wellcome Trust Case Control Consortium WTCCC study, conducted in , was the first study that attempted to identify variants associated with HTN using GWAS; however, no significant association was identified Small sample size and the use of HTN as a discrete variable are some of the reasons for the failure of the WTCCC to identify an association between SNPs and BP 14 , The use of HTN as a discrete variable presence or absence of HTN , as opposed to a continuous variable systolic BP or diastolic BP , decreases study power and has therefore become an important consideration in subsequent GWAS designs In , the International Consortium for BP GWAS identified 29 SNPs that were associated with HTN 41 , Since then, more than 60 SNPs have been identified that affect BP via mechanisms of sodium handling, kidney function, vasoconstriction, and molecular signaling 43 — Examples of some novel SNPs linked to systolic BP and diastolic BP in both children and adults that have been identified through GWAS are listed in Table 2.

Despite the identification of multiple SNPs associated with HTN, each of the common variants that have been discovered to this point appear to have only a small overall effect on BP about 1 mmHg for systolic BP or 0. These findings suggest that several genes may act in concert to modulate BP, and that other factors, such as gene—gene and gene—environment interactions, may contribute to BP variability.

A challenge of GWAS includes the difficulty in identifying the gene affected by the SNP, since the area of influence of the SNP may lie in distant genes Some SNPs with genome-wide significance also exhibit pleiotropy and demonstrate strong independent links to more than one disease.

For example, rs is independently associated with HTN and chronic kidney disease 57 , Selection of cases and controls may also introduce a confounding bias in GWAS.

False associations can be identified if the cases and controls are selected from different populations that have different baseline allele frequencies. This phenomenon is referred to as population stratification and may result when study subjects have different ancestries Methods to address this issue include using genomic information to control for population structure, or using family-based study designs 29 , The selection of unaffected family members as controls in family-based study designs has the additional advantage of reducing environmental exposure confounders The recruitment of a large number of controls can be costly in GWAS due to the extent of genotyping involved.

Thus, more studies are using genotypic information from subjects already enrolled as controls in other studies Epigenetic phenomena refer to changes in gene expression in the absence of alterations of the DNA sequence itself, and include posttranslational histone modification, DNA methylation, and non-coding microRNAs miRNAs Although epigenetic modifications are heritable and can be passed on through several generations, they can also be influenced by nutritional, pharmaceutical, fetal, and environmental factors, and may be reversible.

Epigenetic events play critical roles in physiological processes such as cellular differentiation, by ensuring that only certain genes are expressed in specific cell types 3.

Abnormalities in epigenetic events can lead to the development of HTN, and in fact, HTN has been linked to several epigenetic phenomena as discussed below DNA methylation involves the covalent binding of a methyl group to cytosine, forming 5-methylcytosine 5mC within CpG dinucleotide sequences The methyl groups come from S-adenosylmethionine, the availability of which is dependent on folate metabolism.

This association with folate metabolism provides the basis for the strong link between DNA methylation and nutrition DNA methylation of CpG dinucleotides often located in the promoter regions results in inhibition of transcription and therefore gene silencing The onset and severity of HTN have been reported to be associated with the extent of DNA methylation Smolarek et al.

quantified the amount of 5mC in DNA from patients with essential HTN and found that lower levels of 5mC corresponded to higher stages of HTN Lin et al.

reported that hypomethylation of the angiotensin II type I receptor gene correlated with higher systolic and diastolic BPs. Smokers with HTN were also observed to have a lower level of methylation Interestingly, Meems et al.

discovered that vitamin D-deficient parental rats had offspring with increased systolic and diastolic BPs The offspring were found to have hypermethylation of the promoter region of the Panx1 gene. Furthermore, the offspring rats showed impaired endothelial relaxation, consistent with the fact that Panx1 encodes a hemichannel that plays a role in endothelial relaxation These findings suggest that in utero nutritional status may affect childhood BPs; however, further research will be needed to determine whether prenatal and postnatal nutritional status have effects on the development of HTN in children Posttranslational modification of the N-terminal tail of histone proteins through processes such as methylation and acetylation can lead to changes in chromatin dynamics.

This in turn leads to either decreased or increased gene expression Both animal and human studies have shown associations between histone modifications and HTN.

One such study reported that histone modifications resulted in angiotensin-converting enzyme 1 ACE1 upregulation in organs from hypertensive rats In human endothelial cells, cell-specific histone modifications were found to regulate mRNA levels of endothelial nitric-oxide synthase Endothelial nitric-oxide synthase plays a role in BP regulation by modulating vascular tone through the production of nitric oxide in the vascular endothelium.

Interestingly, Wang et al. reported that ascorbic acid prevented the development of HTN in rat offspring prenatally exposed to lipopolysaccharide LPS LPS exposure induced histone H3 acetylation in the ACE1 promoter region, resulting in increased ACE1 gene expression and HTN in rat offspring.

Prenatal treatment with ascorbic acid, however, reversed the histone modification and led to less ACE1 gene expression These findings suggest potential targets for novel antihypertensive therapies that can prevent or treat HTN early in life. Non-coding RNAs are increasingly recognized as crucial regulators of gene expression and may influence cell-specificity of gene expression Among non-coding RNAs, miRNAs have been the most widely studied in association with HTN.

miRNAs are small non-coding RNAs, approximately 22 nucleotides in length, that silence mRNA expression through mRNA degradation or interference of mRNA translation miRNAs have been reported to modulate BP through various mechanisms.

One such mechanism is through the renin—angiotensin system pathway. In addition, hsa-miRa was also found to regulate the mRNA expression of REN and apoptosis-inducing factor mitochondrion-associated 1 AIFM1. Both miRNAs were downregulated in HTN, leading to increased expression of renin mRNA Studies are also ongoing for potential treatments for HTN based on epigenetic modifications.

Mutations in mitochondrial DNA mtDNA have been linked to the development of HTN, proposedly through the action of reactive oxygen species Consistent with these findings, Li et al.

observed a decrease in mtDNA-encoded cytochrome b mt-Cytb and corresponding increase in reactive oxygen species in hypertensive rats Interestingly, they found that when miR21, an miRNA that was found in higher levels in the hypertensive rats compared with controls, was injected into the hypertensive rats via a recombinant adeno-associated virus, there was an increase in mt-Cytb levels and lower BPs The authors hypothesized that miR21 plays a compensatory role in HTN.

Studies such as these are promising for the development of novel therapies that utilize epigenetic mechanisms, such as miRNAs, to treat HTN. Extensive research has been performed on the genetic aspect of responses to antihypertensive medication, which include drug interaction with the target sites, drug transport, and metabolism.

The Clinical Pharmacogenetics Implementation Consortium CPIC , formed in , establishes guidelines that aid with application of results from pharmacogenetic studies to actionable prescription of drugs However, due to inconsistent results across studies and therefore insufficient evidence, there are no CPIC guidelines to date for antihypertensive medications 77 , To date, the most consistently reproducible pharmacogenomic data have been based on β-blockers and thiazide diuretics Three genes, ADRB1, NEDD4L , and YEATS4 , have been consistently linked with responses to antihypertensive drugs in various studies.

The ADRB1 gene encodes the β-1 adrenergic receptor, which is targeted by the β-blockers. Common SNPs in the ADRB1 gene include the variants Ser49Gly rs and ArgGly rs NEDD4L encodes a protein that downregulates the expression of ENaC in the distal nephron, thereby regulating sodium reabsorption in the kidneys Several studies have shown that the more common G allele of rs, located within the NEDD4L gene, is linked to greater systolic and diastolic BP reduction in response to thiazide diuretics 82 , These findings are consistent with the role of NEDD4L in reducing tubular sodium reabsorption.

The YEATS4 gene encodes a protein, GAS41, which is involved in regulation of cellular proliferation The ATC haplotype was linked to a good response to HCTZ, while the ACT and the ATT haplotypes were associated with a poor response to HCTZ The data on gene polymorphisms affecting responses to calcium channel blockers, ACE inhibitors, and angiotensin II receptor blockers are conflicting, and no candidate gene has shown consistent results 85 , A summary of recent pharmacogenomic findings on responses to antihypertensive medications is provided in Table 3.

Table 3. Genes associated with responses to antihypertensive medications [modified from Burrello et al. Pediatric genetic studies on HTN are scarce in comparison to adult studies and are often limited by small sample size.

A recent study investigated the parental effects of 33 SNPs previously identified by GWAS on the BP of young offspring Based on 1, subjects from the Family Atherosclerosis Monitoring In early life study, significant parental effects, albeit small, were reported for the SNPs rs CYP17A1 and rs MTHFR The paternal genotype of rs was found to be associated with elevated systolic and diastolic BP among offspring, whereas there was no association with the maternal genotype.

Both the maternal and paternal genotypes of rs were associated with elevated systolic and diastolic BP among offspring. This study also observed that the SNP rs CSK demonstrated an association with systolic BP from birth to 5 years of age CSK is a tyrosine kinase that plays a role in actin remodeling, which in turn has been shown to affect constriction of the arterial endothelium in murine newborns Although limited by sample size, this was the first study to investigate the effect of parental SNPs on young offspring, and SNPs that affect BP in the early years of life.

In another study, the polymorphism TC of the Y2 receptor Y2R gene was reported to be associated with systolic and diastolic BPs in obese children Y2R is a receptor for neuropeptide Y, which is a potent constrictor of vascular smooth muscle cells.

Y2R has also been observed to regulate neurogenic vasoconstriction in spontaneously hypertensive rats Obese children homozygous for the T allele in Y2R showed significantly lower systolic and diastolic BPs compared with heterozygotes and C allele homozygotes Genetic predisposition for BP elevation spanning from childhood to adulthood was assessed in a longitudinal study that employed a combined genetic risk score formulated from 13 SNPs previously associated with HTN in adults Subjects with a higher risk score at the age of 9 years had significantly higher diastolic BPs than subjects with a lower risk score.

These subjects also had a higher risk for HTN in adulthood The association between SNPs and BP in certain ethnic pediatric populations has also been reported in several recent studies. In a study of Chinese children, rs ATP2B1 was found to be significantly associated with an increased risk for HTN This polymorphism has also been previously linked to HTN in adults.

ATP2B1 encodes a calcium-transporting ATPase that modulates cellular calcium levels in the vascular endothelium, thereby regulating the contraction of vascular smooth muscle cells Childhood HTN is a significant risk factor for HTN and cardiovascular disease in adulthood 98 — Therefore, pediatric studies that identify genetic risk factors and modifiable epigenetic factors for HTN are further needed to formulate preventive strategies that can reduce childhood HTN, and therefore morbidity and mortality later in life.

Moreover, drug pharmacokinetics differ between children and adults Identifying the genes that predispose a child to poor or adverse drug responses would be beneficial in avoiding complications and optimizing therapeutic responses.

Hypertension results from a complex interplay of genetic, epigenetic, and environmental factors. Due to this multifactorial interaction, elucidating single, specific genetic factors that contribute to the development of HTN has been challenging. Nevertheless, novel gene mutations and epigenetic factors causing BP variability continue to be discovered and have enhanced our understanding of BP modulation and the genetic programming of HTN.

Interpatient variability in response to antihypertensive medication is well established, and the field of pharmacogenomics promises to provide guidelines for precision medicine and individually tailored antihypertensive regimens that would improve medication efficacy.

The majority of genetic studies on HTN to date have been focused on adults, and there are currently few studies that have been conducted in the pediatric population. In view of the prevalence of HTN in the pediatric population, more studies on the genetic risk factors in this population are needed to enhance our understanding of the etiology of childhood HTN and to provide better preventive and therapeutic strategies for the future.

S-YA and CG contributed to the conception and writing of the manuscript. Both authors provided their final approval and agreed to be accountable for all aspects of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics — update: a report from the American Heart Association. Circulation e29— CrossRef Full Text Google Scholar. Hansen ML, Gunn PW, Kaelber DC.

Underdiagnosis of hypertension in children and adolescents. JAMA —9. PubMed Abstract CrossRef Full Text Google Scholar. Morgado J, Sanches B, Anjos R, Coelho C. Programming of essential hypertension: what pediatric cardiologists need to know.

Researchers were able to match certain variations in genes with the drug class's effect on lowering heart disease and stroke risk. But they found a possible complication from one particular category of blood pressure drugs examined in the study. The genetic variants targeted by calcium channel blockers had a "previously unreported possible side effect.

When the pouches get infected or tear, these complications can lead to hospitalization. Dipender Gill, a clinical research fellow at Imperial College London.

Neither ACE inhibitors nor beta-blockers showed previously unknown side effects. Researchers corroborated the association between calcium channel blockers and diverticulosis by tapping into another genetic database, this one of DNA samples available through the biobank operated by Vanderbilt University in Tennessee.

An estimated million adults worldwide have high blood pressure, often called "the silent killer" because it rarely shows obvious symptoms while it wreaks havoc on the body. Also called hypertension, high blood pressure is usually treated through lifestyle modifications — specifically changes in diet and physical activity levels — and the use of one or more medications.

But most high blood pressure drugs are tested in older or high-risk populations for a relatively short period of time, and the trials rarely capture side effects beyond the more obvious ones.

Kiran Musunuru, an associate professor of cardiovascular medicine and genetics at the University of Pennsylvania, who was not involved in the research. But Musunuru warned the connection between calcium channel blockers and diverticulosis is still preliminary and isn't enough for medical providers and their patients to stop using calcium channel blockers for that reason alone.

Experts believe there is a link between a family history of hypertension and the condition occurring. However, many factors contribute to the risk, including lifestyle, age, race or ethnicity, and other health conditions.

Making healthy lifestyle choices, such as maintaining a moderate weight, eating a nutritious diet, and getting regular exercise, can help reduce the risk of developing hypertension.

If lifestyle changes are not enough to control blood pressure, a doctor may prescribe medication. Most experts believe that people should treat hypertension as a risk factor. However, new research suggests that high blood pressure is not always bad. High blood pressure hypertension often has no symptoms but, it can increase the risk of cardiovascular disease and other life threatening….

Resistant hypertension occurs when a person's high blood pressure medication is not working. Learn more about the condition and its causes and….

My podcast changed me Can 'biological race' explain disparities in health? Why Parkinson's research is zooming in on the gut Tools General Health Drugs A-Z Health Hubs Health Tools Find a Doctor BMI Calculators and Charts Blood Pressure Chart: Ranges and Guide Breast Cancer: Self-Examination Guide Sleep Calculator Quizzes RA Myths vs Facts Type 2 Diabetes: Managing Blood Sugar Ankylosing Spondylitis Pain: Fact or Fiction Connect About Medical News Today Who We Are Our Editorial Process Content Integrity Conscious Language Newsletters Sign Up Follow Us.

Medical News Today. Health Conditions Health Products Discover Tools Connect. Is hypertension genetic? Medically reviewed by Alana Biggers, M. Genetic link Reducing risk Other causes Risk factors Treatment Summary People with a family history of hypertension are more likely to develop the condition, possibly due to genetic and shared environmental factors.

Family history of hypertension. What can someone with a family history of hypertension do to reduce their risk of disease? Other causes of hypertension. Risk factors. Genetics Hypertension. How we reviewed this article: Sources. Medical News Today has strict sourcing guidelines and draws only from peer-reviewed studies, academic research institutions, and medical journals and associations.

We avoid using tertiary references. We link primary sources — including studies, scientific references, and statistics — within each article and also list them in the resources section at the bottom of our articles. You can learn more about how we ensure our content is accurate and current by reading our editorial policy.