Genetic factors in the pathogenesis of hypertension

INTRODUCTION — Blood pressure is a major cardiovascular risk factor and also a classic quantitative genetic trait; therefore, primary hypertension (formerly called "essential" hypertension) is of interest to clinicians and geneticists alike [1,2]. Family and twin studies estimate that the heritability (fraction of the trait explained by genes) of blood pressure is 30 to 50 percent [3-5]; consequently, genomics has the potential to contribute to the poorly understood pathogenesis of primary hypertension. Strong empirical evidence of the importance of genes in hypertension comes from the observation that hypertension is 2.4 times more common in subjects who have two hypertensive parents [6].

The genetic contribution to blood pressure regulation is of two fundamentally different types:

●Monogenic hypertension and rare genetic variants – Rare mutations segregating in families can cause secondary hypertension, even in the absence of other risk factors (ie, "monogenic" hypertension, such as Liddle's syndrome) (table 1) (see "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1"). Once a monogenic form of hypertension is identified, these cases should be correctly labeled as secondary rather than primary hypertension.

Additional monogenic hypertension syndromes are due to an inappropriate secretion of norepinephrine and epinephrine or their metabolites (see "Pheochromocytoma in genetic disorders").

In addition to rare variants that are associated with secondary hypertension, there are rare mutations that lower blood pressure and therefore protect against the development of hypertension. One example is Gitelman syndrome in which loss-of-function mutations in the thiazide-sensitive Na-Cl cotransporter in the distal tubule are associated with lower blood pressures than in individuals without this defect (see "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations"). These monogenic hypotension syndromes are not further discussed in this topic.

●Primary hypertension and common genetic variants – There are at least one thousand, possibly many thousands, of common genetic hypertension risk variants that are individually associated with small effect sizes (approximately 1 mmHg or less) [7]. The probability of primary hypertension occurring grows larger with the number of risk alleles present and is modulated by environmental factors such as age, body mass index (BMI), sex, salt consumption, and others. Consequently, primary hypertension cannot be due to one or only a few genetic variants, and there is no such thing as the primary hypertension gene.

Patterns illuminated by the two different types of genetic contributions are distinctly different, and this topic will review both types of genetic variation.

MONOGENIC (SECONDARY) HYPERTENSION — Genetic investigations of rare hypertensive families have yielded 15 monogenic hypertension genes so far, and mutations in these genes are sufficient to cause substantial blood pressure elevations as well as, in some cases, severe forms of hypertension. These hypertension genes have also been termed "Lifton" genes, as they were discovered, to a large extent, by Dr. Richard Lifton [8]. The penetrance of such genetic disorders is highly variable.

Although these mutations increase blood pressure greatly in individuals who harbor them (ie, large effect size of single variants), the impact of these variants on blood pressure and hypertension at the population level appears to be small at best because they are rare to extremely rare [9].

Monogenic hypertension syndromes — The specific genetic mutations identified in 15 genes lead to 11 different monogenic hypertensive syndromes (table 1). Not listed here are genetic diseases that can indirectly lead to hypertension (eg, hereditary pheochromocytoma and monogenic diabetes).

Plasma renin levels are always low in these forms of hypertension, although aldosterone levels vary. The following disorders are classically associated with elevated plasma aldosterone:

●Glucocorticoid-remediable aldosteronism, also known as familial hyperaldosteronism type I, is a disorder in which there is a chimeric gene formed from portions of the 11-beta-hydroxylase gene and the aldosterone synthase gene. This abnormal chimeric gene is stimulated by adrenocorticotropic hormone (ACTH), resulting in the production of aldosterone [10,11]. (See "Familial hyperaldosteronism", section on 'Familial hyperaldosteronism type I (FH type I) or glucocorticoid-remediable aldosteronism (GRA)'.)

●Familial hyperaldosteronism type II, familial hyperaldosteronism type III, and familial hyperaldosteronism type IV are extremely rare defects produced by loss-of-function or gain-of-function mutations in ion channel genes (table 1). The typical presentation is hypertension with hypokalemia and elevated aldosterone [12-14]. (See "Familial hyperaldosteronism", section on 'Familial hyperaldosteronism type III (FH type III)'.)

Conversely, the following disorders are classically associated with reduced plasma aldosterone:

●Liddle's syndrome is a disorder that is associated with hypertension, low plasma renin and aldosterone levels, and hypokalemia, all of which respond to amiloride, an inhibitor of the epithelial sodium channel (ENaC) in collecting tubule principal cells (figure 1). The primary defect is a gain-of-function mutation of this channel with markedly increased sodium reabsorption [15,16]. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1", section on 'Liddle syndrome'.)

●Pseudohypoaldosteronism type 2 (also called Gordon syndrome, familial hyperkalemic hypertension) is characterized by hypertension, hyperkalemia, normal kidney function, and low or low-normal plasma renin activity and aldosterone concentrations. Mutations in WNK kinases 1 and 4 result in increased chloride reabsorption with sodium, thereby producing volume expansion, hypertension, and, due to reduced distal sodium delivery, hyperkalemia [17]. The same clinical presentation can also be observed with mutations in the KLHL3 and CUL3 genes [18,19]. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Pseudohypoaldosteronism type 2 (Gordon's syndrome)'.)

●Syndrome of apparent mineralocorticoid excess arises from mutations in the gene encoding the kidney enzyme, 11-beta-hydroxysteroid dehydrogenase [20]. The defective enzyme allows normal circulating concentrations of cortisol (which are much higher than those of aldosterone) to activate the mineralocorticoid receptors. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)

●Early-onset autosomal dominant hypertension with exacerbation in pregnancy is an extremely rare condition characterized by large blood pressure increases during pregnancy [21]. With this mutation, the mineralocorticoid receptor can be activated by progesterone in addition to aldosterone.

●Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is a disorder that has been associated with mutations of the CYP11B1 gene [22]. Variable degrees of virilization occur, and hypertension often occurs during the first years of life but can also be observed later. (See "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency'.)

●Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency is a very rare defect that frequently presents together with hypogonadism [23]. (See "Uncommon congenital adrenal hyperplasias", section on 'CYP17A1 deficiencies'.)

●Autosomal dominant hypertension with brachydactyly is a syndrome caused by a mutation of the phosphodiesterase 3A gene. Severe hypertension that occurs at older age is associated with brachydactyly [24].

All genes identified in monogenic hypertension so far, with the potential exception of the phosphodiesterase 3A gene, act in the kidney or in the mineralocorticoid pathways. Although their involvement in monogenic hypertension shows that the kidney and the mineralocorticoid pathways regulate blood pressure, this does not imply a role for the same genes or pathways in the pathogenesis of primary hypertension (formerly called "essential" hypertension).

The clinical distinction among these different syndromes is typically based upon renin levels, aldosterone levels, and the response to different pharmacologic agents. It is important to stress that all forms of familial hypertension are associated with low plasma renin levels.

GENETIC VARIANTS CONTRIBUTING TO PRIMARY (ESSENTIAL) HYPERTENSION — The study of genetic variants that contribute to primary hypertension (ie, "hypertension loci") is, necessarily, the study of variants that contribute to blood pressure (ie, "blood pressure loci"). In practice, geneticists examine the determinants of blood pressure (a continuum) rather than determinants of hypertension (a dichotomy) in order to enhance the statistical power of their analyses.

Candidate-gene and linkage studies — Candidate-gene studies are those that examine the association of a disorder (such as hypertension) with variants in one or a handful of genes selected a priori by the scientist based upon what they believe about the pathophysiology of the disease. Candidate-gene approaches have rarely been reproducible for primary hypertension, and their benefit for enhancing the understanding of blood pressure genetics has been limited [25].

Linkage analysis involves the search for genes that are transmitted from parent to child and that correspond to the existence of a specific trait (like hypertension). These family-based studies have been exceptionally successful for the monogenic hypertensive syndromes (see 'Monogenic (secondary) hypertension' above). However, only a few studies have attempted to identify genes associated with primary hypertension [26,27].

Genome-wide association studies — The use of genome-wide association studies, which examine hundreds of thousands to millions of single-nucleotide polymorphisms (SNPs) in large cohorts, has improved the understanding of blood pressure genomics and has demonstrated the presence of clearly reproducible blood pressure loci, and over 1000 such loci have been identified in studies that include samples sizes of >1 million participants [7]. However, these loci have so far only explained a small proportion of the total blood pressure heritability. The advantage of the method is the unbiased approach that is hypothesis generating (in contrast to the candidate-gene approach, which tests a preexisting hypothesis). The disadvantage of such studies is the overall limited statistical power (because of the large number of tests), even with sample sizes that might appear large.

There are hundreds of replicated blood pressure loci from genome-wide association studies. In addition to the large number of blood pressure loci, the main conclusions that can be drawn from these studies are as follows [9,14,28-44]:

●The effect of any specific individual loci on blood pressure is small, approximately 1 mmHg for systolic pressure and 0.5 mmHg for diastolic pressure, or less.

●The majority of blood pressure loci that have been discovered are not near genes that are known to be associated with monogenic secondary hypertension.

●Most of the blood pressure variants that have been discovered are common in the population; statistical power to detect more rare variants is limited, even with very large sample sizes.

●The loci are largely associated with blood pressure in multiple ethnicities, implying a panethnic function of the underlying genes [9,28].

●There is evidence that the effect of some loci is dependent upon environmental factors, such as age [37]. There is no evidence that the effects of blood pressure loci are dependent upon other blood pressure loci (gene-gene interactions).

●A substantial number of the identified genes harbor multiple SNPs that are each independently associated with blood pressure.

●Only a small fraction of the heritability of blood pressure is explained by the loci that have so far been discovered (approximately 5 to 10 percent). The other genetic determinants of blood pressure heritability remain elusive but are likely to be at least partially contained in additional common and rare variants that have yet to be identified.

MAKING USE OF INFORMATION ON BLOOD PRESSURE GENETICS — The identification of monogenic hypertension genes has been useful in improving the understanding of pathways involved in blood pressure control and can, in rare cases, permit targeted therapy of secondary hypertension (eg, glucocorticoid-remediable aldosteronism). At present, there is no clinical impact of these studies on primary hypertension (formerly called "essential" hypertension). Although variants identified in genome-wide association studies of blood pressure are associated with blood pressure and hypertension [45], the effect sizes are small and do not permit clinically relevant prediction of whether or not hypertension will develop in an individual.

Understanding hypertension pathogenesis — The most immediate use of blood pressure loci identified by genome-wide association studies is to identify pathways involved in the pathogenesis of primary hypertension.

As an example, the potential enrichment of active DNA domains near blood pressure loci in microvascular endothelial cells [46] and blood vessels [47] might point to the involvement of the vasculature in the pathogenesis of primary hypertension. Blood pressure genes that have been identified and the corresponding pathways might serve as targets for pharmacological intervention. One example of this in a related field of cardiovascular prevention is the development of anti-PCSK9 antibodies to reduce low-density lipoprotein (LDL)-cholesterol levels.

Mendelian randomization experiments — Mendelian randomization uses the property that genetic variants are "randomly assigned" when they are passed on from parent to offspring during the process of meiosis. The process of randomization of variants can be used to evaluate whether or not a genetically determined trait is a causative factor in the development of another trait. As an example, if a combination of blood pressure loci (ie, a blood pressure genetic risk score) predicts coronary artery disease, then this is evidence for causal involvement of blood pressure in coronary artery disease. An effect of blood pressure risk scores could be shown for stroke, coronary artery disease, heart failure, and left ventricular thickness and mass [9,31,48]; by contrast, no effect of blood pressure risk score on kidney disease was detected. This is evidence for a noncausal relationship between primary hypertension and kidney damage and confirms evidence from clinical studies that progression of kidney damage is difficult to stop even when blood pressure is well controlled.

SUMMARY AND RECOMMENDATIONS

●Hypertension and blood pressure-associated genetic variants are of two fundamentally different types (see 'Introduction' above):

•Rare mutations that segregate in families and cause secondary hypertension, even in the absence of other risk factors (ie, "monogenic" hypertension).

•Common genetic variants that are individually associated with a small blood pressure change (approximately 1 mmHg or less).

●Genetic investigations of rare hypertensive families have yielded 15 monogenic hypertension genes so far, and mutations in these genes are sufficient to cause substantial blood pressure elevations as well as, in some cases, severe forms of hypertension. The specific genetic mutations identified in these 15 genes lead to 11 different monogenic hypertensive syndromes (table 1). (See 'Monogenic (secondary) hypertension' above.)

●All genes identified in monogenic hypertension so far, with the potential exception of the phosphodiesterase 3A gene, act in the kidney or in the mineralocorticoid pathways. (See 'Monogenic (secondary) hypertension' above.)

●The clinical distinction among these different monogenic hypertension syndromes is typically based upon renin levels, aldosterone levels, and the response to different pharmacologic agents. (See 'Monogenic hypertension syndromes' above.)

●The use of genome-wide association studies, which examine hundreds of thousands or millions of single-nucleotide polymorphisms (SNPs) in large cohorts, has improved the understanding of blood pressure genomics and has demonstrated the presence of clearly reproducible blood pressure loci. However, these loci have so far only explained a small proportion of the total blood pressure heritability. There are hundreds of loci associated with blood pressure reported. (See 'Genetic variants contributing to primary (essential) hypertension' above and 'Genome-wide association studies' above.)

●Blood pressure loci that have been identified as contributing to primary hypertension (formerly called "essential" hypertension) using genome-wide association studies are not, at present, useful for prediction of whether or not an individual will develop hypertension. Rather, there are two major uses for these loci (see 'Making use of information on blood pressure genetics' above):

•They can be used to identify pathways involved in the pathogenesis of primary hypertension. (See 'Understanding hypertension pathogenesis' above.)

•A combination of blood pressure loci (ie, a blood pressure "genetic risk score") can be used to evaluate whether blood pressure is a causative factor in the development of another disease. (See 'Mendelian randomization experiments' above.)