ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Genetic factors in the pathogenesis of hypertension

Genetic factors in the pathogenesis of hypertension
Literature review current through: Aug 2023.
This topic last updated: Oct 13, 2022.

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.)

  1. McKusick VA. Genetics and the nature of essential hypertension. Circulation 1960; 22:857.
  2. OLDHAM PD, PICKERING G, ROBERTS JA, SOWRY GS. The nature of essential hypertension. Lancet 1960; 1:1085.
  3. Levy D, Larson MG, Benjamin EJ, et al. Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness. BMC Med Genet 2007; 8 Suppl 1:S3.
  4. Snieder H, Hayward CS, Perks U, et al. Heritability of central systolic pressure augmentation: a twin study. Hypertension 2000; 35:574.
  5. MIALL WE, OLDHAM PD. The hereditary factor in arterial blood-pressure. Br Med J 1963; 1:75.
  6. Wang NY, Young JH, Meoni LA, et al. Blood pressure change and risk of hypertension associated with parental hypertension: the Johns Hopkins Precursors Study. Arch Intern Med 2008; 168:643.
  7. Giri A, Hellwege JN, Keaton JM, et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat Genet 2019; 51:51.
  8. Lifton RP. Genetic dissection of human blood pressure variation: common pathways from rare phenotypes. Harvey Lect 2004-2005; 100:71.
  9. International Consortium for Blood Pressure Genome-Wide Association Studies, Ehret GB, Munroe PB, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011; 478:103.
  10. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992; 355:262.
  11. Rich GM, Ulick S, Cook S, et al. Glucocorticoid-remediable aldosteronism in a large kindred: clinical spectrum and diagnosis using a characteristic biochemical phenotype. Ann Intern Med 1992; 116:813.
  12. Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011; 331:768.
  13. Scholl UI, Stölting G, Schewe J, et al. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet 2018; 50:349.
  14. Scholl UI, Stölting G, Nelson-Williams C, et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife 2015; 4:e06315.
  15. Hansson JH, Nelson-Williams C, Suzuki H, et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 1995; 11:76.
  16. Shimkets RA, Warnock DG, Bositis CM, et al. Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 1994; 79:407.
  17. Wilson FH, Disse-Nicodème S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science 2001; 293:1107.
  18. Boyden LM, Choi M, Choate KA, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 2012; 482:98.
  19. Louis-Dit-Picard H, Barc J, Trujillano D, et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet 2012; 44:456.
  20. Mune T, Rogerson FM, Nikkilä H, et al. Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. Nat Genet 1995; 10:394.
  21. Geller DS, Farhi A, Pinkerton N, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 2000; 289:119.
  22. White PC, Dupont J, New MI, et al. A mutation in CYP11B1 (Arg-448----His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin. J Clin Invest 1991; 87:1664.
  23. Goldsmith O, Solomon DH, Horton R. Hypogonadism and mineralocorticoid excess. The 17-hydroxylase deficiency syndrome. N Engl J Med 1967; 277:673.
  24. Maass PG, Aydin A, Luft FC, et al. PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat Genet 2015; 47:647.
  25. Pratt RE, Dzau VJ. Genomics and hypertension: concepts, potentials, and opportunities. Hypertension 1999; 33:238.
  26. Simino J, Shi G, Kume R, et al. Five blood pressure loci identified by an updated genome-wide linkage scan: meta-analysis of the Family Blood Pressure Program. Am J Hypertens 2011; 24:347.
  27. Caulfield M, Munroe P, Pembroke J, et al. Genome-wide mapping of human loci for essential hypertension. Lancet 2003; 361:2118.
  28. Franceschini N, Fox E, Zhang Z, et al. Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations. Am J Hum Genet 2013; 93:545.
  29. Ganesh SK, Chasman DI, Larson MG, et al. Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. Am J Hum Genet 2014; 95:49.
  30. Johnson T, Gaunt TR, Newhouse SJ, et al. Blood pressure loci identified with a gene-centric array. Am J Hum Genet 2011; 89:688.
  31. Kato N, Loh M, Takeuchi F, et al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nat Genet 2015; 47:1282.
  32. Kato N, Takeuchi F, Tabara Y, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet 2011; 43:531.
  33. Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet 2009; 41:677.
  34. Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 2009; 41:666.
  35. Padmanabhan S, Melander O, Johnson T, et al. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet 2010; 6:e1001177.
  36. Salvi E, Kutalik Z, Glorioso N, et al. Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase. Hypertension 2012; 59:248.
  37. Simino J, Shi G, Bis JC, et al. Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. Am J Hum Genet 2014; 95:24.
  38. Tragante V, Barnes MR, Ganesh SK, et al. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am J Hum Genet 2014; 94:349.
  39. Wain LV, Verwoert GC, O'Reilly PF, et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet 2011; 43:1005.
  40. Zhu X, Feng T, Tayo BO, et al. Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension. Am J Hum Genet 2015; 96:21.
  41. Ehret GB, Caulfield MJ. Genes for blood pressure: an opportunity to understand hypertension. Eur Heart J 2013; 34:951.
  42. Wang Y, O'Connell JR, McArdle PF, et al. From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A 2009; 106:226.
  43. Fox ER, Young JH, Li Y, et al. Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. Hum Mol Genet 2011; 20:2273.
  44. Evangelou E, Warren HR, Mosen-Ansorena D, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet 2018; 50:1412.
  45. Havulinna AS, Kettunen J, Ukkola O, et al. A blood pressure genetic risk score is a significant predictor of incident cardiovascular events in 32,669 individuals. Hypertension 2013; 61:987.
  46. Ehret GB, Ferreira T, Chasman DI, et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 2016; 48:1171.
  47. Hoffmann TJ, Ehret GB, Nandakumar P, et al. Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation. Nat Genet 2017; 49:54.
  48. Wan EYF, Fung WT, Schooling CM, et al. Blood Pressure and Risk of Cardiovascular Disease in UK Biobank: A Mendelian Randomization Study. Hypertension 2021; 77:367.
Topic 3847 Version 26.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟