Genetics of Hypertension and Heart Failure

  • Sandosh Padmanabhan
  • Alisha Aman
  • Anna F. DominiczakEmail author
Part of the Updates in Hypertension and Cardiovascular Protection book series (UHCP)


Hypertension and heart failure are leading causes of death and disability worldwide. Both are complex multifactorial conditions with hypertension and heart failure at either ends of the cardiovascular continuum. Rare mutations resulting in monogenic forms of hypertension, hypotension and cardiomyopathies highlight the importance of genetics in disease causation and consequent implications for disease prediction and treatment. Advances in genomics have accelerated over the last decade leading to an unparalleled leap in our understanding of the genetic architecture of both hypertension and heart failure. In this chapter, we describe the current state of the art in the genetics of both conditions, hypertension and heart failure, focussing on biologic pathways that are perturbed and opportunities for early detection and treatment.


Hypertension Blood pressure Heart failure Cardiomyopathy Genetics Monogenic Polygenic 


  1. 1.
    Krousel-Wood MA, et al. Primary prevention of essential hypertension. Med Clin North Am. 2004;88(1):223–38.PubMedGoogle Scholar
  2. 2.
    Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016;13(6):368–78.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Dzau VJ, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part II: clinical trial evidence (acute coronary syndromes through renal disease) and future directions. Circulation. 2006;114(25):2871–91.PubMedGoogle Scholar
  4. 4.
    Bochud M, et al. High heritability of ambulatory blood pressure in families of East African descent. Hypertension. 2005;45(3):445–50.PubMedGoogle Scholar
  5. 5.
    Havlik RJ, et al. Blood pressure aggregation in families. Am J Epidemiol. 1979;110(3):304–12.PubMedGoogle Scholar
  6. 6.
    Hottenga J-J, et al. Heritability and stability of resting blood pressure. Twin Res Hum Genet. 2005;8(5):499–508.PubMedGoogle Scholar
  7. 7.
    Kupper N, et al. Heritability of daytime ambulatory blood pressure in an extended twin design. Hypertension. 2005;45(1):80–5.PubMedGoogle Scholar
  8. 8.
    Snieder H, Harshfield GA, Treiber FA. Heritability of blood pressure and hemodynamics in African-and European-American youth. Hypertension. 2003;41(6):1196–201.PubMedGoogle Scholar
  9. 9.
    Fagard R, et al. Heritability of conventional and ambulatory blood pressures. A study in twins. Hypertension. 1995;26(6 Pt 1):919–24.PubMedGoogle Scholar
  10. 10.
    Fava C, et al. Heritability of ambulatory and office blood pressure phenotypes in Swedish families. J Hypertens. 2004;22(9):1717–21.PubMedGoogle Scholar
  11. 11.
    Caulfield M, et al. Genome-wide mapping of human loci for essential hypertension. Lancet. 2003;361(9375):2118–23.PubMedGoogle Scholar
  12. 12.
    Lee DS, et al. Association of parental heart failure with risk of heart failure in offspring. N Engl J Med. 2006;355(2):138–47.PubMedGoogle Scholar
  13. 13.
    Swan L, et al. The genetic determination of left ventricular mass in healthy adults. Eur Heart J. 2003;24(6):577–82.PubMedGoogle Scholar
  14. 14.
    Sharma P, et al. Heritability of left ventricular mass in a large cohort of twins. J Hypertens. 2006;24(2):321–4.PubMedGoogle Scholar
  15. 15.
    Post WS, et al. Heritability of left ventricular mass: the Framingham Heart Study. Hypertension. 1997;30(5):1025–8.PubMedGoogle Scholar
  16. 16.
    Busjahn CA, et al. Heritability of left ventricular and papillary muscle heart size: a twin study with cardiac magnetic resonance imaging. Eur Heart J. 2009;30(13):1643–7.PubMedGoogle Scholar
  17. 17.
    Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension. 2005;45(6):1050–5.PubMedGoogle Scholar
  18. 18.
    Lloyd-Jones DM, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106(24):3068–72.PubMedGoogle Scholar
  19. 19.
    Nasir K, et al. Coronary artery calcification and family history of premature coronary heart disease: sibling history is more strongly associated than parental history. Circulation. 2004;110(15):2150–6.PubMedGoogle Scholar
  20. 20.
    Fischer M, et al. Distinct heritable patterns of angiographic coronary artery disease in families with myocardial infarction. Circulation. 2005;111(7):855–62.PubMedGoogle Scholar
  21. 21.
    Lewis GA, et al. Biological phenotypes of heart failure with preserved ejection fraction. J Am Coll Cardiol. 2017;70(17):2186–200.PubMedGoogle Scholar
  22. 22.
    Zakeri R, Cowie MR. Heart failure with preserved ejection fraction: controversies, challenges and future directions. Heart. 2018;104:377.PubMedGoogle Scholar
  23. 23.
    Cordain L, et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81(2):341–54.PubMedGoogle Scholar
  24. 24.
    Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet. 1962;14(4):353–62.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Konner M, Eaton SB. Paleolithic nutrition: twenty-five years later. Nutr Clin Pract. 2010;25(6):594–602.PubMedGoogle Scholar
  26. 26.
    Padmanabhan S, Newton-Cheh C, Dominiczak AF. Genetic basis of blood pressure and hypertension. Trends Genet. 2012;28(8):397–408.PubMedGoogle Scholar
  27. 27.
    Burt VL, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension. 1995;25(3):305–13.PubMedGoogle Scholar
  28. 28.
    Barker DJ, et al. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol. 2002;31(6):1235–9.PubMedGoogle Scholar
  29. 29.
    Nakajima T, et al. Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world. Am J Hum Genet. 2004;74(5):898–916.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Weder AB. Evolution and hypertension. Hypertension. 2007;49(2):260–5.Google Scholar
  31. 31.
    Young JH, et al. Differential susceptibility to hypertension is due to selection during the out-of-Africa expansion. PLoS Genet. 2005;1(6):e82.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Wain LV, et al. Novel blood pressure locus and gene discovery using genome-wide association study and expression data sets from blood and the kidney. Hypertension. 2017;70(3):e4–e19.Google Scholar
  33. 33.
    International Consortium for Blood Pressure Genome-Wide Association Studies, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478(7367):103–9.Google Scholar
  34. 34.
    Warren HR, et al. Corrigendum: genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet. 2017;49(10):1558.PubMedGoogle Scholar
  35. 35.
    Kraja AT, et al. New blood pressure-associated loci identified in meta-analyses of 475 000 individuals. Circ Cardiovasc Genet. 2017;10(5).Google Scholar
  36. 36.
    Padmanabhan S, Joe B. Towards precision medicine for hypertension: a review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans. Physiol Rev. 2017;97(4):1469–528.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Cappola TP, et al. Common variants in HSPB7 and FRMD4B associated with advanced heart failure. Circ Cardiovasc Genet. 2010;3(2):147–54.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Parsa A, et al. Hypertrophy-associated polymorphisms ascertained in a founder cohort applied to heart failure risk and mortality. Clin Transl Sci. 2011;4(1):17–23.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Vasan RS, et al. Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. JAMA. 2009;302(2):168–78.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Meder B, et al. A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. Eur Heart J. 2014;35(16):1069–77.PubMedGoogle Scholar
  41. 41.
    Smith NL, et al. Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. Circ Cardiovasc Genet. 2010;3(3):256–66.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104(4):545–56.PubMedGoogle Scholar
  43. 43.
    Lifton RP, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355(6357):262–5.PubMedGoogle Scholar
  44. 44.
    Lafferty AR, et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J Med Genet. 2000;37(11):831–5.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Cerame BI, New MI. Hormonal hypertension in children: 11beta-hydroxylase deficiency and apparent mineralocorticoid excess. J Pediatr Endocrinol Metab. 2000;13(9):1537–47.PubMedGoogle Scholar
  46. 46.
    New MI, Levine LS. Hypertension of childhood with suppressed renin. Endocr Rev. 1980;1(4):421–30.PubMedGoogle Scholar
  47. 47.
    Levy D, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41(6):677–87.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Kato N, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet. 2011;43(6):531–8.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Ehret GB, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478(7367):103–9.PubMedGoogle Scholar
  50. 50.
    Newton-Cheh C, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41(6):666–76.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Fernandes-Rosa FL, Boulkroun S, Zennaro MC. Somatic and inherited mutations in primary aldosteronism. J Mol Endocrinol. 2017;59(1):R47–63.PubMedGoogle Scholar
  52. 52.
    Hansson JH, et al. Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndrome. Nat Genet. 1995;11(1):76–82.PubMedGoogle Scholar
  53. 53.
    Shimkets RA, et al. Liddle’s syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994;79(3):407–14.PubMedGoogle Scholar
  54. 54.
    Ji W, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40(5):592–9.PubMedPubMedCentralGoogle Scholar
  55. 55.
    John SW, et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science. 1995;267:679–81.PubMedGoogle Scholar
  56. 56.
    Schillinger KJ, et al. Regulatable atrial natriuretic peptide gene therapy for hypertension. Proc Natl Acad Sci U S A. 2005;102(39):13789–94.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Newton-Cheh C, et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet. 2009;41(3):348–53.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Zhu X, et al. Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13: contributions from the CARe consortium. Hum Mol Genet. 2011;20(11):2285–95.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Brosnan MJ, et al. Genes encoding atrial and brain natriuretic peptides as candidates for sensitivity to brain ischemia in stroke-prone hypertensive rats. Hypertension. 1999;33(1):290–7.PubMedGoogle Scholar
  60. 60.
    Jeffs B, et al. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet. 1997;16(4):364–7.PubMedGoogle Scholar
  61. 61.
    Ye P, West MJ. Cosegregation analysis of natriuretic peptide genes and blood pressure in the spontaneously hypertensive rat. Clin Exp Pharmacol Physiol. 2003;30(12):930–6.PubMedGoogle Scholar
  62. 62.
    Rubattu S, et al. Association of atrial natriuretic peptide and type a natriuretic peptide receptor gene polymorphisms with left ventricular mass in human essential hypertension. J Am Coll Cardiol. 2006;48(3):499–505.PubMedGoogle Scholar
  63. 63.
    Padmanabhan S, et al. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet. 2010;6(10):e1001177.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Köttgen A, et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet. 2009;41(6):712–7.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Trudu M, et al. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med. 2013;19(12):1655–60.PubMedGoogle Scholar
  66. 66.
    Esler M, et al. The sympathetic neurobiology of essential hypertension: disparate influences of obesity, stress, and noradrenaline transporter dysfunction? Am J Hypertens. 2001;14(S3):139S–46S.PubMedGoogle Scholar
  67. 67.
    Izzo JL, Taylor AA. The sympathetic nervous system and baroreflexes in hypertension and hypotension. Curr Hypertens Rep. 1999;1(3):254–63.PubMedGoogle Scholar
  68. 68.
    Welander J, Söderkvist P, Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2011;18(6):R253–76.PubMedGoogle Scholar
  69. 69.
    Small KM, et al. Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 2002;347(15):1135–42.PubMedGoogle Scholar
  70. 70.
    Nikpay M, et al. A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet. 2015;47(10):1121–30.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Gupta RM, et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell. 2017;170(3):522–533 e15.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Kiando SR, et al. PHACTR1 is a genetic susceptibility locus for fibromuscular dysplasia supporting its complex genetic pattern of inheritance. PLoS Genet. 2016;12(10):e1006367.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Xiang M, et al. A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension. Proc Natl Acad Sci. 2007;104(47):18677–81.PubMedGoogle Scholar
  74. 74.
    Blaustein MP. Physiological effects of endogenous ouabain: control of intracellular Ca2+ stores and cell responsiveness. Am J Phys Cell Phys. 1993;264(6):C1367–87.Google Scholar
  75. 75.
    Iwamoto T, et al. Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle. Nat Med. 2004;10(11):1193–9.PubMedGoogle Scholar
  76. 76.
    Codd MB, et al. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975-1984. Circulation. 1989;80(3):564–72.PubMedGoogle Scholar
  77. 77.
    Villard E, et al. A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy. Eur Heart J. 2011;32(9):1065–76.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Morita H, et al. Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study. Circulation. 2006;113(23):2697–705.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sandosh Padmanabhan
    • 1
  • Alisha Aman
    • 1
  • Anna F. Dominiczak
    • 1
    • 2
    Email author
  1. 1.Institute of Cardiovascular and Medical SciencesGlasgowUK
  2. 2.College of Medical, Veterinary and Life SciencesUniversity of Glasgow, Wolfson Medical School BuildingGlasgowUK

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