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  • Clinical Implications
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Clinical Implication

Genetic polymorphisms of the β-adrenergic system: association with essential hypertension and response to β-blockade

The Pharmacogenomics Journal volume 4, pages 154–160 (2004)Cite this article

Essential hypertension (EH) is a polygenic, multifactorial disease.1,2 A number of genes and environmental factors must be taken into account to dissect the complexity of EH, as well as drug response.3

Beta adrenergic receptors (βARs) are G-protein-coupled receptors expressed throughout the body, involved in several pathophysiological functions such as blood pressure (BP).4 Genetic polymorphisms of the βARs or of their G proteins could lead to functionally different products, higher/lower BP values or greater/smaller BP fall after β-blockade.

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References

  1. Lander ES, Schork NJ . Genetic dissection of complex traits. Science 1994; 265: 2037–2048.

    Article  CAS  Google Scholar 

  2. Glorioso N, Filigheddu F, Troffa C, Soro A, Parpaglia PP, Tsikoudakis A et al. Interaction of alpha(1)-Na,K-ATPase and Na,K,2Cl-cotransporter genes in human essential hypertension. Hypertension 2001; 38: 204–209.

    Article  CAS  Google Scholar 

  3. Ferrari P, Bianchi G . The genomics of cardiovascular disorders: therapeutic implications. Drugs 2000; 559: 1025–1042.

    Article  Google Scholar 

  4. Liggett SB . Pharmacogenetics of beta-1 and beta-2-adrenergic receptors. Pharmacology 2000; 61: 167–173.

    Article  CAS  Google Scholar 

  5. Bengtsson K, Melander O, Orho-Melander M, Lindblad U, Ranstam J, Rastam L et al. Polymorphism in the beta(1)-adrenergic receptor gene and hypertension. Circulation 2001; 104: 187–190.

    Article  CAS  Google Scholar 

  6. O'Shaughnessy KM, Fu B, Dickerson C, Thurston D, Brown MJ . The gain-of-function G389R variant of the beta1-adrenoceptor does not influence blood pressure or heart rate response to beta-blockade in hypertensive subjects. Clin Sci (Lond) 2000; 99: 233–238.

    Article  CAS  Google Scholar 

  7. Xie HG, Stein CM, Kim RB, Gainer JV, Sofowora G, Dishy V et al. Human beta2-adrenergic receptor polymorphisms: no association with essential hypertension in black or white Americans. Clin Pharmacol Ther 2000; 67: 670–675.

    Article  CAS  Google Scholar 

  8. Kotanko P, Binder A, Tasker J, DeFreitas P, Kamdar S, Clark AJ et al. Essential hypertension in African Caribbeans associates with a variant of the β2-adrenoceptor. Hypertension 1997; 30: 773–776.

    Article  CAS  Google Scholar 

  9. Jia H, Sharma P, Hopper R, Dickerson C, Lloyd DD, Brown MJ . Beta2-adrenoceptor gene polymorphisms and blood pressure variations in East Anglian Caucasians. J Hypertens 2000; 18: 687–693.

    Article  CAS  Google Scholar 

  10. Pamies-Andreu E, Garcia-Lozano R, Palmero-Palmero C, Garcia-Morillo S, Alonso-Arcas A, Stiefel P et al. Genetic variation in the beta-3-adrenergic receptor in essential hypertension. Life Sci 2000; 67: 391–397.

    Article  CAS  Google Scholar 

  11. Ringel J, Kreutz R, Distler A, Sharma AM . The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus. Am J Hypertens 2000; 13: 1027–1031.

    Article  CAS  Google Scholar 

  12. Tonolo G, Melis MG, Secchi G, Atzeni MM, Angius MF, Carboni A et al. Association of Trp64Arg beta 3-adrenergic-receptor gene polymorphism with essential hypertension in the Sardinian population. J Hypertens 1999; 17: 33–38.

    Article  CAS  Google Scholar 

  13. Sofowora GG, Dishy V, Muszkat M, Xie HG, Kim RB, Harris PA et al. A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade. Clin Pharmacol Ther 2003; 73: 366–371.

    Article  CAS  Google Scholar 

  14. Johnson JA, Zineh I, Puckett BJ, McGorray SP, Yarandi HN, Pauly DF . Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 2003; 74: 44–52.

    Article  CAS  Google Scholar 

  15. Jia H, Hingorani AD, Sharma P, Hopper R, Dickerson C, Trutwein D et al. Association of the G(s) α gene with essential hypertension and response to beta-blockade. Hypertension 1999; 34: 8–14.

    Article  CAS  Google Scholar 

  16. Brand E, Herrmann SM, Nicaud V, Ruidavets JB, Evans A, Arveiler D et al. The 825C/T polymorphism of the G-protein subunit beta3 is not related to hypertension. Hypertension 1999; 33: 1175–1178.

    Article  CAS  Google Scholar 

  17. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R et al. Association of a human G-protein beta3 subunit variant with hypertension. Nat Genet 1998; 18: 45–48.

    Article  CAS  Google Scholar 

  18. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E . C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic. Hypertension 2001; 37(Part 2): 739–743.

    Article  CAS  Google Scholar 

  19. Muntner P, He J, Roccella EJ, Whelton PK . The impact of JNC-VI guidelines on treatment recommendations in the US population. Hypertension 2002; 39: 897–902.

    Article  CAS  Google Scholar 

  20. Green SA, Turki J, Innis M, Liggett SB . Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9419.

    Article  CAS  Google Scholar 

  21. Tan S, Hall IP, Dewar J, Dow E, Lipworth B . Association between beta2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350: 995–999.

    Article  CAS  Google Scholar 

  22. Hoit BD, Suresh DP, Craft L, Walsh RA, Liggett SB . beta2-adrenergic receptor polymorphisms at amino acid 16 differentially influence agonist-stimulated blood pressure and peripheral blood flow in normal individuals. Am Heart J 2000; 139: 537–542.

    CAS  PubMed  Google Scholar 

  23. Thursz MR, Thomas HC, Brian MG, Hill AVS . Heterozygote advantage for HLA class-II type in hepatitis B virus infection. Nat Genet 1997; 17: 11–12.

    Article  CAS  Google Scholar 

  24. Wang CH, Schilling RF . Myocardial infarction and thalassemia trait: an example of heterozygote advantage. Am J Hematol 1995; 49: 73–75.

    Article  CAS  Google Scholar 

  25. Mitchison NA . Polymorphism in regulatory gene sequences. Genome Biol 2000; 2: http://genomebiology.com/2000/2/1/comment/2001.1-2001.6.

  26. Tomaszewski M, Brain NJ, Charchar FJ, Wang WY, Lacka B, Padmanabahn S et al. Essential hypertension and beta2-adrenergic receptor gene: linkage and association analysis. Hypertension 2002; 40: 286–291.

    Article  CAS  Google Scholar 

  27. Castellano M, Rossi F, Giacche M, Perani C, Rivadossi F, Muiesan ML et al. Beta(2)-adrenergic receptor gene polymorphism, age, and cardiovascular phenotypes. Hypertension 2003; 41: 361–367.

    Article  CAS  Google Scholar 

  28. Maqbool A, Hall AS, Ball SG, Balmforth AJ . Common polymorphisms of beta1-adrenoceptor: identification and rapid screening assay. Lancet 1999; 353: 897.

    Article  CAS  Google Scholar 

  29. Moser M . Relative efficacy of, and some adverse reactions to, different antihypertensive regimens. Am J Cardiol 1989; 63: 2B–7B.

    Article  CAS  Google Scholar 

  30. Siffert W, Rosskopf D, Moritz A, Wieland T, Kaldenberg-Stasch S, Kettler N et al. Enhanced G protein activation in immortalized lymphoblasts from patients with essential hypertension. J Clin Invest 1995; 96: 759–766.

    Article  CAS  Google Scholar 

  31. Pietruck F, Moritz A, Montemurro M, Sell A, Busch S, Rosskopf D et al. Selectively enhanced cellular signaling by Gi proteins in essential hypertension. G alpha i2, G alpha i3, G beta 1, and G beta 2 are not mutated. Circ Res 1996; 79: 974–983.

    Article  CAS  Google Scholar 

  32. Benjafield AV, Jeyasingam CL, Nyholt DR, Griffiths LR, Morris BJ . G-protein beta3 subunit gene (GNB3) variant in causation of essential hypertension. Hypertension 1998; 32: 1094–1097.

    Article  CAS  Google Scholar 

  33. Bianchi G, Staessen JA, Ferrari P . Pharmacogenomics of primary hypertension—the lessons from the past to look toward the future. Pharmacogenomics 2003; 4: 279–296.

    Article  CAS  Google Scholar 

  34. Kardia SL . Context-dependent genetic effects in hypertension. Curr Hypertens Rep 2000; 2: 32–38.

    Article  CAS  Google Scholar 

  35. Glorioso N, Manunta P, Filigheddu F, Troffa C, Stella P, Barlassina C et al. The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. Hypertension 1999; 34(Part 1): 649–654.

    Article  CAS  Google Scholar 

  36. Perneger TV . What's wrong with Bonferroni adjustments. BMJ 1998; 316: 1236–1238.

    Article  CAS  Google Scholar 

  37. Sham P . Statistics in Human Genetics. John Wiley and Sons: New York 1998.

    Google Scholar 

  38. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG . Replication validity of genetic association studies. Nat Genet 2001; 29: 306–309.

    Article  CAS  Google Scholar 

  39. Shifman S, Darvasi A . The value of isolated populations. Nat Genet 2001; 28: 309–310.

    Article  CAS  Google Scholar 

  40. Cappello N, Rendine S, Griffo R, Mameli GE, Succa V, Vona G et al. Genetic analysis of Sardinia: I. data on 12 polymorphisms in 21 linguistic domains. Ann Hum Genet 1996; 60(Part 2): 125–141.

    Article  CAS  Google Scholar 

  41. Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L et al. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest 1997; 100: 3005–3013.

    Article  CAS  Google Scholar 

  42. Altman DG, Gore SM, Gardner MJ, Pocock SJ . Statistical guidelines for contributors to medical journals. BMJ 1983; 286: 1489–1493.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by a Research Grant of the Italian Society of Hypertension (FF) and by a Grant of the Ministry of University and Research (MIUR: FIRB #RBNE01724C). We are grateful to Dr Anna Pisano (CNR, Research National Council, Reggio Calabria, Italy) for her help in genotyping.

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Authors and Affiliations

  1. Hypertension and Cardiovascular Prevention Center, University of Sassari Medical School, Sassari, Italy

    F Filigheddu, C Troffa, G Argiolas & N Glorioso

  2. Myriad Genetics, Inc., Salt Lake City, UT, USA

    J E Reid & M Skolnick

  3. Emergency Department, Sassari, Italy

    P PinnaParpaglia

  4. CNR-IBIM, Reggio Calabria Unit-Ospedali Riuniti, Reggio Calabria, Italy

    A Testa

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  1. F Filigheddu
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Correspondence to N Glorioso.

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None declared.

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Filigheddu, F., Reid, J., Troffa, C. et al. Genetic polymorphisms of the β-adrenergic system: association with essential hypertension and response to β-blockade. Pharmacogenomics J 4, 154–160 (2004). https://doi.org/10.1038/sj.tpj.6500247

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