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Functional adrenergic receptor polymorphisms and idiopathic orthostatic intolerance

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Abstract

Objectives: Idiopathic orthostatic intolerance (IOI) is a common disorder that is characterized by chronic orthostatic symptoms and substantial increases in heart rate and plasma norepinephrine concentrations that are disproportionately high while standing. Several features of the syndrome, including the tachycardia, tremulousness, and exaggerated norepinephrine have been considered potentially due to hypoactive or hyperactive states of adrenergic receptors of the sympathetic nervous system. The aim of this study was therefore to ascertain whether genotypes at eight polymorphic loci within five relevant adrenergic receptor genes (α2A, α2B, α2C, β1 and β2) influence the risk for IOI. Methods: We studied 80 young men in military service (20 patients with IOI and 60 age-matched controls). All participants underwent a tilt table test including monitoring of blood pressure, heart rate and plasma catecholamines, in the supine position and during 30 min of standing. Genotyping at the eight loci (α2ALys251, α2BDel301-303, α2CDel322-325, β1Gly49, β1Arg389, β2Arg16, β2Glu27, β2Ile164) was performed in all participants. Chi-square tests of independence were used to test for associations between IOI and genotype. In addition, an association of the polymorphisms with haemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way variance analysis. Results: For the β1Gly49 polymorphism we found a decrease in the risk of IOI among persons who were homozygous (odds ratio, 0.88; 95% confidence interval, 0.81–0.97). In addition, we found an association between β1Gly49 and decreased heart rate in the upright position, regardless of IOI diagnosis. There were no associations with the other studied polymorphisms and IOI. Conclusions: Our current results suggest that the β1Gly49 polymorphism is protective for IOI. This is likely one of several common genetic loci that may represent modifiers of IOI phenotypes.

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References

  • Bray MS, Krushkal J, Li L, Ferrell R, Kardia S, Sing CF, Turner ST, Boerwinkle E (2000) Positional genomic analysis identifies the beta(2)-adrenergic receptor gene as a susceptibility locus for human hypertension. Circulation 101:2877–2882

    Google Scholar 

  • Brodde O E, Buscher R, Tellkamp R, Radke J, Dhein S, Insel P A (2001) Blunted cardiac responses to receptor activation in subjects with Thr164Ile beta(2)-adrenoceptors. Circulation 103:1048–1050

    Google Scholar 

  • Dishy V, Sofowora GG, Xie HG, Kim RB, Byrne DW, Stein CM, Wood AJ (2001) The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 345:1030–1035

    Google Scholar 

  • Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, Liggett SB (2000) Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A 97:10483–10488

    Google Scholar 

  • Farquhar W B, Taylor J A, Darling S E, Chase K P, Freeman R (2000) Abnormal baroreflex responses in patients with idiopathic orthostatic intolerance. Circulation 102:3086–3091

    Google Scholar 

  • Gratze G, Fortin J, Holler A, Grasenick K, Pfurtscheller G, Wach P, Schonegger J, Kotanko P, Skrabal F (1998) A software package for non-invasive, real-time beat-to-beat monitoring of stroke volume, blood pressure, total peripheral resistance and for assessment of autonomic function. Comput Biol Med 28:121–142

    Google Scholar 

  • Green SA, Cole G, Jacinto M, Innis M, Liggett SB (1993) A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 268:23116–23121

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Grubb BP, Kosinski DJ, Kanjwal Y (2003) Orthostatic hypotension: causes, classification, and treatment. Pacing Clin Electrophysiol 26:892–901

    Google Scholar 

  • Heinonen P, Jartti L, Jarvisalo MJ, Pesonen U, Kaprio JA, Ronnemaa T, Raitakari OT, Scheinin M (2002) Deletion polymorphism in the alpha2B-adrenergic receptor gene is associated with flow-mediated dilatation of the brachial artery. Clin Sci Lond 103:517–524

    Google Scholar 

  • Hoit BD, Suresh DP, Craft L, Walsh RA, Liggett SB (2000) Beta2-adrenergic receptor polymorphisms at amino acid 16 differentially influence agonist-stimulated blood pressure and peripheral blood flow in normal individuals. Am Heart J 139:537–542

    Google Scholar 

  • Jacob G, Biaggioni I (1999) Idiopathic orthostatic intolerance and postural tachycardia syndromes. Am J Med Sci 317:88–101

    Google Scholar 

  • January B, Seibold A, Allal C, Whaley BS, Knoll BJ, Moore RH, Dickey BF, Barber R, Clark RB (1998) Salmeterol-induced desensitization, internalization and phosphorylation of the human beta2-adrenoceptor. Br J Pharmacol 123:701–711

    Google Scholar 

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

    Google Scholar 

  • Jordan J, Shannon JR, Jacob G, Pohar B, Robertson D (1999) Interaction of genetic predisposition and environmental factors in the pathogenesis of idiopathic orthostatic intolerance. Am J Med Sci 318:298–303

    Google Scholar 

  • Jordan J, Shannon JR, Diedrich A, Black BK, Robertson D (2002) Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity. Hypertension 39:173–178

    Google Scholar 

  • Liggett S B, Wagoner LE, Craft LL, Hornung RW, Hoit BD, McIntosh TC, Walsh RA (1998) The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 102:1534–1539

    Google Scholar 

  • Mason DA, Moore JD, Green SA, Liggett SB (1999) A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 274:12670–12674

    Article  CAS  PubMed  Google Scholar 

  • Mialet Perez J, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Schwartz A, Dorn GW, Liggett SB (2003) Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med 9:1300–1305

    Google Scholar 

  • Ranade K, Jorgenson E, Sheu WH, Pei D, Hsiung CA, Chiang FT, Chen YD, Pratt R, Olshen RA, Curb D, Cox DR, Botstein D, Risch N (2002) A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet 70:935–942

    Google Scholar 

  • Rathz DA, Brown KM, Kramer LA, Liggett SB (2002) Amino acid 49 polymorphisms of the human beta1-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol 39:155–160

    Google Scholar 

  • Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D (2000) Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 342:541–549

    Article  CAS  PubMed  Google Scholar 

  • Shibata K, Hirasawa A, Moriyama N, Kawabe K, Ogawa S, Tsujimoto G (1996) Alpha 1a-adrenoceptor polymorphism: pharmacological characterization and association with benign prostatic hypertrophy. Br J Pharmacol 118:1403–1408

    CAS  PubMed  Google Scholar 

  • Small KM, Liggett SB (2001) Identification and functional characterization of alpha(2)-adrenoceptor polymorphisms. Trends Pharmacol Sci 22:471–477

    Google Scholar 

  • Small KM, Forbes SL, Brown KM, Liggett SB (2000a) An asn to lys polymorphism in the third intracellular loop of the human alpha 2A-adrenergic receptor imparts enhanced agonist-promoted Gi coupling. J Biol Chem 275:38518–38523

    Article  CAS  PubMed  Google Scholar 

  • Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB (2000b) A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem 275:23059–23064

    Article  CAS  PubMed  Google Scholar 

  • Small KM, Brown KM, Forbes SL, Liggett SB (2001) Polymorphic deletion of three intracellular acidic residues of the alpha 2B-adrenergic receptor decreases G protein-coupled receptor kinase-mediated phosphorylation and desensitization. J Biol Chem 276:4917–4922

    Article  CAS  PubMed  Google Scholar 

  • Small KM, Rathz DA, Liggett SB (2002a) Identification of adrenergic receptor polymorphisms. Methods Enzymol 343:459–475

    Google Scholar 

  • Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB (2002b) Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 347:1135–1142

    Google Scholar 

  • Small KM, McGraw DW, Liggett SB (2003) Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol 43:381–411

    Google Scholar 

  • Tschernko EM, Hofer S, Bieglmayer C, Wisser W, Haider W (1996) Early postoperative stress: video-assisted wedge resection/lobectomy vs conventional axillary thoracotomy. Chest 109:1636–1642

    Google Scholar 

  • Turki J, Lorenz JN, Green SA, Donnelly ET, Jacinto M, Liggett SB (1996) Myocardial signaling defects and impaired cardiac function of a human beta 2-adrenergic receptor polymorphism expressed in transgenic mice. Proc Natl Acad Sci U S A 93:10483–10488

    Google Scholar 

  • Wagoner LE, Craft LL, Singh B, Suresh DP, Zengel PW, McGuire N, Abraham WT, Chenier TC, Dorn GW II, Liggett SB (2000) Polymorphisms of the beta(2)-adrenergic receptor determine exercise capacity in patients with heart failure. Circ Res 86:834–840

    Google Scholar 

  • Wagoner LE, Craft LL, Zengel P, McGuire N, Rathz DA, Dorn GW II, Liggett SB (2002) Polymorphisms of the beta1-adrenergic receptor predict exercise capacity in heart failure. Am Heart J 144:840–846

    Google Scholar 

  • Winker R, Rüdiger H (2001) Orthostatische Intoleranz - Bedeutung in der Arbeitsmedizin. ASU 36:325–331

    Google Scholar 

  • Winker R, Barth A, Dorner W, Mayr O, Pilger A, Ivancsits S, Ponocny I, Heider A, Wolf C, Rudiger HW (2003) Diagnostic management of orthostatic intolerance in the workplace. Int Arch Occup Environ Health 76:143–150

    Google Scholar 

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Acknowledgements

We are indebted to Dr Stephen B. Liggett (genotyping) and to Mr Guy Knibbeler (graphical assistance) for their contributions to this study.

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Correspondence to R. Winker.

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Winker, R., Barth, A., Valic, E. et al. Functional adrenergic receptor polymorphisms and idiopathic orthostatic intolerance. Int Arch Occup Environ Health 78, 171–177 (2005). https://doi.org/10.1007/s00420-005-0605-y

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