Beta-Receptor Genetic Polymorphisms and Impact on Clinical Outcomes

Summary:

The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). Although many SNPs have been discovered in beta-receptors, few are clinically relevant. There are 2 clinically relevant SNPs for beta 1-receptors (Ser49Gly and Arg389Gly), 4 for beta 2-receptors (Cys-19Arg, Arg16Gly, Gln27Glu, Thr164Ile), and 1 for beta 3-receptors (Trp64Arg)
Although SNPs may not directly cause disease, they appear to be risk factors for and modifiers of disease. These SNPs also have the potential to alter response to medications when polymorphisms affect drug targets (e.g., beta-receptors), especially with regards to adrenergic agonists and antagonists.
Understanding the functional consequences of specific polymorphisms will lead to the individualization of drug therapy based on a patient's genetic makeup and could explain distinct inter-individual variability.
There is great need for large, randomized, controlled trials to evaluate the conflicting data related to ß-receptor SNPs and related differences regarding disease and medications. These trials should by multinational and include a variety of ethnicities. Future evidence will promote the practice of personalized medicine.

Author: Adriane B. Marino, PharmD
Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editors: Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP and Sabrina W. Cole, PharmD, BCPS
Last Reviewed: August 2015

Explanation
Numerous genetic polymorphisms of adrenergic receptors have been identified. The most common genetic variants in humans are referred to as single nucleotide polymorphisms (SNPs). Although many SNPs have been discovered in beta-receptors, few are clinically relevant. There are 2 clinically relevant SNPs for the beta 1-receptors (Ser49Gly and Arg389Gly), 4 for the beta 2-receptors (Cys-19Arg, Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the beta 3-receptors (Trp64Arg).1 Frequently, polymorphisms occur in certain combinations labeled haplotypes. Results are controversial, but there is data to support a relationship between ß-receptor SNPs and outcomes. Understanding the functional consequences of specific polymorphisms leads to the individualization of drug therapy based on a patient's genetic makeup and could explain distinct inter-individual variability. The table below summarizes clinically relevant ß-receptor polymorphisms, with an emphasis on the specific location of genetic mutations and the populations primarily affected.2-10 ß1- receptor polymorphisms The most clinically relevant SNPs for ß1-receptors include Ser49Gly and Arg389Gly. Ser49Gly leads to impaired down-regulation of the beta-1 receptor, and Arg389Gly leads to higher signal transduction.11, 12 Therefore, carriers of either variant have enhanced ß1-receptor activity and are more sensitive to beta-blocker therapy. ß2-receptor polymorphisms The most clinically relevant SNPs for ß2-receptors include Arg16Gly, Gln27Glu, and Cys-19Arg. Receptors with the Gly16 variant have enhanced down-regulation of the beta-2 receptor. In contrast, receptors with the Glu27 variant appear resistant to down-regulation.3 Finally, the Cys-19 variant is associated with increased beta-2 receptor expression.8 These polymorphisms of beta-receptors alter the sensitivity of patients to drug therapy, changing the pharmacodynamics of drug response. Table 2 discusses clinical outcomes as they relate to each ß-receptor polymorphism. Although the known and studied polymorphisms of beta-receptors do not seem to produce disease, it is evident these genetic mutations can play a role in risk for disease and disease modification. Moreover, the polymorphisms may change how a patient responds to drug therapy, specifically beta-agonist and antagonist therapies. Such genotypic analysis can help guide drug selection and dosing. Although somewhat controversial, the evidence from research continues to improve understanding of beta-receptor signaling. There is a great need for large, randomized, controlled trials to evaluate the conflicting data related to beta-receptor SNPs and related differences regarding disease and medications. Recent studies suggest that analysis of haplotype may be more beneficial than analysis of individual polymorphisms in relation to drug response. These trials should by multinational and include a variety of ethnicities. Future pharmacogenetic evidence will promote the practice of personalized medicine. References: von Homeyer P, Schwinn D. Pharmacogenomics of ß-adrenergic Receptor Physiology and Response to ß-Blockade. Anesth Analg 2011 Dec;113(6):1305-18. Epub 2011 Sep 29. Moore JD, Mason DA, Green SA, Hsu J, Liggett, SB. Racial differences in the frequencies of cardiac ß1-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum Mutat 1999;14,271. Small KM, McGraw DW, Liggett SB. Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol 2003;43: 381−411. Kirstein SL, Insel PA. Autonomic nervous system pharmacogenomics: a progress report. Pharmacol Rev 2004;56,31−52. Taylor MR, Bristow MR. The emerging pharmacogenomics of the β-adrenergic receptors. Congest Heart Fail 2004;10, 281−8. Pacanowski MA, Johnson JA. PharmGKB submission update: IX. ADRB1 gene summary. Pharmacol Rev 2007;59,2−4. Xie HG, Dishy V, Sofowora G, Kim RB, Landau R, Smiley RM, et al. Arg389Gly β1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo. Pharmacogenetics 2001; 11, 191−7. McGraw DW, Forbes SL, Kramer LA, Liggett SB. Polymorphisms of the 5' leader cistron of the human beta 2- adrenergic receptor regulate receptor expression J Clin Invest 1998;102:1927-32. Xie HG, Stein CM, Kim RB, Xiao ZS, He N, Zhou HH, et al. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian, and Chinese individuals. Pharmacogenetics 1999; 9, 511−16. Maxwell TJ, Ameyaw MM, Pritchard S, Thornton N, Folayan G, Githanga J, et al. Beta-2 adrenergic receptor genotypes and haplotypes in different ethnic groups. Int J Mol Med 2005;16, 573−80. Rathz DA, Brown KM, Kramer LA, Liggett SB. Amino acid 49 polymorphisms of the human beta1-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol 2009; 39, 155-60. Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 2009; 274,12670-4. Biolo A, Clausell N, Santos KG, Salvaro R, Ashton-Prolla P, Borges A, Rohde LE. Impact of beta-1 adrenergic receptor polymorphisms on susceptibility to heart failure, arrhythmogenesis, prognosis, and response to beta-blocker therapy. Am J Cardiol 2008;102:726-32. Leineweber K, Bogedain P, Wolf C, Wagner S, Weber M, Jakob HG, Heusch G, Philipp T, Brodde OE. In patients chronically treated with metoprolol, the demand of inotropic catecholamine support after coronary artery bypass grafting is determined by the Arg389Gly-beta 1-adrenoceptor polymorphism. Naunyn Schmiedebergs Arch Pharmacol 2007; 375:303-9. Barbato E, Berger A, Delrue L, Van Durme F, Manoharan G, Boussy T, Heyndrickx GR, De Bruyne B, Ciampi Q, Vanderheyden M, Wijns W, Bartunek J. GLU-27 variant of beta 2- adrenergic receptor polymorphisms is an independent risk factor for coronary atherosclerotic disease. Atherosclerosis 2007;194:e80-6. Lanfear DE, Jones PG, Marsh S, Cresci S, McLeod HL, Spertus JA. Beta-2 adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome. JAMA 2005;294:1526-33. Metra M, Covolo L, Pezzali N, Zaca V, Bugatti S, Lombardi C, Bettari L, Romeo A, Gelatti U, Giubbini R, Donato F, Dei Cas L. Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure. Cardiovasc Drugs Ther 2010;24:49-60. Liggett SB, Wagoner LE, Craft LL, Hornung RW, Hoit BD, McIntosh TC, Walsh RA. The Ile164 beta 2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998;102:1534-9. Turki J, Lorenz JN, Green SA, Donnelly ET, Jacinto M, Liggett SB. Myocardial signaling defects and impaired cardiac function of a human beta 2-adrenergic receptor polymorphism expressed in transgenic mice. Proc Natl Acad Sci USA 1996;93:10483-8. Petersen M, Andersen JT, Hjelvang BR, Broedbaek K, Afzal S, Nyegaard M, Borglum AD, Stender S, Kober L, Torp Pedersen C, Poulsen HE. Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart failure patients. Br J Clin Pharmacol 2011;71:556-65. Turki J, Pak J, Green SA, Martin RJ, Liggett SB. Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and non-nocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest 1995;95:1635-41. Weir TD, Mallek N, Sandford AJ, Bai TR, Awadh N, Fitzgerald JM, Cockcroft D, James A, Liggett SB, Pare PD. Beta 2-adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma. Am J Respir Crit Care Med 1998;158:787-91. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, Kraft M, Kunselman SJ, Lazarus SC, Lemanske RF Jr, Liggett SB, Martin RJ, Mitra N, Peters SP, Silverman E, Sorkness CA, Szefler SJ, Wechsler ME, Weiss ST, Drazen JM. Use of regularly scheduled albuterol treatment in asthma: genotype stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364:1505-12. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr, Boushey HA, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, DiMango E, Kraft M, Leone F, Martin RJ, Peters SP, Szefler SJ, Liu W, Israel E. Beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006;173:519-26. Carroll CL, Stoltz P, Schramm CM, Zucker AR. Beta 2- adrenergic receptor polymorphisms affect response to treatment in children with severe asthma exacerbations. Chest 2009;135:1186-92. Martin AC, Zhang G, Rueter K, Khoo SK, Bizzintino J, Hayden CM, Geelhoed GC, Goldblatt J, Laing IA, Le Souef PN. Beta 2-adrenoceptor polymorphisms predict response to beta 2-agonists in children with acute asthma. J Asthma 2008;45:383-8. Iwamoto Y, Ohishi M, Yuan M, Tatara Y, Kato N, Takeya Y,Onishi M, Maekawa Y, Kamide K, Rakugi H. Beta-adrenergic receptor gene polymorphism is a genetic risk factor for cardiovascular disease: a cohort study with hypertensive patients. Hypertens Res 2011;34:573-7. 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;139:537-42. Cockcroft JR, Gazis AG, Cross DJ, Wheatley A, Dewar J, Hall IP, Noon JP. Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension 2000;36:371-5. Kotanko P, Binder A, Tasker J, DeFreitas P, Kamdar S, Clark AJL, Skrabal F, Caulfield M. Essential hypertension in African Caribbean associates with a variant of the beta(2)-adrenoceptor. Hypertension 1997;30:773-6. Nonen S, Yamamoto I, Liu JM, Maeda M, Motomura T, Igarashi T, Fujio Y, Azuma J. Adrenergic beta (1) receptor polymorphism (Ser49Gly) is associated with obesity in type II diabetic patients. Biol Pharm Bull 2008;31:295-8. Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L, Arner P. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest 1997;100:3005-13. Hoffstedt J, Iliadou A, Pedersen NL, Schalling M, Arner P. The effect of the beta (2) adrenoceptor gene Thr164Ile polymorphism on human adipose tissue lipolytic function. Brit J Pharmacol 2001;133:708-12. Yamada K, Ishiyama-Shigemoto S, Ichikawa F, Yuan XH, Koyanagi A, Koyama W, Nonaka K. Polymorphism in the 5'- leader cistron of the beta (2)-adrenergic receptor gene associated with obesity and type 2 diabetes. J Clin Endocr Metab 1999;84:1754-7. Gjesing AP, Andersen G, Borch-Johnsen K, Jorgensen T, Hansen T, Pedersen O. Association of the beta 3-adrenergic receptor Trp64Arg polymorphism with common metabolic traits: studies of 7605 middle-aged white people. Mol Genet Metab 2008;94:90-7. Widen E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC. Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 1995;333:348-51. Kim NS, Lee IO, Lee MK, Lim SH, Choi YS, Kong MH. The effects of beta 2 adrenoceptor gene polymorphisms on vasopressor response during laryngoscopy and tracheal intubation. Anaesthesia 2002;57:227-32. Smiley RM, Blouin JL, Negron M, Landau R. Beta 2- adrenoceptor genotype affects vasopressor requirements during spinal anesthesia for cesarean delivery. Anesthesiology 2006;104:644-50. Zaugg M, Bestmann L, Wacker J, Lucchinetti E, Boltres A, Schulz C, Hersberger M, Kalin G, Furrer L, Hofer C, Blumenthal S, Muller A, Zollinger A, Spahn DR, Borgeat A. Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: a double-blinded, placebo-controlled, multicenter trial with 1 year follow-up. Anesthesiology 2007;107:33-44.

Explanation

Numerous genetic polymorphisms of adrenergic receptors have been identified. The most common genetic variants in humans are referred to as single nucleotide polymorphisms (SNPs). Although many SNPs have been discovered in beta-receptors, few are clinically relevant. There are 2 clinically relevant SNPs for the beta 1-receptors (Ser49Gly and Arg389Gly), 4 for the beta 2-receptors (Cys-19Arg, Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the beta 3-receptors (Trp64Arg).1 Frequently, polymorphisms occur in certain combinations labeled haplotypes. Results are controversial, but there is data to support a relationship between ß-receptor SNPs and outcomes. Understanding the functional consequences of specific polymorphisms leads to the individualization of drug therapy based on a patient's genetic makeup and could explain distinct inter-individual variability.

The table below summarizes clinically relevant ß-receptor polymorphisms, with an emphasis on the specific location of genetic mutations and the populations primarily affected.2-10

ß1- receptor polymorphisms
The most clinically relevant SNPs for ß1-receptors include Ser49Gly and Arg389Gly. Ser49Gly leads to impaired down-regulation of the beta-1 receptor, and Arg389Gly leads to higher signal transduction.11, 12 Therefore, carriers of either variant have enhanced ß1-receptor activity and are more sensitive to beta-blocker therapy.

ß2-receptor polymorphisms

The most clinically relevant SNPs for ß2-receptors include Arg16Gly, Gln27Glu, and Cys-19Arg. Receptors with the Gly16 variant have enhanced down-regulation of the beta-2 receptor. In contrast, receptors with the Glu27 variant appear resistant to down-regulation.3 Finally, the Cys-19 variant is associated with increased beta-2 receptor expression.8

These polymorphisms of beta-receptors alter the sensitivity of patients to drug therapy, changing the pharmacodynamics of drug response. Table 2 discusses clinical outcomes as they relate to each ß-receptor polymorphism.

Although the known and studied polymorphisms of beta-receptors do not seem to produce disease, it is evident these genetic mutations can play a role in risk for disease and disease modification. Moreover, the polymorphisms may change how a patient responds to drug therapy, specifically beta-agonist and antagonist therapies. Such genotypic analysis can help guide drug selection and dosing. Although somewhat controversial, the evidence from research continues to improve understanding of beta-receptor signaling. There is a great need for large, randomized, controlled trials to evaluate the conflicting data related to beta-receptor SNPs and related differences regarding disease and medications. Recent studies suggest that analysis of haplotype may be more beneficial than analysis of individual polymorphisms in relation to drug response. These trials should by multinational and include a variety of ethnicities. Future pharmacogenetic evidence will promote the practice of personalized medicine.

References:
1. von Homeyer P, Schwinn D. Pharmacogenomics of ß-adrenergic Receptor Physiology and Response to ß-Blockade. Anesth Analg 2011 Dec;113(6):1305-18. Epub 2011 Sep 29.
2. Moore JD, Mason DA, Green SA, Hsu J, Liggett, SB. Racial differences in the frequencies of cardiac ß1-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum Mutat 1999;14,271.
3. Small KM, McGraw DW, Liggett SB. Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol 2003;43: 381−411.
4. Kirstein SL, Insel PA. Autonomic nervous system pharmacogenomics: a progress report. Pharmacol Rev 2004;56,31−52.
5. Taylor MR, Bristow MR. The emerging pharmacogenomics of the β-adrenergic receptors. Congest Heart Fail 2004;10, 281−8.
6. Pacanowski MA, Johnson JA. PharmGKB submission update: IX. ADRB1 gene summary. Pharmacol Rev 2007;59,2−4.
7. Xie HG, Dishy V, Sofowora G, Kim RB, Landau R, Smiley RM, et al. Arg389Gly β1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo. Pharmacogenetics 2001; 11, 191−7.
8. McGraw DW, Forbes SL, Kramer LA, Liggett SB. Polymorphisms of the 5' leader cistron of the human beta 2- adrenergic receptor regulate receptor expression J Clin Invest 1998;102:1927-32.
9. Xie HG, Stein CM, Kim RB, Xiao ZS, He N, Zhou HH, et al. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian, and Chinese individuals. Pharmacogenetics 1999; 9, 511−16.
10. Maxwell TJ, Ameyaw MM, Pritchard S, Thornton N, Folayan G, Githanga J, et al. Beta-2 adrenergic receptor genotypes and haplotypes in different ethnic groups. Int J Mol Med 2005;16, 573−80.
11. Rathz DA, Brown KM, Kramer LA, Liggett SB. Amino acid 49 polymorphisms of the human beta1-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol 2009; 39, 155-60.
12. Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 2009; 274,12670-4.
13. Biolo A, Clausell N, Santos KG, Salvaro R, Ashton-Prolla P, Borges A, Rohde LE. Impact of beta-1 adrenergic receptor polymorphisms on susceptibility to heart failure, arrhythmogenesis, prognosis, and response to beta-blocker therapy. Am J Cardiol 2008;102:726-32.
14. Leineweber K, Bogedain P, Wolf C, Wagner S, Weber M, Jakob HG, Heusch G, Philipp T, Brodde OE. In patients chronically treated with metoprolol, the demand of inotropic catecholamine support after coronary artery bypass grafting is determined by the Arg389Gly-beta 1-adrenoceptor polymorphism. Naunyn Schmiedebergs Arch Pharmacol 2007; 375:303-9.
15. Barbato E, Berger A, Delrue L, Van Durme F, Manoharan G, Boussy T, Heyndrickx GR, De Bruyne B, Ciampi Q, Vanderheyden M, Wijns W, Bartunek J. GLU-27 variant of beta 2- adrenergic receptor polymorphisms is an independent risk factor for coronary atherosclerotic disease. Atherosclerosis 2007;194:e80-6.
16. Lanfear DE, Jones PG, Marsh S, Cresci S, McLeod HL, Spertus JA. Beta-2 adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome. JAMA 2005;294:1526-33.
17. Metra M, Covolo L, Pezzali N, Zaca V, Bugatti S, Lombardi C, Bettari L, Romeo A, Gelatti U, Giubbini R, Donato F, Dei Cas L. Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure. Cardiovasc Drugs Ther 2010;24:49-60.
18. Liggett SB, Wagoner LE, Craft LL, Hornung RW, Hoit BD, McIntosh TC, Walsh RA. The Ile164 beta 2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998;102:1534-9.
19. Turki J, Lorenz JN, Green SA, Donnelly ET, Jacinto M, Liggett SB. Myocardial signaling defects and impaired cardiac function of a human beta 2-adrenergic receptor polymorphism expressed in transgenic mice. Proc Natl Acad Sci USA 1996;93:10483-8.
20. Petersen M, Andersen JT, Hjelvang BR, Broedbaek K, Afzal S, Nyegaard M, Borglum AD, Stender S, Kober L, Torp Pedersen C, Poulsen HE. Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart failure patients. Br J Clin Pharmacol 2011;71:556-65.
21. Turki J, Pak J, Green SA, Martin RJ, Liggett SB. Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and non-nocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest 1995;95:1635-41.
22. Weir TD, Mallek N, Sandford AJ, Bai TR, Awadh N, Fitzgerald JM, Cockcroft D, James A, Liggett SB, Pare PD. Beta 2-adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma. Am J Respir Crit Care Med 1998;158:787-91.
23. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, Kraft M, Kunselman SJ, Lazarus SC, Lemanske RF Jr, Liggett SB, Martin RJ, Mitra N, Peters SP, Silverman E, Sorkness CA, Szefler SJ, Wechsler ME, Weiss ST, Drazen JM. Use of regularly scheduled albuterol treatment in asthma: genotype stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364:1505-12.
24. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr, Boushey HA, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, DiMango E, Kraft M, Leone F, Martin RJ, Peters SP, Szefler SJ, Liu W, Israel E. Beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006;173:519-26.
25. Carroll CL, Stoltz P, Schramm CM, Zucker AR. Beta 2- adrenergic receptor polymorphisms affect response to treatment in children with severe asthma exacerbations. Chest 2009;135:1186-92.
26. Martin AC, Zhang G, Rueter K, Khoo SK, Bizzintino J, Hayden CM, Geelhoed GC, Goldblatt J, Laing IA, Le Souef PN. Beta 2-adrenoceptor polymorphisms predict response to beta 2-agonists in children with acute asthma. J Asthma 2008;45:383-8.
27. Iwamoto Y, Ohishi M, Yuan M, Tatara Y, Kato N, Takeya Y,Onishi M, Maekawa Y, Kamide K, Rakugi H. Beta-adrenergic receptor gene polymorphism is a genetic risk factor for cardiovascular disease: a cohort study with hypertensive patients. Hypertens Res 2011;34:573-7.
28. 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;139:537-42.
29. Cockcroft JR, Gazis AG, Cross DJ, Wheatley A, Dewar J, Hall IP, Noon JP. Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension 2000;36:371-5.
30. Kotanko P, Binder A, Tasker J, DeFreitas P, Kamdar S, Clark AJL, Skrabal F, Caulfield M. Essential hypertension in African Caribbean associates with a variant of the beta(2)-adrenoceptor. Hypertension 1997;30:773-6.
31. Nonen S, Yamamoto I, Liu JM, Maeda M, Motomura T, Igarashi T, Fujio Y, Azuma J. Adrenergic beta (1) receptor polymorphism (Ser49Gly) is associated with obesity in type II diabetic patients. Biol Pharm Bull 2008;31:295-8.
32. Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L, Arner P. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest 1997;100:3005-13.
33. Hoffstedt J, Iliadou A, Pedersen NL, Schalling M, Arner P. The effect of the beta (2) adrenoceptor gene Thr164Ile polymorphism on human adipose tissue lipolytic function. Brit J Pharmacol 2001;133:708-12.
34. Yamada K, Ishiyama-Shigemoto S, Ichikawa F, Yuan XH, Koyanagi A, Koyama W, Nonaka K. Polymorphism in the 5'- leader cistron of the beta (2)-adrenergic receptor gene associated with obesity and type 2 diabetes. J Clin Endocr Metab 1999;84:1754-7.
35. Gjesing AP, Andersen G, Borch-Johnsen K, Jorgensen T, Hansen T, Pedersen O. Association of the beta 3-adrenergic receptor Trp64Arg polymorphism with common metabolic traits: studies of 7605 middle-aged white people. Mol Genet Metab 2008;94:90-7.
36. Widen E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC. Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 1995;333:348-51.
37. Kim NS, Lee IO, Lee MK, Lim SH, Choi YS, Kong MH. The effects of beta 2 adrenoceptor gene polymorphisms on vasopressor response during laryngoscopy and tracheal intubation. Anaesthesia 2002;57:227-32.
38. Smiley RM, Blouin JL, Negron M, Landau R. Beta 2- adrenoceptor genotype affects vasopressor requirements during spinal anesthesia for cesarean delivery. Anesthesiology 2006;104:644-50.
39. Zaugg M, Bestmann L, Wacker J, Lucchinetti E, Boltres A, Schulz C, Hersberger M, Kalin G, Furrer L, Hofer C, Blumenthal S, Muller A, Zollinger A, Spahn DR, Borgeat A. Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: a double-blinded, placebo-controlled, multicenter trial with 1 year follow-up. Anesthesiology 2007;107:33-44.

MESH Terms & Keywords
Beta receptor polymorphism, polymorphisms beta receptor, beta 1 receptor polymorphisms, beta 1 receptor SNP, beta 2 polymorphisms, beta 2 receptor SNP, beta receptor variants, beta 1 receptor variants, beta 2 receptor variants, Ser49Gly, Arg389Gly

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Beta-Receptor Genetic Polymorphisms and Impact on Clinical Outcomes

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