Beta-adrenergic receptor polymorphisms: A basis for pharmacogenetics

Efstratios K. Theofilogiannakos, Konstantinos Dean Boudoulas, Brian E. Gawronski, Taimour Y. Langaee, Timotheos G. Kelpis, Antonios A. Pitsis, Julie A. Johnson, Harisios Boudoulas

Agios Lukas Hospital, Thessaloniki, Greece.
The Ohio State University, Division of Cardiovascular Medicine, Columbus, Ohio, USA.
The Ohio State University, Division of Cardiovascular Medicine, Columbus, Ohio, USA;Aristotelian University of Thessaloniki, Thessaloniki, Greece.
University of Florida, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, Gainesville, Florida, USA.

DOI: 10.4236/wjcd.2013.36063                

Abstract

Aims: Polymorphisms of the β-adrenergic receptor, the frequency of which may differ in ethnic groups, alters β-receptor function. The aim of this study was to elucidate the frequency of β1 and β2-adrenergic receptor polymorphisms in healthy Greeks and to compare with those of Caucasian European (Euro) and African American (AA) origin. Methods: Ninety-nine individuals with a median age of 63 without clinical evidence of any disease were studied. Blood samples were obtained and common β1 and β2-adrenergic receptor polymorphisms that change the en-coded amino acid were determined by pyrosequencing. Results: The most common β1-adrenergic receptor polymorphism in Greeks is nucleotide substitution cytosine for guanine at position 1165 (1165 C/G) resulting in amino acid substitution arginine for glycine at position 389 (389 Arg/Gly) with a minor allele frequency of 28% (Euro 27%, AA 42%); this polymorphism increases the sensitivity of the β1-receptor. The most common β2-adrenergic receptor polymorphism in Greeks is the nucleotide substitution guanine for adenine at position 46 (46 G/A) resulting in amino acid substitution glycine for arginine at position 16 (16 Gly/Arg) with a minor allele frequency of 38% (Euro 41%, AA 50%); this polymerphism facilitates receptor down-regulation during chronic adrenergic stimulation. Conclusion: The most common β1 and β2-adrenergic receptor polymorphisms in the Greek population are similar to those of other European ancestry, and less common than in those of African origin indicating variability in ethnic groups. This information provides insight into common polymorphisms that may assist in optimizing β-antagonist and agonist therapy.

Keywords

β₁ and β₂-Adrenergic Receptor; Polymorphism; Ethnic Variability

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Brunton, L.L. (2011) Goodman and Gilman’s the pathophysiologic basis of therapeutics. 12th Edition, The McGraw-Hill Companies, Inc., New York.
[2]	Johnson, J.A. and Liggett, S.B. (2011) Cardiovascular pharmacogenomics of adrenergic receptor signaling: Clinical implications and future directions. Clinical Pharmacology & Therapeutics, 89, 366-378. doi:10.1038/clpt.2010.315
[3]	Shin, J. and Johnson, J.A. (2007) Pharmacogenetics of beta-blockers. Pharmacotherapy, 27, 874-887. doi:10.1592/phco.27.6.874
[4]	Johnson, J.A., Zineh, I., Puckett, B.J., McGorray, S.P., Yarandi, H.N. and Pauly, D.F. (2003) Beta1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clinical Pharmacology & Therapeutics, 74, 44-52. doi:10.1016/S0009-9236(03)00068-7
[5]	Stakos, D.A. and Boudoulas, H. (2002) Pharmacogenetics and pharmacogenomics in cardiology. The Hellenic Journal of Cardiology, 43, 1-15.
[6]	Papatheodorou, A., Makrythanasis, P., Kaliakatsos, M., Dimakou, A., Orfanidou, D., Roussos, C., et al. (2010) Development of novel microarray methodology for the study of mutations in the SERPINA1 and ADRB2 genes—their association with obstructive pulmonary disease and disseminated bronchiectasis in Greek patients. Clinical Biochemistry, 43, 43-50. doi:10.1016/j.clinbiochem.2009.08.026
[7]	Shin, J., Lobmeyer, M.T., Gong, Y., Zineh, I., Langaee, T.Y., Yarandi, H., et al. (2007) Relation of beta(2)-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure. American Journal of Cardiology, 99, 250-255. doi:10.1016/j.amjcard.2006.08.020
[8]	Boudoulas, H., Reynolds, J.C., Mazzaferri, E. and Wooley, C.F. (1983) Mitral valve prolapse syndrome: The effect of adrenergic stimulation. Journal of the American College of Cardiology, 2, 638-644. doi:10.1016/S0735-1097(83)80303-9
[9]	Voora, D. and Ginsburg, G.S. (2012) Clinical application of cardiovascular pharmacogenetics. Journal of the American College of Cardiology, 60, 9-20. doi:10.1016/j.jacc.2012.01.067
[10]	Salari, K., Watkins, H. and Ashley, E.A. (2012) Personalized medicine: Hope or hype? The European Heart Journal, 33, 1564-1570. doi:10.1093/eurheartj/ehs112
[11]	Diogenis Laertios, “Pythagoras,” Vitae Philosophoru VIII, 8.33.6-8.34.6.
[12]	Humma, L.M., Puckett, B.J., Richasdson, H.E., Terra, S.G., Andrisin, T.E., Lejeune, B.L., et al. (2001) Effects of beta1-adrenergic polymorphisms on resting hemodynamics in patients undergoing diagnostic testing for ischemia. American Journal of Cardiology, 88, 1034-1037. doi:10.1016/S0002-9149(01)01986-5
[13]	Peng, Y., Xue, H., Luo, L., Yao, W. and Li, R. (2009) Polymorphisms of the adrenergic receptor gene are associated with essential hypertension in Chinese. Clinical Chemistry and Laboratory Medicine, 47, 1227-1231. doi:10.1515/CCLM.2009.276
[14]	Kaye, D.M., Smirk, B., Williams, C., Jennings, G., Esler, M. and Holst, D. (2003) Beta-adrenoreceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics, 13, 379-382. doi:10.1097/00008571-200307000-00002
[15]	Borjesson, M., Magnusson, Y., Hjalmarson, A. and Anderson, B. (2000) A novel polymorphism in the gene coding for the beta 1-adrenergic receptor is associated with survival in patients with heart failure. The European Heart Journal, 21, 1853-1858. doi:10.1053/euhj.1999.1994
[16]	Biolo, A., Clausell, N., Santos, K.G., Salvaro, R., AshtonProlla, P., Borges, A., et al. (2008) Impact of beta1-adrenergic receptor polymorphisms on susceptibility to heart failure, arrhythmogenesis, prognosis, and response to betablocker therapy. American Journal of Cardiology, 102, 726-732. doi:10.1016/j.amjcard.2008.04.070
[17]	Rydén, L., Ariniego, R., Arnman, K., Herlitz, J., Hjalmarson, A., Holmberg, S., et al. (1983) A double-blind trial of metoprolol in acute myocardial infarction. Effects on ventricular tachyarrhythmias. The New England Journal of Medicine, 308, 614-618. doi:10.1056/NEJM198303173081102
[18]	Roqué, F., Amuchastegui, L.M., Lopez Morillos, M.A., Mon, G.A., Girotti, A.L., Drajer, S., et al. (1987) Beneficial effects of timolol on infarct size and late ventricular tachycardia in patients with acute myocardial infarction. Circulation, 76, 610-617. doi:10.1161/01.CIR.76.3.610
[19]	Boudoulas, H. (1990) Therapeutic interventions which may improve survival in patients with coronary artery disease. Acta Cardiologica, 45, 477-487.
[20]	The MIAMI Trial Research Group (1985) Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. The European Heart Journal, 6, 199-226.
[21]	Hjalmarson, A., Elmfeldt, D., Herlitz, J., Holmberg, S., Málek, I., Nyberg, G., et al. (1981) Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet, 2, 823-827. doi:10.1016/S0140-6736(81)91101-6
[22]	Hjalmarson, A., Herlitz, J., Holmberg, S., Rydén, L., Swedberg, K., Vedin, A., et al. (1983) The Goteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation, 67, I26-I32.
[23]	Hjalmarson, A. and Olsson, G. (1991) Myocardial infarction. Effects of beta-blockade. Circulation, 84, VI101-VI107.
[24]	Chen, Z.M., Pan, H.C., Chen, Y.P., Peto, R., Collins, R., Jiang, L.X., et al. (2005) COMMIT (ClOpidogrel and Me-toprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet, 366, 1622-1632. doi:10.1016/S0140-6736(05)67661-1
[25]	Johnson, J.A. (2008) Ethnic differences in cardiovascular drug response: Potential contribution of pharmacogenetics. Circulation, 23, 1383-1393. doi:10.1161/CIRCULATIONAHA.107.704023
[26]	Suonsyrja, T., Donner, K., Hannila-Handelberg, T., Fodstad, H., Kontula, K. and Hiltunen, T.P. (2010) Common genetic variation of beta1and beta2-adrenergic receptor and response to four classes of antihypertensive treatment. Pharmacogenetics and Genomics, 20, 342-345. doi:10.1097/FPC.0b013e328338e1b8
[27]	Parvez, B., Chopra, N., Rowan, S., Vaglio, J.C., Muhammad, R., Roden, D.M., et al. (2012) A common 1-adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation. Journal of the American College of Cardiology, 59, 49-56. doi:10.1016/j.jacc.2011.08.061
[28]	Cresci, S., Dorn II, G.W., Jones, P.G., Beitelshees, A.L., Li, A.Y., Lenzini, P.A., et al. (2012) Adrenergic-pathway gene influence beta-blocker-related outcomes after acute coronary syndrome in a race-specific manner. Journal of the American College of Cardiology, 60, 898-907. doi:10.1016/j.jacc.2012.02.051
[29]	Puri, R., Liew, G.Y.H., Nicholls, S.J., Nelson, A.J., Leong, D.P., Carbone, A., et al. (2012) Coronary 2-adrenoreceptors mediate endothelium-dependent vasoreactivity in humans: Novel insights from an in vivo intravascular ultrasound study. The European Heart Journal, 33, 495-504. doi:10.1093/eurheartj/ehr359
[30]	Evans, W.E. and Relling, M.V. (1999) Pharmacogenetics: Translating functional genomics into rational therapeutics. Science, 286, 487-91. doi:10.1126/science.286.5439.487
[31]	Wachter, S.B. and Gilbert, E.M. (2012) Beta-adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application. Cardiology, 122, 104-112. doi:10.1159/000339271
[32]	Roden, D.M., Altman, R.B., Benowitz, N.L., et al. (2006) Pharmacogenomics: Challenges and opportunities. Annals of Internal Medicine, 145, 749-757. doi:10.7326/0003-4819-145-10-200611210-00007