Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers

The Pharmacogenomics Journal volume 22, pages 62–68 (2022)Cite this article

Subjects

Abstract

Single nucleotide polymorphisms (SNPs) have been associated with differential beta-blocker (BB) effects on heart rate, blood pressure, and left ventricular ejection fraction in various patient populations. This study aimed to determine if SNPs previously associated with BB response are also associated with differential survival in heart failure (HF) patients receiving BBs. HF patient data were derived from electronic health records and the Social Security Death Index. Associations and interactions between BB dose, SNP genotype, and the outcome of death were assessed using a Cox proportional-hazard model adjusting for covariates known to be associated with differential survival in HF patients. Two SNPs, ADRB1 Arg389Gly and ADRB2 Glu27Gln, displayed significant interactions (Pint = 0.043 and Pint = 0.017, respectively) with BB dose and their association with mortality. Our study suggests that ADRB2 27Glu and ADRB1 389Arg may confer a larger survival benefit with higher BB doses in patients with HF.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Adjusted Kaplan–Meier curves for Gln27Glu (in ADRB2) genotype associations with all-cause mortality in the PGx comprehensive model by BB dose levels.
Fig. 2: Adjusted Kaplan–Meier curves for Arg389Gly (in ADRB1) genotype associations with all-cause mortality in the PGx comprehensive model, by BB dose levels.
Fig. 3: Adjusted Kaplan–Meier curves for polygenic response allele associations with all-cause mortality in the PGx comprehensive model, by BB dose levels.

Similar content being viewed by others

References

  1. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart disease and stroke statistics–2021 update: a report from the American Heart Association. Circulation 2021;143:e254–e743.

    Article  Google Scholar 

  2. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007–18.

    Article  Google Scholar 

  3. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54:1747–62.

    Article  CAS  Google Scholar 

  4. Hollenberg SM, Warner Stevenson L, Ahmad T, Amin VJ, Bozkurt B, Butler J, et al. ACC expert consensus decision pathway on risk assessment, management, and clinical trajectory of patients hospitalized with heart failure: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2019;74:1966–2011.

    Article  Google Scholar 

  5. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–e239.

    Article  Google Scholar 

  6. Metra M, Torp-Pedersen C, Swedberg K, Cleland JG, Di Lenarda A, Komajda M, et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial. Eur Heart J. 2005;26:2259–68.

    Article  CAS  Google Scholar 

  7. Lteif C, Arwood MJ, Kansal M, Cavallari LH, Desai AA, Duarte JD. Beta-blocker dose stratifies mortality risk in a racially diverse heart failure population. J Cardiovasc Pharm. 2020;75:250–8.

    CAS  Google Scholar 

  8. Johnson AE, Hanley-Yanez K, Yancy CW, Taylor AL, Feldman AM, McNamara DM. Adrenergic polymorphisms and survival in African Americans with heart failure: results from A-HeFT. J Card Fail. 2019;25:553–60.

    Article  Google Scholar 

  9. Huang J, Li C, Song Y, Fan X, You L, Tan L, et al. ADRB2 polymorphism Arg16Gly modifies the natural outcome of heart failure and dictates therapeutic response to β-blockers in patients with heart failure. Cell Disco. 2018;4:57.

    Article  Google Scholar 

  10. Thomas CD, Johnson JA. Pharmacogenetic factors affecting β-blocker metabolism and response. Expert Opin Drug Metab Toxicol. 2020;16:953–64.

    Article  CAS  Google Scholar 

  11. Terra SG, Hamilton KK, Pauly DF, Lee CR, Patterson JH, Adams KF, et al. Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. Pharmacogenet Genomics. 2005;15:227–34.

    Article  CAS  Google Scholar 

  12. Terra SG, Pauly DF, Lee CR, Patterson JH, Adams KF, Schofield RS, et al. beta-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure. Clin Pharm Ther. 2005;77:127–37.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Shahin MH, Rouby NE, Conrado DJ, Gonzalez D, Gong Y, Lobmeyer MT, et al. β. J Clin Pharmacol 2019;59:1462–70.

    Article  CAS  Google Scholar 

  15. Sehnert AJ, Daniels SE, Elashoff M, Wingrove JA, Burrow CR, Horne B, et al. Lack of association between adrenergic receptor genotypes and survival in heart failure patients treated with carvedilol or metoprolol. J Am Coll Cardiol. 2008;52:644–51.

    Article  CAS  Google Scholar 

  16. White HL, de Boer RA, Maqbool A, Greenwood D, van Veldhuisen DJ, Cuthbert R, et al. An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. Eur J Heart Fail. 2003;5:463–8.

    Article  CAS  Google Scholar 

  17. TENORMIN® (atenolol) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2011.

  18. TOPROL-XL® (metoprolol succinate) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013.

  19. BYSTOLIC® (nebivolol) [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc; 2011.

  20. COREG® (carvedilol) [package insert]. Research Triangle Park, NC: GlaxoSmithKline, Inc; 1995.

  21. CAPOTEN® (Captopril) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies, Inc; 2012.

  22. VASOTEC® (Enalapril Maleate) [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2011.

  23. ALTACE® (ramipril) [package insert]. New York, NY: Pfizer Inc; 2013.

  24. ZESTRIL® (lisinopril) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2014.

  25. LOTENSIN® (benazepril hydrochloride) [package insert]. Parsippany, NJ: Validus Pharmaceuticals LLC; 2015.

  26. ATACAND® (candesartan cilexetil) [package insert]. Wilmington, DE: AstraZeneca LP; 2015.

  27. COZAAR® (Losartan potassium) [package insert]. Whitehouse Station, NJ: MERCK & CO, INC; 2013.

  28. DIOVAN® (valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2011.

  29. AVAPRO® (irbesartan) [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2016.

  30. LASIX® (furosemide) [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC 2011.

  31. DEMADEX® (torsemide) [package insert]. Somerset, NJ: Meda Pharmaceuticals Inc; 2017.

  32. BUMEX® (bumetanide) [package insert]. Parsippany, NJ: Validus Pharmaceuticals LLC; 2009.

  33. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374:1840–8.

    Article  CAS  Google Scholar 

  34. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;100:2312–8.

    Article  CAS  Google Scholar 

  35. Wikstrand J. MERIT-HF-description of the trial. Basic Res Cardiol. 2000;95:I90–7.

    Article  Google Scholar 

  36. Axiom™ Genome-Wide PanAFR Genotyping Bundle. 2018. https://www.thermofisher.com/order/catalog/product/901788#/901788.

  37. Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48:1284–7.

    Article  CAS  Google Scholar 

  38. Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 2021;590:290–9.

    Article  CAS  Google Scholar 

  39. Shin J, Johnson JA. Beta-blocker pharmacogenetics in heart failure. Heart Fail Rev. 2010;15:187–96.

    Article  CAS  Google Scholar 

  40. Shin J, Johnson JA. Pharmacogenetics of beta-blockers. Pharmacotherapy 2007;27:874–87.

    Article  CAS  Google Scholar 

  41. Alexander M, Grumbach K, Remy L, Rowell R, Massie BM. Congestive heart failure hospitalizations and survival in California: patterns according to race/ethnicity. Am Heart J. 1999;137:919–27.

    Article  CAS  Google Scholar 

  42. Kamimura D, Cain LR, Mentz RJ, White WB, Blaha MJ, DeFilippis AP, et al. Cigarette Smoking and Incident Heart Failure: Insights From the Jackson Heart Study. Circulation 2018;137:2572–82.

    Article  Google Scholar 

  43. Fowler MB, Lottes SR, Nelson JJ, Lukas MA, Gilbert EM, Greenberg B, et al. Beta-blocker dosing in community-based treatment of heart failure. Am Heart J. 2007;153:1029–36.

    Article  CAS  Google Scholar 

  44. Greene SJ, DeVore AD, Sheng S, Fonarow GC, Butler J, Califf RM, et al. Representativeness of a heart failure trial by race and sex: results from ASCEND-HF and GWTG-HF. JACC Heart Fail. 2019;7:980–92.

    Article  Google Scholar 

  45. Hess KR. Graphical methods for assessing violations of the proportional hazards assumption in Cox regression. Stat Med. 1995;14:1707–23.

    Article  CAS  Google Scholar 

  46. Fox JWS Fox J, W S, Cox proportional-hazards regression for survival data in R. In: An R companion to applied regression. Thousand Oaks, CA: SAGE Publications, Inc; 2011.

  47. Bristow MR. beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558–69.

    Article  CAS  Google Scholar 

  48. Kaye DM, Smirk B, Williams C, Jennings G, Esler M, Holst D. Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics 2003;13:379–82.

    Article  CAS  Google Scholar 

  49. Metra M, Covolo L, Pezzali N, Zaca V, Bugatti S, Lombardi C, et al. 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.

    Article  CAS  Google Scholar 

  50. Hori M, Okamoto H. Heart rate as a target of treatment of chronic heart failure. J Cardiol. 2012;60:86–90.

    Article  Google Scholar 

  51. Luzum JA, English JD, Ahmad US, Sun JW, Canan BD, Sadee W, et al. Association of genetic polymorphisms in the beta-1 adrenergic receptor with recovery of left ventricular ejection fraction in patients with heart failure. J Cardiovasc Transl Res. 2019;12:280–9.

    Article  Google Scholar 

  52. Liu J, Liu ZQ, Tan ZR, Chen XP, Wang LS, Zhou G, et al. Gly389Arg polymorphism of beta1-adrenergic receptor is associated with the cardiovascular response to metoprolol. Clin Pharm Ther. 2003;74:372–9.

    Article  CAS  Google Scholar 

  53. Liu J, Liu ZQ, Yu BN, Xu FH, Mo W, Zhou G, et al. beta1-Adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension. Clin Pharm Ther. 2006;80:23–32.

    Article  CAS  Google Scholar 

  54. Fiuzat M, Neely ML, Starr AZ, Kraus WE, Felker GM, Donahue M, et al. Association between adrenergic receptor genotypes and beta-blocker dose in heart failure patients: analysis from the HF-ACTION DNA substudy. Eur J Heart Fail. 2013;15:258–66.

    Article  CAS  Google Scholar 

  55. Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, et al. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci USA. 2006;103:11288–93.

    Article  CAS  Google Scholar 

  56. Heckbert SR, Hindorff LA, Edwards KL, Psaty BM, Lumley T, Siscovick DS, et al. Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation 2003;107:2021–4.

    Article  CAS  Google Scholar 

  57. Forleo C, Resta N, Sorrentino S, Guida P, Manghisi A, De Luca V, et al. Association of beta-adrenergic receptor polymorphisms and progression to heart failure in patients with idiopathic dilated cardiomyopathy. Am J Med. 2004;117:451–8.

    Article  CAS  Google Scholar 

  58. Petersen M, Andersen JT, Hjelvang BR, Broedbaek K, Afzal S, Nyegaard M, et al. Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients. Br J Clin Pharm. 2011;71:556–65.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This project was funded in part by the University of Illinois at Chicago Office of the Vice Chancellor for Research as well as American Heart Association Midwest Affiliate Scientist Development Grant 0335361Z (LHC), NIH/NIA R03 AG033381 (LHC), NIH/NHLBI R01 HL141281 (AAD), and NIH/NIGMS K23 GM112014 (JDD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Author notes

  1. These authors contributed equally: Leonardo A. Guerra, Christelle Lteif.

Authors and Affiliations

  1. Center for Pharmacogenomics and Precision Medicine, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA

    Leonardo A. Guerra, Christelle Lteif, Caitrin W. McDonough, Leanne Dumeny, Larisa H. Cavallari & Julio D. Duarte

  2. Tabula Rasa HealthCare Precision Pharmacotherapy R&D Institute, Orlando, FL, USA

    Meghan J. Arwood

  3. Genetics and Genomics, Genetics Institute, University of Florida, Gainesville, FL, USA

    Leanne Dumeny

  4. Krannert Institute of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, USA

    Ankit A. Desai

Authors
  1. Leonardo A. Guerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christelle Lteif
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meghan J. Arwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Caitrin W. McDonough
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leanne Dumeny
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ankit A. Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Larisa H. Cavallari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Julio D. Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JDD conceived the work; JDD and CL designed the project; MJA, AAD, LHC, and JDD collected the data; LAG, LD, CM, and CL completed the analysis; LAG and CL wrote the manuscript; MJA, AAD, LHC, CM, LD, and JDD edited the manuscript.

Corresponding author

Correspondence to Julio D. Duarte.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guerra, L.A., Lteif, C., Arwood, M.J. et al. Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers. Pharmacogenomics J 22, 62–68 (2022). https://doi.org/10.1038/s41397-021-00257-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-021-00257-1

Search

Advanced search

Quick links