β-adrenergic receptor polymorphisms in susceptibility, response to treatment and prognosis in heart failure: Implication of ethnicity

Pereira,Sabrina   Bernardez; Velloso,Mônica  Wanderley Monçores; Chermont,Sérgio; Quintão,Mônica  Maria Pena; Nunes Abdhala,Rosemery; Giro,Camila; Oliveira E Alves,Thiago; Camacho,Viviane; Contarato,Luiza  De Fátima Maia; Pena,Felipe   Montes; Balieiro,Henrique  Miller; Garcia,Maria  Luiza Rosa; Da Nóbrega,Antônio  Cláudio Lucas; Ribeiro,Georgina   Severo; Mesquita,Evandro  Tinoco

doi:10.3892/mmr.2012.1120

β-adrenergic receptor polymorphisms in susceptibility, response to treatment and prognosis in heart failure: Implication of ethnicity

Authors:
- Sabrina Bernardez Pereira
- Mônica Wanderley Monçores Velloso
- Sérgio Chermont
- Mônica Maria Pena Quintão
- Rosemery Nunes Abdhala
- Camila Giro
- Thiago Oliveira E Alves
- Viviane Camacho
- Luiza De Fátima Maia Contarato
- Felipe Montes Pena
- Henrique Miller Balieiro
- Maria Luiza Rosa Garcia
- Antônio Cláudio Lucas Da Nóbrega
- Georgina Severo Ribeiro
- Evandro Tinoco Mesquita
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Affiliations: Fluminense Federal University/Antonio Pedro University Hospital, Niterói, Rio de Janeiro CEP 24033-900, Brazil
Published online on: October 9, 2012 https://doi.org/10.3892/mmr.2012.1120
Pages: 259-265

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Abstract

Common functional polymorphisms in β-adrenergic receptor (βAR) genes have been associated with heart failure (HF) phenotypes and pharmacogenetic interactions with βAR blockers. This study evaluated the association between βAR polymorphisms and carvedilol drug response and prognosis in patients with HF. In this prospective cohort controlled study, 326 volunteers were enrolled [146 HF patients (ejection fraction (EF) <50% by Simpson) and 180 healthy controls]. Drug response was evaluated by echocardiography and outcomes were mortality and hospitalization. DNA was extracted from peripheral blood leukocytes, fragments were amplified by the polymerase reaction and genotyped by restriction fragment length polymorphism (RFLP) for Ser49Gly and Arg389Gly βAR-1 polymorphisms and Gln27Glu and Arg16Gly βAR-2 polymorphisms. The study population was in Hardy‑Weinberg equilibrium. The survival rate was adjusted using the Kaplan-Meier method. HF patients showed the following characteristics: EF 35±9%, 69.9% male, age 59±13 years, 50.7% self-identified as black, 46% had ischemic etiology. The mean follow-up of 23 months showed 18 mortalities and 46 hospitalizations. The genotypes Glu27Glu (24.7 vs. 6.1%, p=0.0004) and Arg16Arg (72.6 vs. 22.8, p<0.0001) of βAR2 polymorphisms and Gly49Gly (33.6 vs. 4.3%, p<0.0001) of the βAR1 polymorphism were higher in HF patients compared with controls. Patients with hospital admission showed a significantly higher Gly389 allelic frequency (54.9 vs. 42.1%, p=0.039), and the trend prevailed among patients who succumbed to the disease (61.1%, p=0.047). Black patients with the Ser49Ser genotype showed a reduced survival compared with the Gly49Gly or Ser49Gly genotypes (p=0.028). There was no association between improved LVEF >20% and βAR polymorphisms. HF patients with β-blocker therapy and the Gly389 allele have reduced event-free survival compared to those carrying the Arg389 allele. Additionally, systolic HF outpatients undergoing β-blocker therapy, self‑identified as black and homozygous for Ser49Ser may have reduced event-free survival, while Glu27Glu, Arg16Arg and Gly49Gly genotypes may be associated with risk for HF.

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1	El Armouche A and Eschenhagen T: β-Adrenergic stimulation and myocardial function in the failing heart. Heart Fail Rev. 14:225–241. 2009.
2	Cohn JN, Levine TB and Olivari MT: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 311:819–823. 1984. View Article : Google Scholar : PubMed/NCBI
3	Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G and Butler J: The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 54:1747–1762. 2009. View Article : Google Scholar : PubMed/NCBI
4	Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et al: A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and betablocker response in human heart failure. Proc Natl Acad Sci USA. 103:11288–11293. 2006. View Article : Google Scholar : PubMed/NCBI
5	McNamara DM: Emerging role of pharmacogenomics in heart failure. Curr Opin Cardiol. 23:261–268. 2008. View Article : Google Scholar : PubMed/NCBI
6	Lang RM, Bierig M, Devereux RB, et al: Recommendations of chamber quantification. Eur J Echocardiogr. 7:79–108. 2006. View Article : Google Scholar : PubMed/NCBI
7	De Groote P, Lamblin N, Helbecque N, et al: The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. Eur J Heart Fail. 7:966–973. 2005.PubMed/NCBI
8	Maqbool A, Hall A, Ball S and Balmforth AJ: Common polymorphisms of beta1-adrenoceptor: identification and rapid screening assay. Lancet. 353:8971999. View Article : Google Scholar : PubMed/NCBI
9	Xie HG, Dishy V, Sofowora G, et al: Arg389Gly beta 1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo. Pharmacogenetics. 11:191–197. 2001. View Article : Google Scholar : PubMed/NCBI
10	Moore JD, Mason DA, Green SA, Hsu J and Liggett SB: Racial differences in the frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum Mutat. 14:2711999. View Article : Google Scholar : PubMed/NCBI
11	Small KM, McGraw DW and Liggett SB: Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol. 43:381–411. 2003. View Article : Google Scholar : PubMed/NCBI
12	Small KM, Wagoner LE, Levin AM, Kardia SL and Liggett SB: Synergistic polymorphisms of β1- and α2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 347:1135–1142. 2002.
13	Tesson F, Charron P, Peuchmaurd M, et al: Characterization of a unique genetic variant in the beta1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. Cardigene Group. J Mol Cell Cardiol. 31:1025–1032. 1999. View Article : Google Scholar : PubMed/NCBI
14	Börjesson M, Magnusson Y, Hjalmarson A and Andersson B: A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure. Eur Heart J. 21:1853–1858. 2000.PubMed/NCBI
15	Podlowski S, Wenzel K, Luther HP, et al: Beta1-adrenoceptor gen variations: a role in idiopathic dilated cardiomyopathy? J Mol Med. 78:87–93. 2000. View Article : Google Scholar : PubMed/NCBI
16	Liggett SB, Wagoner LE, Craft LL, Hornung RW, Hoit BD, McIntosh TC and Walsh RA: The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest. 102:1534–1539. 1998. View Article : Google Scholar : PubMed/NCBI
17	Forleo C, Resta N, Sorrentino S, et al: Association of β-adrenergic receptor polymorphisms and progression of heart failure in patients with idiopathic dilated cardiomyopathy. Am J Med. 117:451–458. 2004.
18	Moraga F, Troncoso R, Mellado R, et al: Interactions between beta1 and beta2 adrenergic receptor polymorphisms as risk factors for chronic heart failure. Rev Med Chil. 136:1371–1380. 2008.(In Spanish).
19	Bray MS, Krushkal J, Li L, et al: Positional genomic analysis identifies the beta(2)-adrenergic receptor gen as a susceptibility locus for human hypertension. Circulation. 101:2877–2882. 2000. View Article : Google Scholar : PubMed/NCBI
20	Terra SG, Hamilton KK, Pauly DF, et al: β1-Adenergic receptor polymorphisms and left ventricular remodeling changes in response to β-blocker therapy. Pharmacogenet Genomics. 15:227–234. 2005.
21	White HL, de Boer RA, Maqbool A, 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. 5:463–468. 2003. View Article : Google Scholar : PubMed/NCBI
22	Magnusson Y, Levin MC, Eggertsen R, Nyström E, Mobini R, Schaufelberger M and Andersson B: Ser49Gly of β1-adrenergic receptor is associated with effective β-blocker dose in dilated cardiomyopathy. Clin Pharmacol Ther. 78:221–231. 2005.
23	Latado AL, Lopes MB, Passos LC and Lopes AA: Does any evidence exist to treat heart failure based on race or ethnicity? Rev Assoc Med Bras. 55:110–116. 2009.(In Portuguese).
24	McNamara DM, Tam W, Sabolisnski ML, et al: Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial. J Card Fail. 15:191–198. 2009. View Article : Google Scholar : PubMed/NCBI
25	Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 344:1659–1667. 2001. View Article : Google Scholar : PubMed/NCBI
26	Cohn JN, Fowler MB, Bristow MR, et al: Safety and efficacy of carvedilol in severe heart failure. The US Carvedilol Heart Failure Study Group. J Card Fail. 3:173–179. 1997. View Article : Google Scholar : PubMed/NCBI
27	Packer M, Fowler MB, Roecker EB, et al: Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 106:2194–2199. 2002. View Article : Google Scholar
28	Yancy CW, Laskar S and Eichhorn E: The use of beta-adrenergic receptor antagonists in the treatment of African Americans with heart failure. Congest Heart Fail. 10:34–37. 2004. View Article : Google Scholar : PubMed/NCBI
29	López-Sendón J, Swedberg K, McMurray J, et al: Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J. 25:1341–1362. 2004.PubMed/NCBI
30	Wood AJ: Racial differences in the response to drugs-pointers to genetic differences. N Engl J Med. 344:1394–1396. 2001. View Article : Google Scholar : PubMed/NCBI