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Thromb Haemost 2009; 101(02): 351-358
DOI: 10.1160/TH08-05-0284
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Association between polymorphisms in the β2-adrenergic receptor gene with myocardial infarction and ischaemic stroke in women

Markus Schürks
1   Division of Preventive Medicine, Department of Medicine; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachussetts, USA
6   Department of Neurology, University Hospital Essen, Essen, Germany
,
Tobias Kurth
1   Division of Preventive Medicine, Department of Medicine; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachussetts, USA
2   Division of Aging, Department of Medicine; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachussetts, USA
3   Department of Epidemiology, Harvard School of Public Health, Boston, Massachussetts, USA
5   INSERM Unit 708, Neuroepidemiology and University Pierre et Marie Curie, Paris, France
,
Paul M. Ridker
1   Division of Preventive Medicine, Department of Medicine; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachussetts, USA
3   Department of Epidemiology, Harvard School of Public Health, Boston, Massachussetts, USA
,
Julie E. Buring
1   Division of Preventive Medicine, Department of Medicine; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachussetts, USA
2   Division of Aging, Department of Medicine; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachussetts, USA
3   Department of Epidemiology, Harvard School of Public Health, Boston, Massachussetts, USA
4   Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachussetts, USA
,
Robert Y. L. Zee
1   Division of Preventive Medicine, Department of Medicine; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachussetts, USA
› InstitutsangabenFinancial support: The Women’s Health Study is supported by grants from the National Heart, Lung, and Blood Institute (HL-43851; HL-080467), and the National Cancer Institute (CA-47988). The research for this work was supported by grants from the Donald W. Reynolds Foundation, the Leducq Foundation, and the Doris Duke Charitable Foundation. The authors also thank F. Hoffmann La-Roche and Roche Molecular Systems, Inc. for supporting the genotype-determination financially and with in-kind contribution of reagents and consumables. Dr. Schürks was supported by a grant from the Deutsche Forschungsgemeinschaft. The funding agencies played no role in the design, conduct, data management, analysis, or manuscript preparation related to this manuscript.
Weitere Informationen

Publikationsverlauf

Received: 05. Mai 2008

Accepted after major revision: 05. Januar 2008

Publikationsdatum:
23. November 2017 (online)

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Summary

Results from studies investigating the association between polymorphisms in the β2-adrenergic receptor gene (ADRB2) and cardiovascular disease (CVD) are controversial. Using haplo-type-based analysis, we have previously shown a protective effect of the Gly16-Gln27-Ile164 haplotype on myocardial infarction in men. We sought to replicate these findings in women and further investigated whether the gene variants exert differential effects on myocardial infarction and ischaemic stroke. We performed a prospective study among 25,224 women, participating in the Women’s Health Study and free of CVD at study entry. We had information on polymorphisms Gly16Arg, Gln27Glu, and Thr164Ile in the ADRB2. Incident CVD was self-reported and confirmed after medical record review. We used proportional hazards models to investigate the association between genotypes and haplotypes with any myocardial infarction, any ischaemic stroke, and CVD death. During a mean of 11.8 years of follow-up, 274 myocardial infarctions, 299 ischaemic strokes, and 159 CVD deaths occurred. Among the whole cohort genotypeand haplotype-based analyses did not show an association for any of the gene variants with any of the CVD outcomes. When we focused on Caucasian women, the haplotype-based analysis, however, suggested an inverse association of the haplotype Gly16-Gln27-Thr164 with incident myocardial infarction (multivariable-adjusted hazard ratio 0.75; 95% confidence interval 0.58–0.97; p=0.03). We did not find associations in the haplo-type-based analyses with incident ischaemic stroke or CVD death. Our results suggest that the haplotype Gly16-Gln27-Thr164 is associated with reduced risk of incident myocardial infarction but not ischaemic stroke in Caucasian women and suggest differential pathophysiologies for myocardial infarction and stroke.

Keywords

β2-adrenergic receptor gene - ischaemic stroke - myocardial infarction - polymorphism
 

  • References

  • 1 Liggett SB. Update on current concepts of the molecular basis of beta2-adrenergic receptor signaling. J Allergy Clin Immunol 2002; 110: S223-227.
    CrossrefPubMedGoogle Scholar
  • 2 Johnson JA, Terra SG. Beta-adrenergic receptor polymorphisms: cardiovascular disease associations and pharmacogenetics. Pharm Res 2002; 19: 1779-1787.
    CrossrefPubMedGoogle Scholar
  • 3 Liggett SB. beta(2)-adrenergic receptor pharmacogenetics. Am J Respir Crit Care Med 2000; 161: S197-201.
    CrossrefPubMedGoogle Scholar
  • 4 Reihsaus E, Innis M, MacIntyre N. et al. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8: 334-339.
    CrossrefPubMedGoogle Scholar
  • 5 Chong LK, Chowdry J, Ghahramani P. et al. Influence of genetic polymorphisms in the beta2-adrenoceptor on desensitization in human lung mast cells. Pharmacogenetics 2000; 10: 153-162.
    CrossrefPubMedGoogle Scholar
  • 6 Green SA, Turki J, Bejarano P. et al. Influence of beta 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995; 13: 25-33.
    CrossrefPubMedGoogle Scholar
  • 7 Green SA, Turki J, Innis M. et al. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414-9419.
    CrossrefPubMedGoogle Scholar
  • 8 Bray MS, Krushkal J, Li L. et al. Positional genomic analysis identifies the beta(2)-adrenergic receptor gene as a susceptibility locus for human hypertension. Circulation 2000; 101: 2877-2882.
    CrossrefPubMedGoogle Scholar
  • 9 Gu D, Su S, Ge D. et al. Association study with 33 single-nucleotide polymorphisms in 11 candidate genes for hypertension in Chinese. Hypertension 2006; 47: 1147-1154.
    CrossrefPubMedGoogle Scholar
  • 10 Lin RCY, Ericsson JO, Benjafield AV. et al. Association of beta2-adrenoceptor Gln27Glu variant with body weight but not hypertension. Am J Hypertens 2001; 14: 1201-1204.
    CrossrefPubMedGoogle Scholar
  • 11 Masuo K, Katsuya T, Fu Y. et al. Beta2– and beta3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years. Circulation 2005; 111: 3429-3434.
    CrossrefPubMedGoogle Scholar
  • 12 Sethi AA, Tybjaerg-Hansen A, Jensen GB. et al. 164Ile allele in the beta2-Adrenergic receptor gene is associated with risk of elevated blood pressure in women. The Copenhagen City Heart Study. Pharmacogenet Genomics 2005; 15: 633-645.
    CrossrefPubMedGoogle Scholar
  • 13 Xie HG, Stein CM, Kim RB. et al. Human beta2-adrenergic receptor polymorphisms: no association with essential hypertension in black or white Americans. Clin Pharmacol Ther 2000; 67: 670-675.
    CrossrefPubMedGoogle Scholar
  • 14 Heckbert SR, Hindorff LA, Edwards KL. et al. Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation 2003; 107: 2021-2024.
    CrossrefPubMedGoogle Scholar
  • 15 Stanzione R, Di Angelantonio E, Evangelista A. et al. Beta2-adrenergic receptor gene polymorphisms and risk of ischemic stroke. Am J Hypertens 2007; 20: 657-662.
    CrossrefPubMedGoogle Scholar
  • 16 Herrmann SM, Nicaud V, Tiret L. et al. Polymorphisms of the beta2 -adrenoceptor (ADRB2) gene and essential hypertension: the ECTIM and PEGASE studies. J Hypertens 2002; 20: 229-235.
    CrossrefPubMedGoogle Scholar
  • 17 Wallerstedt SM, Eriksson AL, Ohlsson C. et al. Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor in a Swedish hypertensive population. J Hum Hypertens 2005; 19: 705-708.
    CrossrefPubMedGoogle Scholar
  • 18 Zee RY, Cook NR, Reynolds R. et al. Haplotype analysis of the beta2 adrenergic receptor gene and risk of myocardial infarction in humans. Genetics 2005; 169: 1583-1587.
    CrossrefPubMedGoogle Scholar
  • 19 Ridker PM, Cook NR, Lee IM. et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352: 1293-1304.
    CrossrefPubMedGoogle Scholar
  • 20 Zee RY, Hoh J, Cheng S. et al. Multi-locus interactions predict risk for post-PTCA restenosis: an approach to the genetic analysis of common complex disease. Pharmacogenomics J 2002; 2: 197-201.
    PubMedGoogle Scholar
  • 21 Atiya M, Kurth T, Berger K. et al. Interobserver agreement in the classification of stroke in the Women’s Health Study. Stroke 2003; 34: 565-567.
    CrossrefPubMedGoogle Scholar
  • 22 Devlin B, Risch N. A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 1995; 29: 311-322.
    CrossrefPubMedGoogle Scholar
  • 23 Cordell HJ, Clayton DG. Genetic association studies. Lancet 2005; 366: 1121-1131.
    CrossrefPubMedGoogle Scholar
  • 24 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978-989.
    CrossrefPubMedGoogle Scholar
  • 25 Wallenstein S, Hodge SE, Weston A. Logistic regression model for analyzing extended haplotype data. Genet Epidemiol 1998; 15: 173-181.
    CrossrefPubMedGoogle Scholar
  • 26 Sala G, Di Castelnuovo A, Cuomo L. et al. The E27 beta2-adrenergic receptor polymorphism reduces the risk of myocardial infarction in dyslipidemic young males. Thromb Haemost 2001; 85: 231-233.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 27 Yamada Y, Izawa H, Ichihara S. et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med 2002; 347: 1916-1923.
    CrossrefPubMedGoogle Scholar
  • 28 Zee RY, Cook NR, Cheng S. et al. Polymorphism in the beta2-adrenergic receptor and lipoprotein lipase genes as risk determinants for idiopathic venous thromboembolism: a multilocus, population-based, prospective genetic analysis. Circulation 2006; 113: 2193-2200.
    CrossrefPubMedGoogle Scholar
  • 29 Nossent AY, Dai L, Rosendaal FR. et al. Beta 2 adrenergic receptor polymorphisms: association with factor VIII and von Willebrand factor levels and the risk of venous thrombosis. J Thromb Haemost 2005; 3: 405-407.
    CrossrefPubMedGoogle Scholar
  • 30 O’Donnell J, Manning RA, Laffan MA. Beta-adrenergic receptor polymorphisms in patients with elevated factor VIII levels with venous thrombosis. Br J Haematol 2003; 123: 139-141.
    CrossrefPubMedGoogle Scholar
  • 31 Folsom AR, Peacock JM, Boerwinkle E. et al. beta2-adrenergic receptor polymorphism and venous thromboembolism. Thromb Haemost 2008; 99: 240.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 32 Zee RY, Cook NR, Cheng S. et al. Multi-locus candidate gene polymorphisms and risk of myocardial infarction: a population-based, prospective genetic analysis. J Thromb Haemost 2006; 4: 341-348.
    CrossrefPubMedGoogle Scholar
  • 33 Voko Z, Bereczky Z, Katona E. et al. Factor XIII Val34Leu variant protects against coronary artery disease. A meta-analysis. Thromb Haemost 2007; 97: 458-463.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 34 Everett BM, Kurth T, Buring JE. et al. The relative strength of C-reactive protein and lipid levels as determinants of ischemic stroke compared with coronary heart disease in women. J Am Coll Cardiol 2006; 48: 2235-2242.
    CrossrefPubMedGoogle Scholar
  • 35 Schürks M, Zee RY, Buring JE. et al. Interrelationships among the MTHFR 677C>T polymorphism, migraine, and cardiovascular disease. Neurology 2008; 71: 505-513.
    CrossrefPubMedGoogle Scholar