Abstract
Three subtypes of β-adrenoceptor, β1, β2 and β3, are involved in the sympathetic nervous system, which plays an important role in the development of hypertension and hypertensive complications. These complications can include left ventricular hypertrophy and arterial stiffness, which are reported risk factors for cardiovascular diseases. We designed clinical trials to clarify the association between hypertensive complications and β-adrenoceptor single nucleotide polymorphisms in essential hypertension. Using Taqman PCR methods, we detected five polymorphisms of three β-adrenoceptors: Ser49Gly and Arg389Gly for the β1-adrenoceptor; Gly16Arg and Glu27Gln for the β2-adrenoceptor; and Trp64Arg for the β3-adrenoceptor. We included 300 subjects and measured pulse wave velocity, vasodilator response to hyperemia, left ventricular hypertrophy (by electrocardiogram and echocardiography), and cardiac enlargement (by chest X-ray). We found that pulse wave velocity and nitroglycerin-induced hyperemia were both closely associated with the Ser49Gly polymorphism (p<0.05), and Glu27Gln was found by both electrocardiogram and echocardiography to be significantly associated with left ventricular hypertrophy (p<0.05). These data suggested that two polymorphisms of different β-adrenoreceptor subtypes are the genetic influences on the development of arterial stiffness and left ventricular hypertrophy in essential hypertension.
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Walston J, Lowe A, Silver K, et al: The beta3-adrenergic receptor in the obesity and diabetes prone rhesus monkey is very similar to human and contains arginine at codon 64. Gene 1997; 188: 207–213.
Naga Prasad SV, Nienaber J, Rockman HA : Beta-adrenergic axis and heart disease. Trends Genet 2001; 17: S44–S49.
Johnson M : The beta-adrenoceptor. Am J Respir Crit Care Med 1998; 158: S146–S153.
Krum H : Sympathetic activation and the role of beta-blockers in chronic heart failure. Aust N Z J Med 1999; 29: 418–427.
Bohm M, Flesch M, Schnabel P : Beta-adrenergic signal transduction in the failing and hypertrophied myocardium. J Mol Med 1997; 75: 842–848.
Scarpace PJ, Tumer N, Mader SL : Beta-adrenergic function in aging. Basic mechanisms and clinical implications. Drugs Aging 1991; 1: 116–129.
Feldman RD : Adrenergic receptor polymorphisms and cardiac function (and dysfunction): a failure to communicate? Circulation 2001; 103: 1042–1043.
Dzimiri N : Regulation of beta-adrenoceptor signaling in cardiac function and disease. Pharmacol Rev 1999; 51: 465–501.
Diamond J, Phillips R : Hypertensive heart disease. Hypertens Res 2005; 28: 191–202.
Imanishi R, Seto S, Toda G, et al: High brachial-ankle pulse wave velocity is an independent predictor of the presence of coronary artery disease in men. Hypertens Res 2004; 27: 71–78.
Nitta K, Akiba T, Uchida K, et al: Left ventricular hypertrophy is associated with arterial stiffness and vascular calcification in hemodialysis patients. Hypertens Res 2004; 27: 47–52.
Erickson RP, Graves PE : Genetic variation in beta-adrenergic receptors and their relationship to susceptibility for asthma and therapeutic response. Drug Metab Dispos 2001; 29: 557–561.
Johnson JA, Terra SG : Beta-adrenergic receptor polymorphisms: cardiovascular disease associations and pharmacogenetics. Pharm Res 2002; 19: 1779–1787.
Iwai C, Akita H, Kanazawa K, et al: Arg389Gly polymorphism of the human beta1-adrenergic receptor in patients with nonfatal acute myocardial infarction. Am Heart J 2003; 146: 106–109.
Shioji K, Kokubo Y, Mannami T, et al: Association between hypertension and the α-adducin, β1-adrenoreceptor, and G-protein β3 subunit genes in the Japanese population; the Suita study. Hypertens Res 2004; 27: 31–37.
Svetkey LP, Timmons PZ, Emovon O, Anderson NB, Preis L, Chen YT : Association of hypertension with beta2- and alpha2c10-adrenergic receptor genotype. Hypertension 1996; 27: 1210–1215.
Fujisawa T, Ikegami H, Yamato E, et al: Association of Trp64Arg mutation of the beta3-adrenergic-receptor with NIDDM and body weight gain. Diabetologia 1996; 39: 349–352.
Fujisawa T, Ikegami H, Yamato E, et al: Trp64Arg mutation of beta3-adrenergic receptor in essential hypertension: insulin resistance and the adrenergic system. Am J Hypertens 1997; 10: 101–105.
Katsuya T, Baba S, Ishikawa K, et al: Epsilon 4 allele of apolipoprotein E gene associates with lower blood pressure in young Japanese subjects: the Suita Study. J Hypertens 2002; 20: 2017–2021.
Ranade K, Jorgenson E, Sheu WH, et al: A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet 2002; 70: 935–942.
Komai N, Ohishi M, Morishita R, et al: Serum hepatocyte growth factor concentration is correlated with the forearm vasodilator response in hypertensive patients. Am J Hypertens 2002; 15: 499–506.
Komai N, Ohishi M, Moriguchi A, et al: Low-dose doxazosin improved aortic stiffness and endothelial dysfunction as measured by noninvasive evaluation. Hypertens Res 2002; 25: 5–10.
Asmar R, Rudnichi A, Blacher J, London GM, Safar ME : Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. Am J Hypertens 2001; 14: 91–97.
Ouchi N, Ohishi M, Kihara S, et al: Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 2003; 43: 231–234.
Sokolow M, Lyon T : The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 1949; 37: 161–186.
Devereux R, Alonso D, Lutas E, et al: Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: 450–458.
Bengtsson K, Melander O, Orho-Melander M, et al: Polymorphism in the β1-adrenergic receptor gene and hypertension. Circulation 2001; 104: 187–190.
Yoshida N, Nishimaki Y, Sugiyama M, et al: SNP genotyping in the β2-adrenergic receptor by electronic microchip assay, DHPLC, and direct sequencing. J Hum Genet 2002; 47: 500–503.
Chang TJ, Tsai MH, Jiang YD, et al: The Arg16Gly polymorphism of human beta2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people. Clin Endocrinol (Oxf) 2002; 57: 685–690.
Okumura K, Matsui H, Ogawa Y, et al: The polymorphism of the beta3-adrenergic receptor gene is associated with reduced low-density lipoprotein particle size. Metabolism 2003; 52: 356–361.
Karlsson J, Lind L, Hallberg P, et al: Beta1-adrenergic receptor gene polymorphisms and response to beta1-adrenergic receptor blockade in patients with essential hypertension. Clin Cardiol 2004; 27: 347–350.
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 1999; 274: 12670–12674.
Masuo K, Katsuya T, Kawaguchi H, et al: Rebound weight gain as associated with high plasma norepinephrine levels that are mediated through polymorphisms in the beta2-adrenoceptor. Am J Hypertens 2005; 18: 1508–1516.
Eisenach J, Schroeder D, Pike T, et al: Dietary sodium restriction and β2-adrenergic receptor polymorphism modulate cardiovascular function in humans. J Physiol 2006; 574: 955–965.
Hojlund K, Christiansen C, Bjornsbo K, et al: Energy expenditure, body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the beta3-adrenergic receptor gene. Diabetes Obes Metab 2006; 8: 322–330.
Kuusela T, Jartti T, Tahvanainen K, Kaila T : Effects of terbutaline on peripheral vascular resistance and arterial compliance. J Cardiovasc Pharmacol 2004; 44: 74–81.
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Yuan, M., Ohishi, M., Ito, N. et al. Genetic Influences of β-Adrenoceptor Polymorphisms on Arterial Functional Changes and Cardiac Remodeling in Hypertensive Patients. Hypertens Res 29, 875–881 (2006). https://doi.org/10.1291/hypres.29.875
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DOI: https://doi.org/10.1291/hypres.29.875
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