The Glu27 allele of the â 2 adrenergic receptor increases the risk of cardiac hypertrophy in hypertension Guido Iaccarino, Francesca Lanni, Ersilia Cipolletta, Valentina Trimarco, Raffaele Izzo, Gianni Luigi Iovino, Nicola De Luca and Bruno Trimarco Objective Cardiac and vascular remodeling occur in response to hypertension. Genetic background appears to modify the development of target organ damage (TOD). We evaluated the impact on hypertension-associated TOD of a highly polymorphic gene with elevated significance for the regulation of the cardiovascular system, the â 2 AR gene. Methods We recruited 775 hypertensives (mean 6 SE: age 53.5 6 0.5, from 20 to 84 years; female 32.7%; systolic (SBP)/diastolic (DBP) blood pressure: 159 6 1.2/ 101 6 0.6 mmHg) referred to the departmental outpatient clinic and screened them for the Arg16Gly, Gln27Glu, and Ile164Thr variants of â 2 AR gene. We performed association analyses on clinical, anamnesis, anthropometrical and biochemical parameters as well as cardiac and vascular ultrasound. Results We found that the three polymorphisms did not affect blood pressure levels. Cardiac TOD appeared to be related to the Glu27 variant. In fact, the Glu27 allele associates with a 1.4-fold higher risk of developing cardiac hypertrophy, and directly correlated with larger systolic and diastolic left ventricle internal diameters. Vascular TOD was not affected by the three polymorphisms. Ancillary to our finding we observed that the Glu27 variant is associated with a higher incidence of dyslipidemia. Conclusions Our data indicate that â 2 AR gene polymorphisms participate in the determination of cardiac TOD associated with hypertension. J Hypertens 22: 2117–2122 & 2004 Lippincott Williams & Wilkins. Journal of Hypertension 2004, 22:2117–2122 Keywords: hypertension, cardiac hypertrophy, genetics Department of Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Federico II University, Naples, Italy. Sponsorship: This work was supported by a grant from the Italian Ministry of Instruction University and Research (MIUR). Correspondence and requests for reprints to Bruno Trimarco, Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Federico II University, Via Pansini 5, 80131 Naples, Italy. Tel: +39 081 746 2250; fax: +39 081 746 2256; e-mail: trimarco@unina.it Received 27 February 2004 Revised 28 April 2004 Accepted 8 July 2004 Introduction About one-third of the population of western societies is hypertensive, and a large amount of medicaid expendi- ture is for the fighting of this ‘silent killer’. Indeed, hypertension represents an injury for the cardiovascular system, since chronic exposure to high blood pressure levels results in increased cardiac size evolving to heart failure and arteriosclerosis [1]. Target organ damage (TOD) prevention represents the objective of modern anti-hypertensive therapy, even more than reduction of blood pressure levels itself. Recent guidelines, indeed, indicate to start pharmacological treatment in pre-hyper- tensive patients based on the presence of TOD [1,2]. The progression towards TOD may vary within the hypertensive population and patients sharing anthropo- metrical characteristics and blood pressure levels have different incidence of complications. Several population studies have demonstrated that the reasons for the different risk of cardiovascular complications are likely to involve a genetic predisposition [3]. Indeed, familiar- ity and genetics are recognized as determinants of the global cardiovascular risk [4,5]. The â 2 adrenergic receptor (â 2 AR) is present both in the heart, where it increases heart rate and contrac- tility, and in the vasculature, where it causes vasodila- tion and contributes to the regulation of peripheral resistance. The relative gene in humans is highly polymorphic, but only three variants, namely the arginine (Arg)/glycine (Gly) at aminoacid 16, the glutamine (Gln)/glutamate (Glu) at position 27 and the arg/isoleucine (Ile) at aminoacid 164, have con- sequences in terms of function and physiological responses [6–8]. Given the pivotal role of â 2 ARs in the regulation of cardiac output and peripheral vascular resistance, it has been proposed that these variants may participate in the setting of hypertension [9]. Nevertheless, associa- tion studies have gathered contrasting results, with different outcomes depending on race, sex and size of studied population [10–13]. All together, these studies fail to definitively pin-point the role of â 2 AR poly- morphisms in the pathogenesis of elevated blood pressure levels. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Original article 2117 0263-6352 & 2004 Lippincott Williams & Wilkins