Atherosclerosis 139 (1998) 153 – 159 ACE I/D gene polymorphism: presence of the ACE D allele increases the risk of coronary artery disease in younger individuals Andreas Gardemann a, *, Monika Fink a , Ju ¨ rgen Stricker a , Quoc D. Nguyen a , Jo ¨ rg Humme a , Norbert Katz a , Harald Tillmanns b , Friedrich Wilhelm Hehrlein c , Matthias Rau d , Werner Haberbosch d a Institut fu ¨r Klinische Chemie und Pathobiochemie, Klinikum der Justus -Liebig -Uniersita ¨t Giessen, Gaffky -Strasse 11, Giessen 35392, Germany b Abteilung Kardiologie und Angiologie, Justus -Liebig -Uniersita ¨t Giessen, Giessen 35392, Germany c Klinik fu ¨r Herz - und Gefa ¨ßchirurgie der Justus -Liebig -Uniersita ¨t Giessen, Giessen 35392, Germany d Max -Planck -Institut fu ¨r Experimentelle und Klinische Forschung, Kerckhoff -Klinik, Bad Nauheim, Germany Received 10 October 1997; received in revised form 22 December 1997; accepted 16 January 1998 Abstract Background: Presence of the D allele or homozygosity for the deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism has been discussed as potent risk factor for coronary artery disease (CAD) and myocardial infarction (MI). Methods and results: In 2267 male Caucasians the relation of the ACE I/D gene polymorphism to CAD and MI were investigated. An association of the D allele to CAD was detected in younger subjects (e.g. 61.7 years, mean value), but not in older patients (e.g. 61.7 years). Additional exclusion of individuals with other cardiovascular risk factors (e.g. high BMI) produced an even stronger association of the D allele to CAD. In contrast, a relation of this polymorphism to non-fatal MI was only observed in older subjects; additional limitation to individuals without cardiovascular risk factors (e.g. BMI and/or diabetes) yielded a further enhancement of this association to MI. In younger subjects (e.g. 61.7 years) the gene polymorphism was not related to non-fatal MI even after exclusion of additional risk factors. Conclusions: The present large case-control study strengthens the assumption of an association of the ACE D allele with the risk of ischemic heart disease. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: ACE I/D gene polymorphism; Cardiovascular diseases; Myocardial infarction; Risk factors; Renin-angiotensin-aldos- teron system; Gensini score 1. Introduction The results of in vitro studies [1–4] and clinical investigations [5,6] suggest that the renin-angiotensin system is involved in the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI). The most likely mechanism by which ACE affects the risks of these diseases is by increasing the level of angiotensin II and by reducing that of bradykinin [7,8]. The latter peptide is known to reduce vascular tone and to inhibit smooth muscle cell proliferation in vitro [9,10]. In contrast, angiotensin II has been demon- strated in vitro to induce hyperplasia and hypertrophy of human vascular smooth muscle cells [11], to enhance expression of platelet-derived growth factor [12], to induce expression of protooncogenes c-fos and c-myc [12,13] and to cause neovascularisation [14]. In humans, the serum level of ACE is determined genetically. A deletion polymorphism in intron 16 of the angiotensin I-converting enzyme (ACE) gene has been shown to be associated with increased ACE activ- * Corresponding author. Tel.: +49 641 9941553; fax: +49 641 9941569. 0021-9150/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0021-9150(98)00040-9