THE ALU POLYMORPHISM OF ANGIOTENSIN I CONVERTING ENZYME (ACE) AND ATHEROSCLEROSIS, INCIDENT CHRONIC DISEASES



1. Department of Medicine & Therapeutics; 2. Department of Chemical Pathology; 3. The Jockey club Centre for Osteoporosis Care and Control, Faculty of Medicine, The Chinese University of Hong Kong. Address for Correspondence: Prof Jean Woo, Department of Medicine & Therapeutics, Prince of Wales Hospital, Shatin, N.T. Hong Kong, Tel: 852-26323493,

Abstract: Objective: We examined the contribution of ACE I/D polymorphism in a large Chinese population to four year change in ankle-brachial index (ABI), development of cardiovascular diseases and mortality in a prospective study adjusting for many confounding factors. Method: Data are drawn from a longitudinal study of 4000 community-living men and women aged 65 years and over, for which detailed information regarding lifestyle, chronic diseases, body mass index (BMI), ABI measurements and ACE polymorphisms were documented at baseline. During the fifth year of follow up, incident cardiovascular diseases, ABI, and mortality were documented, and related to ACE genotype adjusting for age, smoking, alcohol, dietary intake, physical activity, body mass index, and use of ACE inhibitors. Results: Women with the D/D genotype had the greatest reduction in mean ABI after adjusting for confounding factors. D/D genotype was also more common among women who developed hypertension or myocardial infarction. However D/D genotype was associated with mortality only in men. Conclusion: In a Chinese elderly population, ACE polymorphism may be considered ‘deleterious’ to longevity, the D/D genotype being associated with mortality, the atherosclerotic process, hypertension and myocardial infarction. There are gender differences in the relationship between D/D genotype





variations in study selection criteria, study design, and the existence of many possible environmental confounding factors

Renin-angiotensin system blockade has been considered a cornerstone of strategies to reduce cardiovascular risk, through antihypertensive, anti-inflammatory, anti-proliferative and oxidative stress lowering actions (1). Therefore it might be expected that ACE gene polymorphisms resulting in increased ACE activity would be associated with the atherosclerotic process and consequently cardiovascular diseases and mortality. In vitro studies showed that endothelial cells carrying the I/I (homozygote for Alu insertion) genotype of the ACE Alu polymorphism had lower angiotensin II levels and a twenty-fold increased viability after slow starvation compared with cells with the D/D (homozygote for deletion) genotype (2). Association between ACE polymorphism and ankle- brachial index, an indicator of atherosclerosis, has also been documented (3). Various population studies showed that the D/D genotype confers an increased risk of hypertension (4-10) and cardiovascular disease (4, 11), although there was a suggestion that the association may be stronger among Asians compared with Caucasians, and that there was a gender difference in the association. However, other studies reported no association (12) and a meta-analyses among Caucasians concluded that although ACE gene polymorphisms affect plasma ACE activity, an association of the polymorphism with hypertension, cerebrovascular disease, myocardial infarction or ischaemic heart disease was not observed in large studies but only in small ones (4). Inconsistent results were also observed

With respect to mortality, the concept of deleterious versus longevity-enabling genes in defining life expectancy (16) has emerged based on population studies of associations between gene polymorphisms and survival. However the association between ACE polymorphism and mortality is not clear cut. Some studies have concluded that the D/D genotype is deleterious to survival, based on observations of declining frequency of this polymorphism in successively older age groups (17-19). On the contrary higher frequency of the D allele was observed among centenarians (20, 21), while others reported no change in frequency of the D allele as a function of age (12). Differences in gender and ethnicity were also observed. To address some of the methodological issues that may account for previous conflicting findings, we examined the contribution of ACE polymorphism in a large Chinese population to change in ankle-brachial index, development of cardiovascular diseases and 4-year mortality prospectively, adjusting for many environmental confounding factors including dietary and alcohol intake, physical activity, and





The study was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. Informed