of cardiovascular diseases, and mortality in a four-year prospective study. The study included 4000 community-living men and women aged 65 years and over, and 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.

The results showed that women with the D/D genotype had the greatest reduction in mean ABI after adjusting for confounding factors. The D/D genotype was also more common among women who developed hypertension or myocardial infarction. However, the D/D genotype was associated with mortality only in men. In conclusion, in a Chinese elderly population, ACE polymorphism may be considered deleterious to longevity. The D/D genotype was associated with mortality, the atherosclerotic process, hypertension, and myocardial infarction. There are gender differences in the relationship between D/D genotype variations.

The 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-analysis among Caucasians concluded that although ACE gene polymorphisms affect plasma ACE activity, an association of the polymorphism with hypertension, cerebrovascular disease, myocardial infarction, or ischemic 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, a 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 mortality in a four-year prospective study.The study aimed to investigate the relationship between cardiovascular diseases and 4-year mortality prospectively, while adjusting for environmental confounding factors such as dietary and alcohol intake, physical activity, and more. The Clinical Research Ethics Committee of the Chinese University of Hong Kong approved the study, and informed consent was obtained from the 4000 men and women aged 65 and over who were invited to attend a health check in the School of Public Health of the university. Recruitment notices were placed in community centers for the elderly and housing estates, and several talks were given to explain the purpose, procedures, and investigations to be carried out. Subjects who were unable to walk without assistance or had bilateral hip replacements were excluded from the stratified sample, which aimed to recruit approximately one third from each of these age groups: 65-69, 70-74, 75+. The study sample differed from the general Hong Kong population of the same age group in that they were more educated and more likely to be married. The study commenced in 2001, and after five years of follow-up, the results are reported in this study. During this period, 614 subjects did not return for follow-up, while 233 subjects died (Fig 1). There was no difference in frequencies of the three ACE gene polymorphisms between participants who returned.