The mean ages among ACE genotypes were related to ethnic group. The GP showed an association between age and ACE genotype, whereas JP did not. The DD and ID genotypes correlated with higher ages in GP, more than the II genotype, suggesting a D allele-related dose effect. A multivariate analysis using logistic regression that included sex showed that in GP, the association between ACE polymorphism and age was independent.

Different results were found in the two ethnic groups studied. While GP showed genotype and allele frequencies of the ACE gene as a function of age, JP did not show this association. An association between II genotype frequencies and age was apparent in GP but not observed in JP. Researchers have suggested that the association could be spurious due to biases resulting from small samples that increase the risk of false positive reports.

In conclusion, this study highlights the complexity of analyzing associations between gene polymorphism and longevity or advanced age due to possible gene-environment or gene-gene interaction phenomena.In some cases, polymorphism in the presence of different environmental conditions or genetic variables could produce differential responses. Luft's article (12) is a good example. The author studied the relationship among cardiovascular risk factors, such as hypertension, lipid disturbances, diabetes mellitus, left ventricular hypertrophy, and smoking, all of which are influenced by genetic variance. Luft postulated that genes that influence these factors could have a considerable bearing on longevity. Although mortality rates increase exponentially with increasing age, an interesting tendency toward a plateau occurs, suggesting that older individuals are somewhat protected from their inclination to die. This phenomenon is difficult to explain. One possibility is a model of repair in which certain alleles exert a beneficial influence at an advanced age. An alternative explanation could be a mutation that exerts both negative and positive effects. The authors used the insertion/deletion (I/D) polymorphism in the ACE gene as an example leading to the notion that the ACE gene I/D polymorphism may be a genetic variant with both negative and positive effects. The study reported that in a cohort of the German population aged older than 80 years, the D allele occurred at a higher frequency than expected, as seen in the results obtained here with the GP group. Alvarez and colleagues (16) studied the association between ACE polymorphism and Alzheimer's disease based on several lines of evidence suggesting that the endothelial constitutive nitric oxide synthase (ecNOS) and ACE may have a biological role in the disease. A total of 400 young healthy controls and 350 patients with Alzheimer's disease were genotyped for ACE and ecNOS polymorphisms. To define a possible role for these polymorphisms in longevity, 117 healthy controls older than 85 years were also analyzed. The results showed that the ACE-I allele was associated with a slightly increased risk of developing late-onset Alzheimer's disease. In this case, Luft (12) reported an ACE polymorphism effect on heart size. The D allele was linked to a greater heart size compared with the I allele in a modified sib-pair model. This potentially deleterious effect was counterbalanced by linkage of the D allele to increased heart rate variability, which is a potentially beneficial attribute.

Table 3. Comparison of Angiotensin-Converting Enzyme Genotype and Gene Frequencies by Different Age Cut-Off Points for the Japanese Population and Gaucha Population Living in the Southern 60 70 80 Genotype n (%) n (%) n (%) GP Samples II 10 (13.9) 5 (6.9) 0 ID 75 (33.2) 46 (20.4) 32 (14.2) DD 70 (32.1) 37 (16.9) 32 (14.6) v2 10.44, df 2, v2 7.03, df 2, v2 11.83, df 2, p .005 p .03 p .003 JP Samples II 85 (57.4) 42 (28.4) 13 (8.8) ID 72 (57.6) 34 (27.2) 10 (8.0) DD 18 (47.4) 12 (31.6) 5 (13.2) v2 1.39, df 2, v2 0.27, df 2, v2 0.93, df 2, p .498 p .871 p .618

Galinsky and colleagues (13) also found an association between ACE and age dependent on sex that indicated a gene interaction phenomenon. In this case, the I/I ACE was depleted in elderly men but not in elderly women, suggesting that the penetrance of loci that influence survival may vary according to sex. As we found an association between II frequencies and early age indicating that individuals with this genotype could die earlier, a complementary study testing Luft's hypothesis could help us understand the association between ACE polymorphism and longevity, or conversely, why II-genotype individuals die earlier. Associations between ACE polymorphism and age involve gene interactions. Hibberd and colleagues (14) investigated the frequency of ACE polymorphism in 249 patients with Alzheimer's disease (OR 1.28, 95% CI 1.04, 1.58). These latter studies present some level of evidence for an association of I with diseases that could explain earlier mortality as found here for the GP group. Beohar N, Damaraju S, Prather P. Angiotensin I-converting enzyme genotype DD is a risk factor for CAD. J Invest Med. ; : Samani NJ, Thompson JR, O'Toole L, Channer K, Woods KL. A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. CirculationThe text enclosed in the ``` ``` is already correct and requires no further processing.