An association between II genotype frequencies and age, although apparent in the GP group, was not observed in the JP group. The different results obtained suggest that association could be influenced by linkage disequilibrium or some other hidden conditions. It is also possible that there were gene–environmental interactions that could be influ- encing the results obtained. A meta-analysis of the associa- tion of the D allele with myocardial infarction combining over 8500 participants from all currently available stud- ies was carried out (5). The authors reported that an impor- tant confounding factor recognized in association studies is ethnicity, and they suggested two possibilities to explain this concern: (a) the existence of bias because several stud- ies have been performed with small samples, and (b) dif- ferences in the relationship between DD genotype and myocardial infarction risks due to ethnic factors.

Researchers have suggested that the association could be spurious due to biases as a result of small samples, which increase the risk of false positive reports. One case that supports this theory came from French centenarians. During the 1990s, an association between ACE and ApoE poly- morphism and extremes of longevity in this population was published. However, a later study with a larger number of centenarians did not confirm the ACE association (7). Based on these data, the authors discussed recommendations to set up a rigorous experimental design involving analyses of association between gene polymorphism and longevity.

However, in Blanche’s study (7), a comparison was made with ACE frequencies from a younger group to determine ACE polymorphism association with centenarians. There is probably no association between ACE polymorphism and centenarians as reported in Blanche’s study. However, an association between ACE polymorphism and advanced age could exist.

Considering the results of previously published studies and those of the present study, we cannot dismiss the possibility of this being due to a gene–environment or gene– gene interaction phenomenon. The gene–environment in- teraction was defined by Ottman (11) as ‘‘a different effect of an environmental exposure on disease risk in persons with different genotypes’’ or, alternatively, ‘‘a different ef- fect of a genotype on disease risk in persons with different environmental exposures.’’ She suggested five general models for the relation between a high-risk genotype and an environmental exposure, in terms of their effect on disease risk. The same concept could be applied to gene polymorphism associated with age (or longevity?). In this

A large retrospective cohort study in an ethnically homogeneous white population has been conducted (6). The authors did not observe any changes in ACE genetic frequencies as a function of age after examining participants aged 20 to 80 years. However, the authors did not include participants older than 80 years, and perhaps, this condition

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Figure 2. Percentile distribution of age as a function of angiotensin-converting enzyme polymorphism in two ethnically different populations living in the region of Brazil (RS). A, Gaucha population (GP); B, Japanese population (JP). Numbers represent the age estimated on different percentiles. I ¼ Insertion; D deletion.

Table 2. Comparison Among Mean Ages in Samples of the Japanese Ethnic Population and Gaucha Population Living in the Southern Region of Brazil With Different Angiotensin-Converting Enzyme Genotypes

JP GP Genotype n Mean 6 SD 95% CI n Mean 6 SD 95% CI II 148 61.91 6 14.25a 59.59–64.22 73 37.63 6 20.23a 32.90–42.35 ID 125 62.22 6 14.04a 59.73–64.71 222 47.617 6 24.23b 44.46–50.88 DD 38 59.05 6 18.46a 52.98–65.12 228 47.72 6 24.97b 44.46–50.98 Total 311 61.69 6 14.73 60.04–63.33 523 46.29 6 24.26 44.20–48.37

Notes: Values with the same letter are not statistically significant (p , .05) in one-way analysis of variance followed by Student’s t test in each population (JP and GP) analyzed separately. n ¼ Number of the sample; SD ¼ standard deviation; JP ¼ Japanese population; GP ¼ Gaucha population; CI ¼ confidence interval; I ¼ insertion; D ¼ de-

n ¼ Number of the sample; SD ¼ standard deviation; JP ¼ Japanese population; GP ¼ Gaucha population; CI ¼ confidence interval; I ¼ insertion; D ¼ de-

type I diabetes and 162 healthy controls. An analysis of the ACE genotypes with respect to age and duration of diabetes showed that homozygosity for the insertion (I/I) genotype was significantly decreased with longer duration of diabetes in ACE and age association. The authors suggested that the ACE locus may be associated with longevity and survival in patients with type I diabetes. Thomas and colleagues (15) described an association between I allele and diabetes in a Chinese population. The results showed that the ACE-I allele was significantly more frequent in each group com- posed of participants with type 2 diabetes/glucose intoler- ance (GIT), and that the I allele was associated with higher fasting plasma glucose levels.

case, some polymorphism in the presence of different environmental conditions or in the presence of other genetic variables could possibly produce differential responses.