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

Luft’s article (12) is a good example. This 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 ad- vanced 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 frequency higher 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

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 counter- balanced 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

(cid:1)60 (cid:1)70 (cid:1)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 ¼ 10.44, df ¼ 2, v2 ¼ 7.03, df ¼ 2, v2 ¼ 11.83, df ¼ 2, p ¼ .005 p ¼ .03 p ¼ .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 ¼ 1.39, df ¼ 2, v2 ¼ 0.27, df ¼ 2, v2 ¼ 0.93, df ¼ 2, p ¼ .498 p ¼ .871 p ¼ .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 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 hy- pothesis 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 involving gene interactions. Hibberd and colleagues (14) investigated the frequency of ACE polymorphism in 249 patients with

Notes: v2 value; df ¼ degrees of freedom; p ¼ significance level. GP ¼ Gaucha population; JP ¼ Japanese population; I ¼ insertion; D deletion.

Alzheimer’s disease (OR ¼ 1.28, 95% CI ¼ 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. Circulation.

;

:

–

Agerholm-Larsen B, Nordestgaard BG, Steffensen R, Sorensen TIA, Jense GJ, Tybjaerg-Hansen A. ACE gene polymorphism: ischemic heart disease and longevity in

,

individuals. Circulation.

;

:

–

Blanche H, Cabanne L, Sabattou M, Thomas G. A Study of French centenarians: are ACE and APOE associated with longevity. C R Acad Sci.

;

–

Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res.

:

:

SPSS for Windows: Base System User’s Guide. Release

Chicago: Norusis MJ/SPSS, Inc.;

Nakai K, Fusazaki T, Zhang T, et al. Polymorphism of the apolipo- protein E and angiotensin I converting enzyme genes in Japanese patients with myocardial infarction. Pathophysiol Nat Hist.

;

:

–

Ottman, R. An epidemiologic approach to gene-environmental in- teraction. Genet Epidemiol.

;

:

–

Luft FC. Bad genes, good people, association, linkage, longevity and the prevention of cardiovascular disease. Clin Exp Pharmacol Physiol.

;

:

–

Galinsky D, Tysoe C, Brayne CE, et al. Analysis of the ap

/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reduc- tase genes as candidates affecting human longevity. Atheros.

;

:

–

Hibberd ML, Millward BA, Demaine AG. The angiotensin I-converting enzyme (ACE) locus is strongly associated with age and duration of diabetes in patients with type I diabetes. J Diabetes Compl.

;

:

–