5. Shared Frequencies of Apolipoprotein E (ApoE) and Angiotensin-Converting Enzyme (ACE) Alleles in a Cohort of 1344 Healthy Elderly Persons and 64 Centenarians

e2/D e4/I* Crude Values Adjusted Values Crude Values Adjusted Values Group (N) p OR (95% CI) p OR (95% CI) p OR (95% CI) p R (95% CI) Group 1 (n ¼ 292) .450 1.170 (0.779–1.757) .353 1.274 (0.764–2.123) .228 1.275 (0.859–1.894) .031 1.690 Group 2 (n ¼ 629) .001 0.548 (0.381–0.789) .026 0.590 (0.371–0.940) .264 0.822 (0.583–1.159) .193 0.743 Group 3 (n ¼ 270) .252 0.762 (0.478–1.214) .932 0.976 (0.557–1.710) .080 1.426 (0.959–2.122) .137 1.464 Group 4 (n ¼ 153) .006 1.919 (1.209–3.044) .423 0.724 (0.328–1.598) .910 0.969 (0.560–1.676) .224 0.592 Centenarians (n ¼ 64) .001 3.378 (1.885–6.054) .001 4.503 (2.342–8.657) Not determined Not determined

Notes: *No centenarian participants with e4/I were observed. OR odds ratio; CI ¼ confidence interval.

Indeed, e4 has been defined as a frailty allele (30). The second hypothesis suggests that e2 could be a longevity- promoting allele, functioning independently from other apoE alleles. This hypothesis is supported by our findings showing that the frequency of e3 did not change with advancing age, as would be expected if the e2 increase was due to e4 disappearance in the oldest age group. Indeed, an unchanged e3 allele frequency across age has been reported to be an important prerequisite in carrying out genetic association studies on aging (31).

considering a sample of healthy individuals, we greatly reduced the number of these variables.

alleles with age, was observed in Groups 1, 2, and 4. Heterosis occurs when heterozygotes show either a greater or lesser association with a phenotypic trait than do homo- zygotes or the wild type. Until now, this genetic phe- nomenon has not been described in ACE polymorphism, and may prove to be a confounding factor in studies investigating the relationship between ACE polymorphism and age. Indeed, heterosis is common in humans, being demonstrated in up to 50% of all gene associations (35).

an increase of e2 occurred only in elderly and centenarian men and not in women. Given the observation that in Western countries women live longer than man do, a differential sex ratio among age groups changes the number of individuals investigated group-by-group, that is, with advancing age. Accordingly, we used sex as a covariate to correct this bias. Logistic regression analysis confirmed this sex-related increase of e2 with aging. To our knowledge, this is the first time that a sex-related interaction between apoE alleles and aging is reported in a healthy population and in centenarians. As this was a cross-sectional study, we cannot explain the biological role, if any, of the e2 allele in healthy aging men. Similarly, we cannot evaluate the impact of the described genetic associations and heterosis in the excluded persons. However, the increased e2 frequency observed in men can be, on the contrary, consistent with or explained by the association of e4 with the well-known higher vascular risk reported in men than in women (13,14). Nevertheless, the number of individuals included in this study, as well as their age distribution, reflected the healthy population of our regional area, thus warranting a lower type 1 error rate (false positive) and recruitment bias (28).

In disagreement with previous studies demonstrating a significant interaction between apoE and ACE alleles in patients with age-related diseases (36,37), no interaction between the two alleles was found in our population, indicating that these polymorphisms are probably indepen- dent factors in healthy aging and longevity. In view of these findings, the e2 and D alleles in healthy male and female elderly and/or centenarian persons most likely play in- dependent, parallel roles in aging and human longevity. Further studies are needed to clarify their relationship with health and disease.

ACKNOWLEDGMENTS

This work was exclusively supported by grants from Ministero della Salute, Ricerca Corrente 2003-2005, Linea n. 1 ‘‘Malattie cardio e cerebrovascolari’’ and Ricerca Corrente 2006-2008, Linea n. 2 ‘‘Malattie di rilevanza sociale.’’

Address correspondence to Davide Seripa, PhD, Laboratory of Geriatrics and Gerontology, Research Department c/o Poliambulatorio ‘‘Giovanni Paolo II,’’ IRCCS ‘‘Casa Sollievo della Sofferenza,’’ Viale Cappuccini, San Giovanni Rotondo (FG), I-71013. E-mail: dseripa@operapadrepio.it

In this study, D allele frequencies were uniform in all age groups, including centenarians. This finding is in agreement with the majority of studies (28,32,33) that have tried unsuccessfully to replicate the previously reported associ- ation of increased ACE frequency with longevity by Schachter and colleagues (3). After adjustment for sex, however, a significant association between the D allele and centenarian age was found, thus suggesting a sex-dependent interaction of ACE alleles with longevity. It is clear that other factors influencing aging should be considered to be covariate in the logistic regression analysis. However, in

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