Experimental Gerontology 38 (2003) 1015–1020



Angiotensin I converting enzyme (ACE) gene polymorphism centenarians: Different allele frequencies between the North and South of Europe

Francesco Vincenzo , Alessia , Anna Maria , a b a Cristiano Capurso , Patrick G. Kehoe , Antonio Capurso

aDepartment of Geriatrics, Centre for Aging Brain, Memory Unit, University of Bari, Policlinico, Piazza Giulio Cesare, 11, Bari 70124, Italy bDepartment of Care of the Elderly, University of Bristol, The John James Building, Frenchay Hospital, Bristol BS16 1LE, England, UK

Received 3 January 2003; received in revised form 28 May 2003; accepted 30 May 2003

Abstract

Variants of the angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE1) gene and the apolipoprotein E gene (APOE) have been suggested to be associated with human longevity. We tested the association between the ACE1 insertion (I allele)/deletion (D allele) polymorphism and longevity in a population from Southern Italy and examined the impact of geographical variation on ACE1 allele frequencies on reported associations from other European countries. ACE1 and APOE genotypes were obtained on 82 centenarians and 252 middle-aged, unrelated subjects or volunteers. No statistically significant differences were found in ACE1 genotype or allele frequencies between centenarians and controls in this Southern Italian population nor was there any observed interaction with APOE alleles that are also reputed to be linked to longevity. However, decreasing gradients in ACE1*I allele frequencies, both in centenarians and controls, with concomitant increases in ACE1*D allele frequencies (particularly the ACE1*D/*D genotype) were observed to be statistically significant from Northern to Southern regions of Europe. These findings did not support the previously reported association between ACE1 polymorphism and longevity. However, there were interesting and significant differences, as one moves from Northern to Southern Europe, with regard to the distribution of ACE1 alleles. Such genetic differences in conjunction with differing environmental factors may explain in part previous results suggesting a role of this polymorphism in longevity.

Keywords: Angiotensin I converting enzyme 1; Centenarians; Longevity; Southern Italy; Apolipoprotein E

1. Introduction

The angiotensin I converting enzyme (peptidyl-dipepti- dase A) 1 (ACE1) gene, located on chromosome 17, has an insertion (I allele)/deletion(D allele) genetic polymorphism in its non-coding region (Rigat et al., 1990) and has been recently associated with an increased risk for development of sporadic Alzheimer’s disease (AD) (Kehoe et al., 1999). Homozygosity of the ACE1*D allele has also been associated with an increased risk for coronary artery disease (CAD) (Cambien et al., 1992). Findings of a higher pre- valence of ACE1*D allele in a large cohort of French centenarians compared with younger elderly controls have

Apolipoprotein E (APOE) is a major constituents of very low density lipoproteins, and a polymorphism in APOE, to an even greater degree than the ACE1 polymorphism, has been extensively examined in populations worldwide for its association with an increased risk for CAD and AD (Davignon et al., 1988; Saunders et al., 1993). Recent findings of a higher prevalence of the APOE 1 2 allele and a lower prevalence of the APOE 1 4 allele in centenarians than in younger controls suggested a role of the APOE polymorphism in longevity (Schachter et al., 1994; Louhija et al., 1994; Panza et al., 1999). We have recently shown that the APOE 1 4 allele frequency decreases according to

* Corresponding author. Tel.: þ

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E-mail address: geriat.dot@geriatria.uniba.it (F. Panza).

Panza et al. / Experimental Gerontology 38 (2003) 1015–1020

2.2. APOE and ACE1 genotyping

in centenarians (Panza et al., 1999). Furthermore, our group has also recently reported the novel finding that the frequency of the ACE1*I allele (and ACE1*I/*I genotype) decreases according to a geographical gradient from Northern to Southern Europe in AD patients and sex and age-matched controls (Panza et al., 2003). Considering previous conflicting findings between ACE1 and longevity and our fortunate access to such a rare cohort of individuals we attempted to examine whether the conflicting findings may be the result of similar regional differences in ACE1 allele frequencies as we have observed with APOE (Panza et al., 1999). The first aim of the present study was to examine the distribution of ACE1 genotype and allele frequencies in a sample of Southern Italian centenarians and middle-aged subjects and test for any evidence of association with longevity. Second, we compared our data with previously reported data from Northern (Danish) and Central (French) European populations, that also tested for association between ACE1 variation and longevity (Bladbjerg et al., 1999; Blanche` et al., 2001). With these data we examined the impact of geographical genetic variation on reported longevity associations.

2.3. Statistical analysis