Results

Table 2 shows the frequency of AAT M, Z, S alleles in the groups under study. The Z allele frequency was most frequent in centenarians (13.3%), intermediate in healthy young controls (3.1%) and less frequent in AMI patients (1.2%) (P = 0.0000001). None of the Sicilian subjects was the ZZ, SS homozygotes and SZ heterozygotes. The heterozygous MZ genotype was significantly over represented in centenarians (38/143) and under represented in AMI patients (3/127) with intermediate values in young controls (16/255) (Table 3, P = 0.0000001). All the genotypes were in HWE.

Discussion

The risk of CVD in patients with severe AAT deficiency has not been sufficiently investigated to formulate firm conclusions. There should be a theoretical association between aortic aneurismal disease and AAT deficiency due to uninhibited

By performing a series of 2 · 2 separate comparisons, high significance for the different

Table 2 Frequency of alleles of AAT in 143 Centenarians, 127 AMI patients and 255 controls from Sicily

Alleles Allele M Allele Z Allele S Centenarians 242 (85%) 38 (13.3%) 5 (1.7%) AMI Patients 249 (98%) 3 (1.2%) 2 (0.8%) Young controls 486 (95.3%) 16 (3.1%) 8 (1.6%)

Significance was obtained by v2 (3 · 3 table) as the alleles were distributed unevenly between the three (P = 0.0000001)

Table 3 Prevalence of the heterozygous MZ genotype in 143 Centenarians, 127 AMI patients and 255 controls from Sicily

Genotypes MM MZ MS Centenarians 100 (70%) 38 (26.5%) 5 (3.5%) AMI Patients 122 (96%) 3 (2.4%) 2 (1.6%) Young controls 231 (90.5%) 16 (6.3%) 8 (3.2%)

Significance was obtained by v2 (3 · 3 Table) for the MZ genotype which was distributed unevenly between the cohorts (P = 0.0000001)

Table 4 2 · 2 Comparisons between the different groups with odd ratio (OR) and confidence interval (CI)

Centenarians (N = 143) Young controls (N = 255) AMI patients (N = 127) Centenarians (MZ genotypes) P < 0.0001 OR 0.185 (0.098–0.35) P < 0.0001 OR 0.06 (0.02–0.22) Centenarians (Z allele) P < 0.0001 OR 0.21 (0.115–0.39) P < 0.0001 OR 0.078 (0.02–0.25)

The frequency of MZ genotype and Z allele in AMI was lower (but not significantly) than that observed in the young control cohort. Taking into account smoking habits, family history of CAD, and the presence of type 2 diabetes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia, significant differences in genotype frequency persisted be- tween male AMI patients (N = 117) and male centenarians (N = 46) (P < 0.0001, OR 0.0544 (0.015–0.19)) and were found male AMI patients (N = 117) and male young controls (N = 107) (P < 0.0001; OR 0.35 (0.01–0.15) (by multiple logistic

elastase activity on the elastic tissue of arterial walls, but this has not been supported in pub- lished data nor has an association been shown with intracranial aneurysms (St Jean et al. 1996; Needham and Stockley 2004). However, elastin is a major component of vessel wall elastic lamina, and degradation of elastic fibbers may be impor- tant in the lowering of blood pressure, which is a well-known risk factor for CVD and AMI. Increased elastase activity attributable to AAT deficiency has therefore been claimed to play a favourable role in CVD because destroying elas- tic tissue of the arterial wall, it alters the disten- sibility of the vessel wall and so blood pressure and cardiac load (Robert et al. 1998; Dahl et al. 2003). In fact, in a Danish study the PI Z and PIMZ phenotypes have been associated with lower blood pressure in men and PI MZ has been associated with a reduced risk of ICVD and CAD (Dahl et al. 2003). However, in another study opposite results have been reported (Talmud et al. 2003). The causes of the discrepancies are not clear, but the inclusion criteria, the study populations, and the measured endpoint differed substantially among the two studies (Dahl et al. 2003; Talmud et al. 2003).

population since the frequencies of healthy con- trols are close to those expected from literature data. In Caucasoids the most common alleles are the M variants with allele frequencies of greater than 0.95, the Z variant occurring with a fre- quency of 0.01–0.03 (de Serres et al. 2003; Lomas and Parfrey 2004). So, according to Danish data, our results support a protective role for Z allele in CVD. Besides, they show a positive role of MZ heterozygosity in attainment of successful ageing likely linked to the positive effects of this geno- type versus the cardiovascular ischemic diseases. Concerning the meaning of our results, as

Concerning the meaning of our results, as previously discussed, a better control of blood pressure in AAT deficiency has been proposed (Robert et al. 1998; Dahl et al. 2003). However, it has to point out that the interaction of AAT with elastase results in the suicide cleavage of AAT. During this process, the C-terminal 36 amino acids (C-36) are cleaved off yet remain attached to the complex. This C-36 cleaved peptide is biologically active and increases low-density lipoprotein (LDL) binding and internalization, upregulates the LDL-receptor, induces cytokine and glutathione production. Thus, there is strong suggestive evidence that C-36 participates in inflammatory processes involved in atherogenesis. AAT deficiency could lead to less cleaved frag- ments of AAT in atherosclerotic plaques and thereby reduce atherosclerotic inflammation and

The aim of this report was to investigate whe- ther the variants of AAT gene play an opposite role in AMI and longevity. To this purpose, all the subjects were screened for M, Z and S alleles which are the more common variants. We found a higher frequency of MZ heterozygosity and Z allele in centenarians respect to controls and AMI patients. In agreement with these results, Z allele was overrepresented in longevous and underrep- resented in patients with AMI with intermediate value in young controls. These results are not due to bias in allele frequencies assessment in our