More than 100 genetic variants of AAT have been identified, and these are strictly associated withCentenarians (Table 4). These results indicate that the MZ genotype is an independent negative risk factor for developing AMI in the male Sicilian population. Frequencies were tested for Hardy-Weinberg equilibrium (HWE) using the chi-squared test. Due to the different number of women in the groups under study, logistic regression analysis was performed only in men. We performed multiple logistic regression analysis to test the association of MZ genotype with AMI, taking into account smoking habits, family history of CAD, and the presence of type 2 diabetes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia. The odds ratio (OR) (with CI) was calculated as an exponential of regression coefficient and its standard error. Results: Table 2 shows the frequency of AAT M, Z, S alleles in the groups under study. The Z allele frequency was highest in centenarians (13.3%), intermediate in healthy young controls (3.1%), and least frequent in AMI patients (1.2%) (P = 0.0000001). None of the Sicilian subjects were ZZ, SS homozygotes or SZ heterozygotes. The heterozygous MZ genotype was significantly overrepresented in centenarians (38/143) and underrepresented in AMI patients (3/127) with intermediate values in young controls (16/255) (Table 3, P = 0.0000001). All 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 aneurysmal disease and AAT deficiency due to uninhibited elastase activity on the elastic tissue of arterial walls, but this has not been supported in published 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 fibers may be important in lowering 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 favorable role in CVD because destroying elastic tissue of the arterial wall alters the distensibility of the vessel wall, 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, opposite results have been reported in another study (Talmud et al. 2003). The causes of the discrepancies are not clear, but the inclusion criteria, study populations, and measured endpoints differed substantially between the two studies (Dahl et al. 2003; Talmud et al. 2003). The most common alleles in Caucasoids are the M variants with allele frequencies greater than 0.95; the Z variant occurs with a frequency of 0.010.03 (de Serres et al. 2003; Lomas and Parfrey 2004). Therefore, according to Danish data, our results support a protective role for Z allele in CVD. Additionally, they show a positive role of MZ heterozygosity in attainment of successful aging likely linked to the positive effects of this genotype versus cardiovascular ischemic diseases. Concerning the meaning of our results, as previously discussed, better control of blood pressure in AAT deficiency has been proposed (Robert et al. 1998; Dahl et al. 2003). However, it has to be pointed 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 fewer cleaved fragments of AAT in atherosclerotic plaques and thereby reduce atherosclerotic inflammation and deficiency: genetic aspects of alpha-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax: de Serres FJ, Blanco I, Fernandez-Bustillo E (2003) Genetic epidemiology of alpha-antitrypsin deficiency in southern EuropeC. Innate immunity and inflammation in aging: a key for understanding age-related diseases. Immun Ageing. Lio D, Candore G, Crivello A, Scola L, Colonna-Romano G, Cavallone L, Hoffman E, Caruso M, Licastro F, Caldarera CM, Branzi A, Franceschi C, Caruso C. Opposite effects of IL-common gene polymorphisms in cardiovascular diseases and in successful aging: the genetic background of male centenarians is protective against coronary heart disease. J Med Genet. Lomas DA, Parfrey H. Alpha-antitrypsin deficiency: molecular pathophysiology. Thorax. Luisetti M, Seersholm N. Alpha-antitrypsin deficiency: epidemiology of alpha-antitrypsin deficiency. Thorax. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med. Miller SA, Dykes DD, Polesky HF. A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res.

Acknowledgments
This work was supported by grants from the Italian Ministry of Education, University and Research to GC, DL, GCR, CC. Funds from the Italian Ministry of Health (Markers genetici di sindrome coronarica acuta e valutazione della L-arginina nella prevenzione di eventi ischemici) to CC and CF are also acknowledged. MPG is a PhD student at Pathobiology PhD course (directed by Prof. C.Caruso) of Palermo University and this work is in partial fulfillment of the requirement for the PhD.