heterozygosity plays a positive in attainment of longevity

Received: 6 June 2006/Accepted: 7 August 2006/Published online: 20 September 2006   Springer Science+Business Media B.V. 2006

Abstract Genes involved in cardiovascular dis- eases (CVD) play an opposite role in human longevity. The a1-antitrypsin (AAT) is a serine- protease inhibitor required for the prevention of proteolytic tissue damage, by neutrophil elastase. The role of AAT in CVD has not been defini- tively assessed and its effect on longevity has not yet fully been studied. To clarify these points, we

have studied the distribution of AAT allele vari- ants in 3 cohorts: 127 young patients affected by acute myocardial infarction (AMI), 255 young controls and 143 centenarians from Sicily. The Z allele frequency was most frequent in centenari- ans (13.3%), intermediate in healthy young con- trols (3.1%) and less frequent in AMI patients (1.2%) (P = 0.0000001). 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) (P = 0.0000001). After adjustment for well-recognized AMI risk factors, the MZ genotype still predicted a significant negative risk factor for developing AMI in the Sicilian population. Thus, our data show a posi- tive role of MZ heterozygosity in attainment of successful ageing linked to the positive effects of this genotype versus the cardiovascular ischemic diseases.

F. Listı` Æ G. Candore (&) Æ M. P. Grimaldi Æ D. Lio Æ G. Colonna-Romano Æ V. Orlando Æ C. Caruso Dipartimento di Biopatologia e Metodologie Biomediche, Gruppo di Studio sull’Immunosenescenza, Corso Tukory

, Palermo

, Italy e-mail: gcandore@unipa.it

G. Paolisso

Dipartimento di Medicina Geriatria e Malattie Metaboliche, II Universita` di Napoli, Napoli, Italy

Centenarian offspring, that have an increased likelihood of surviving up to 100 years, show a reduced prevalence of cardiovascular diseases (CVD), and less frequency of cardiovascular risk

Istituto Nazionale di Riposo e Cura per Anziani, Ancona, Italy

Alpha-1 antitrypsin (AAT), also referred to as a -proteinase inhibitor (Pi), is a 52 kD glycopro- 1 tein secreted by hepatocytes and, to a lesser extent, by lung epithelial cells and phagocytes, into the plasma at a concentration of 1.9–3.5 mg/ml. It is proposed to play an important role in protect- ing vulnerable elastic tissue in the lungs, gut, and vasculature from degradation by neutrophil elas- tase and its severe deficiency is involved in chronic obstructive pulmonary disease (COPD) (De Meo and Silverman 2004; Lomas and Parfrey 2004; Luisetti and Seersholm 2004). The Pi gene, located on chromosome 14q32.1 (OMIM: 107400), is 12.2 Kb in length with seven exons and six introns. The encoded protein includes 394 amino acids with the active site of the enzyme inhibitor at methionine 358. It inhibits a variety of serine proteinases but its preferred target is neu- trophil elastase that is bound to active site and permanently inactivated (De Meo and Silverman

assessed. A Danish study (Dahl et al. found that ZZ AAT deficiency and MZ deficiency patients affected by cor- artery disease (CAD) have lower blood than MM/MS patients. Furthermore, heterozygosity was associated with reduced of ischemic cerebrovascular disease (ICVD) CAD. The authors supposed that neutrophil can play a favourable role in CVD destroying elastic tissue of the arterial it alters the distensibility of the vessel wall thus blood pressure and cardiac load. Since blood pressure is protective against ICVD CAD, AAT deficiency might be associated reduced risk of development of these dis- through this mechanism (Ooyama and 1995; Zureik et al. 2002; Dahl et al. However, in that year, another report seemingly contrasting results (Talmud al. 2003). In fact, the other authors demon- that the progression of atherosclerosis was with low AAT levels. They suggested elastase activity attributable to AAT defi- accelerates hardening of arterial walls and (Talmud et al. 2003). However, analysis was very limited in scope and num- (several dozens of patients), and mostly dealt

More than 100 genetic variants of AAT have been identified and these are strictly associated with specific AAT plasma levels in a co-domi- nantly inherited fashion. Current listings of all polymorphisms can be derived by visiting a database found at: http://www.innateimmuni- ty.net (De Meo and Silverman 2004; Luisetti and Seersholm 2004). The most common allele is PiM; MM homozygotes product a normal level of AAT. Other common variants are PiZ and PiS. The PiZ variant, Glu342 to Lys, results in a severe protein deficiency that is characterised in the homozygote state by levels of plasma concentra- tions lower by 84% when compared with levels in MM individuals and in the MZ heterozygote state by intermediate levels lower by 17%. So, Z homozygosity is a proven genetic risk factor for COPD and emphysema. The PiS variant, Glu264 to Val, is associated in homozygosity with AAT levels lower by 7% when compared with levels in MM and in MS individuals with AAT levels lower by 3%. This S variant is not associated to an increased chance of the symptomatology by defi- ciency syndrome. However, PI MZ and PI MS