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Alpha1-antitrypsin heterozygosity plays a positive role in attainment of longevity

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Abstract

Genes involved in cardiovascular diseases (CVD) play an opposite role in human longevity. The α1-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 definitively assessed and its effect on longevity has not yet fully been studied. To clarify these points, we have studied the distribution of AAT allele variants 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 centenarians (13.3%), intermediate in healthy young controls (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 positive role of MZ heterozygosity in attainment of successful ageing linked to the positive effects of this genotype versus the cardiovascular ischemic diseases.

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References

  • Balistreri CR, Candore G, Colonna-Romano G, Lio D, Caruso M, Hoffman E, Franceschi C, Caruso C (2004) Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA 292:2339–2340

    Article  PubMed  CAS  Google Scholar 

  • Bessenyei B, Marka M, Urban L, Zeher M, Semsei I (2004). Single nucleotide polymorphisms: aging and diseases. Biogerontology 5:291–303

    Article  PubMed  CAS  Google Scholar 

  • Candore G, Colonna-Romano G, Balistreri CR, Di Carlo D, Grimaldi MP, Listi F, Nuzzo D, Vasto S, Lio D, Caruso C (2006a) Biology of longevity: role of the innate immune system. Rejuvenation Res 9:143–148

    Article  CAS  Google Scholar 

  • Candore G, Vasto S, Colonna-Romano G Lio D, Caruso M, Rea IM, Caruso C (2006b) Cytokine gene polymorphisms and atherosclerosis. In: Vandenbroeck K (ed) Cytokine gene polymorphisms in multifactorial conditions. ISBN: 0849336198. Florida, CRC press

  • Caruso C, Candore G, Cavallone L, Colonna-Romano G, Scola L, Hoffman E, Caruso M, Franceschi C, Lio D (2004) Genetic background of centenarians may be protective against cardiovascular diseases. International Congress of Immunology 29–34. ISBN/ISSN: 88-7857-070-5

  • Caruso C, Candore G, Colonna-Romano G, Lio D, Franceschi C (2005) Inflammation and life-span. Science 307:208–209

    Article  PubMed  CAS  Google Scholar 

  • Cox DW (1995) Alpha-1 antitrypsin deficiency. In: Scriver C, Beaudet A, Sly W, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, p 4125

  • Dahl M, Tybjaerg-Hansen A, Sillesen H, Jensen G, Steffensen R, Nordestgaard BG (2003) Blood Pressure, risk of ischemic cerebrovascular and ischemic heart disease, and longevity in α1-antitrypsin deficiency. Circulation 107:747–752

    Article  PubMed  CAS  Google Scholar 

  • De Meo DL, Silverman EK (2004) α1-antitrypsin deficiency 2: genetic aspects of α1-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax 59:259–264

    Article  Google Scholar 

  • de Serres FJ, Blanco I, Fernandez-Bustillo E (2003) Genetic epidemiology of alpha-1 antitrypsin deficiency in southern Europe: France, Italy, Portugal and Spain. Clin Genet 63:490–509

    Article  PubMed  Google Scholar 

  • Dichtl W, Moraga F, Ares MPS, Crisby M, Nilsson J, Lindgren S, Janciauskiene S (2000) The carboxyl-terminal fragment of α1-antitrypsin is present in atherosclerotic plaques and regulates inflammatory transcription factors in primary human monocytes. Mol Cell Biol Res Comm 4:50–61

    Article  CAS  Google Scholar 

  • Franceschi C, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Capri M, Salvioli S, Valensin S, De Benedictis G, Di Iorio A, Caruso C, Paolisso G, Monti D (2005) Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians. Mech Ageing Dev 126:351–361

    Article  PubMed  CAS  Google Scholar 

  • Grimaldi MP, Candore G, Vasto S , Caruso M, Caimi G, Hoffman E, Colonna-Romano G, Lio D, Shinar Y, Franceschi C, Caruso C (2006) Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population. J Leukoc Biol 79:611–615

    Article  PubMed  CAS  Google Scholar 

  • Hersh CP, Dahl M, Ly NP, Berkey CS, Nordestgaard BG, Silverman EK (2004) Chronic obstructive pulmonary disease in α 1-antitrypsin PiMZ heterozygotes: a meta-analysis. Thorax 59:843–849

    Article  PubMed  CAS  Google Scholar 

  • Lam CWK, Pang CP, Poon PMK, Yin CH, Bharathi G (1997) Rapid Screening for α1-antitrypsin Z and S mutations. Clin Chem 43:403–404

    PubMed  CAS  Google Scholar 

  • Licastro F, Candore G, Lio D, Porcellini E, Colonna-Romano G, Franceschi C, Caruso C (2005) Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immun Ageing 2:8

    Article  PubMed  CAS  Google Scholar 

  • 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 (2004) Opposite effects of IL-10 common gene polimorphisms in cardiovascular diseases and in successful ageing: genetic background of male centenarians is protective against coronary heart disease. J Med Genet 41:790–794

    Article  PubMed  CAS  Google Scholar 

  • Lomas DA, Parfrey H (2004) α1-antitrypsin deficiency 4: Molecular pathophysiology. Thorax 59:529–535

    Article  PubMed  CAS  Google Scholar 

  • Luisetti M, Seersholm N (2004) α1-antitrypsin deficiency 1: Epidemiology of α1-antitrypsin deficiency. Thorax 59:164–169

    Article  PubMed  CAS  Google Scholar 

  • Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U (1994) Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 330:1041–1046

    Article  PubMed  CAS  Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1998) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 16:1215

    Article  Google Scholar 

  • Needham M, Stockley RA (2004) α1-antitrypsin deficiency 3: Clinical manifestations and natural history. Thorax 59:441–445

    Article  PubMed  CAS  Google Scholar 

  • Ooyama T, Sakamato H (1995) Elastase in the prevention of arterial ageing and the treatment of atherosclerosis. In: The molecular biology and patology of elastic tissues. Ciba Found Symp 192:307–320

  • Robert L, Robert AM, Jacotot B (1998) Elastin-elastase-atherosclerosis revisited. Atherosclerosis 140:281–295

    Article  PubMed  CAS  Google Scholar 

  • Seersholm N (2004) PiMZ and COPD: will we ever Know? Thorax 59:823–825

    Article  PubMed  CAS  Google Scholar 

  • Seersholm N, Wilcke JTR, Kok-Jensen A, Dirksen A (2000) Risk of hospital admission for obstructive pulmonary disease in α1-antitrypsin heterozygotes of phenotype PiMZ. Am J Respir Crit Care Med 161:81–84

    PubMed  CAS  Google Scholar 

  • St Jean P, Hart B, Webster M, Steed D, Adamson J, Powell J, Ferrell R (1996) Alpha-1-antitrypsin deficiency in aneurysmal disease. Hum Hered 46:92–97

    Article  PubMed  CAS  Google Scholar 

  • Talmud PJ, Martin S, Steiner G, Flavell DM, Whitehouse DB, Nagl S, Jackson R, Taskinen MR, Frick MH, Nieminen MS, Kesaniemi YA, Pasternack A, Humphries SE, Syvanne M (2003) Progression of atherosclerosis is associated with variation in the α1- antitrypsin gene. Arterioscler Thromb Vasc Biol 23:644–649

    Article  PubMed  CAS  Google Scholar 

  • Tazelaar JP, Friedman KJ, Kline RS, Guthrie ML, Farber RA (1992). Detection of α1-antitrypsin Z and S mutations by polymerase chain reaction-mediated site-directed mutagenesis. Clin Chem 38:1486–1488

    PubMed  CAS  Google Scholar 

  • Terry DF, Wilcox M, McCormick MA, Lawler E, Perls TT (2004) Cardiovascular advantages among the offspring of centenarians. J Gerontol A Biol Sci Med Sci 58:425–431

    Google Scholar 

  • Zureik M, Robert L, Courbon D (2002) Serum elastase activity, serum elastase inhibitors, and occurrence of carotid atherosclerotic plaques: the etude sur le vieillissement arteriel (EVA) study. Circulation 105:2638–2645

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the Italian Ministry of Education, University and Research to GC, DL, GCR, CC. Funds from 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 fulfilment of the requirement for the PhD.

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Authors and Affiliations

  1. Dipartimento di Biopatologia e Metodologie Biomediche, Gruppo di Studio sull’Immunosenescenza, Corso Tukory 211, Palermo, 90134, Italy

    Florinda Listì, Giuseppina Candore, Maria Paola Grimaldi, Domenico Lio, Giuseppina Colonna-Romano, Valentina Orlando & Calogero Caruso

  2. Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, Università di Palermo, Palermo, Italy

    Marco Caruso & Enrico Hoffmann

  3. Dipartimento di Medicina Geriatria e Malattie Metaboliche, II Università di Napoli, Napoli, Italy

    Giuseppe Paolisso

  4. Dipartimento di Patologia Sperimentale and Centro Interdipartimentale “L. Galvani”, Università di Bologna, Bologna, Italy

    Claudio Franceschi

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

    Claudio Franceschi

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  1. Florinda Listì
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  2. Giuseppina Candore
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  3. Maria Paola Grimaldi
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  4. Domenico Lio
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  5. Giuseppina Colonna-Romano
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  6. Valentina Orlando
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  7. Marco Caruso
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  8. Enrico Hoffmann
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  9. Giuseppe Paolisso
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  10. Claudio Franceschi
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  11. Calogero Caruso
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Correspondence to Giuseppina Candore.

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Listì, F., Candore, G., Grimaldi, M.P. et al. Alpha1-antitrypsin heterozygosity plays a positive role in attainment of longevity. Biogerontology 8, 139–145 (2007). https://doi.org/10.1007/s10522-006-9041-y

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  • DOI: https://doi.org/10.1007/s10522-006-9041-y

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