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. 2004 Mar;59(3):259–264. doi: 10.1136/thx.2003.006502

α1-Antitrypsin deficiency · 2: Genetic aspects of α1-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk

D DeMeo, E Silverman
PMCID: PMC1746953  PMID: 14985567

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Selected References

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  1. Bartmann K., Fooke-Achterrath M., Koch G., Nagy I., Schütz I., Weis E., Zierski M. Heterozygosity in the Pi-system as a pathogenetic cofactor in chronic obstructive pulmonary disease (COPD). Eur J Respir Dis. 1985 Apr;66(4):284–296. [PubMed] [Google Scholar]
  2. Beatty K., Bieth J., Travis J. Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem. 1980 May 10;255(9):3931–3934. [PubMed] [Google Scholar]
  3. Black L. F., Kueppers F. alpha1-Antitrypsin deficiency in nonsmokers. Am Rev Respir Dis. 1978 Mar;117(3):421–428. doi: 10.1164/arrd.1978.117.3.421. [DOI] [PubMed] [Google Scholar]
  4. Brantly M. L., Paul L. D., Miller B. H., Falk R. T., Wu M., Crystal R. G. Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis. 1988 Aug;138(2):327–336. doi: 10.1164/ajrccm/138.2.327. [DOI] [PubMed] [Google Scholar]
  5. Brennan S. O., Carrell R. W. alpha 1-Antitrypsin Christchurch, 363 Glu----Lys: mutation at the P'5 position does not affect inhibitory activity. Biochim Biophys Acta. 1986 Sep 5;873(1):13–19. doi: 10.1016/0167-4838(86)90183-4. [DOI] [PubMed] [Google Scholar]
  6. Carrell R. W. alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage. J Clin Invest. 1986 Dec;78(6):1427–1431. doi: 10.1172/JCI112731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cox D. W., Levison H. Emphysema of early onset associated with a complete deficiency of alpha-1-antitrypsin (null homozygotes). Am Rev Respir Dis. 1988 Feb;137(2):371–375. doi: 10.1164/ajrccm/137.2.371. [DOI] [PubMed] [Google Scholar]
  8. Cox D. W., Markovic V. D., Teshima I. E. Genes for immunoglobulin heavy chains and for alpha 1-antitrypsin are localized to specific regions of chromosome 14q. Nature. 1982 Jun 3;297(5865):428–430. doi: 10.1038/297428a0. [DOI] [PubMed] [Google Scholar]
  9. Crystal R. G. The alpha 1-antitrypsin gene and its deficiency states. Trends Genet. 1989 Dec;5(12):411–417. doi: 10.1016/0168-9525(89)90200-x. [DOI] [PubMed] [Google Scholar]
  10. Curiel D. T., Holmes M. D., Okayama H., Brantly M. L., Vogelmeier C., Travis W. D., Stier L. E., Perks W. H., Crystal R. G. Molecular basis of the liver and lung disease associated with the alpha 1-antitrypsin deficiency allele Mmalton. J Biol Chem. 1989 Aug 15;264(23):13938–13945. [PubMed] [Google Scholar]
  11. Curiel D. T., Vogelmeier C., Hubbard R. C., Stier L. E., Crystal R. G. Molecular basis of alpha 1-antitrypsin deficiency and emphysema associated with the alpha 1-antitrypsin Mmineral springs allele. Mol Cell Biol. 1990 Jan;10(1):47–56. doi: 10.1128/mcb.10.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dahl Morten, Tybjaerg-Hansen Anne, Lange Peter, Vestbo Jørgen, Nordestgaard Børge G. Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes: A longitudinal study of the general population. Ann Intern Med. 2002 Feb 19;136(4):270–279. doi: 10.7326/0003-4819-136-4-200202190-00006. [DOI] [PubMed] [Google Scholar]
  13. Darlington G. J., Astrin K. H., Muirhead S. P., Desnick R. J., Smith M. Assignment of human alpha 1-antitrypsin to chromosome 14 by somatic cell hybrid analysis. Proc Natl Acad Sci U S A. 1982 Feb;79(3):870–873. doi: 10.1073/pnas.79.3.870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Elliott P. R., Bilton D., Lomas D. A. Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. Am J Respir Cell Mol Biol. 1998 May;18(5):670–674. doi: 10.1165/ajrcmb.18.5.3065. [DOI] [PubMed] [Google Scholar]
  15. Eriksson S. Studies in alpha 1-antitrypsin deficiency. Acta Med Scand Suppl. 1965;432:1–85. [PubMed] [Google Scholar]
  16. Fagerhol M. K., Laurell C. B. The polymorphism of "prealbumins" and alpha-1-antitrypsin in human sera. Clin Chim Acta. 1967 May;16(2):199–203. doi: 10.1016/0009-8981(67)90181-7. [DOI] [PubMed] [Google Scholar]
  17. Frants R. R., Eriksson A. W. alpha1-antitrypsin: common subtypes of Pi M. Hum Hered. 1976;26(6):435–440. doi: 10.1159/000152838. [DOI] [PubMed] [Google Scholar]
  18. Frazier G. C., Siewertsen M. A., Hofker M. H., Brubacher M. G., Cox D. W. A null deficiency allele of alpha 1-antitrypsin, QOludwigshafen, with altered tertiary structure. J Clin Invest. 1990 Dec;86(6):1878–1884. doi: 10.1172/JCI114919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Garver R. I., Jr, Mornex J. F., Nukiwa T., Brantly M., Courtney M., LeCocq J. P., Crystal R. G. Alpha 1-antitrypsin deficiency and emphysema caused by homozygous inheritance of non-expressing alpha 1-antitrypsin genes. N Engl J Med. 1986 Mar 20;314(12):762–766. doi: 10.1056/NEJM198603203141207. [DOI] [PubMed] [Google Scholar]
  20. Hofker M. H., Nukiwa T., van Paassen H. M., Nelen M., Kramps J. A., Klasen E. C., Frants R. R., Crystal R. G. A Pro----Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen. Hum Genet. 1989 Feb;81(3):264–268. doi: 10.1007/BF00279001. [DOI] [PubMed] [Google Scholar]
  21. Hutchison D. C., Tobin M. J., Cook P. J. Alpha 1 antitrypsin deficiency: clinical and physiological features in heterozygotes of Pi type SZ. A survey by the British Thoracic Association. Br J Dis Chest. 1983 Jan;77(1):28–34. doi: 10.1016/0007-0971(83)90003-7. [DOI] [PubMed] [Google Scholar]
  22. Janus E. D., Phillips N. T., Carrell R. W. Smoking, lung function, and alpha 1-antitrypsin deficiency. Lancet. 1985 Jan 19;1(8421):152–154. doi: 10.1016/s0140-6736(85)91916-6. [DOI] [PubMed] [Google Scholar]
  23. Joost Oscar, Wilk Jemma B., Cupples L. Adrienne, Harmon Michael, Shearman Amanda M., Baldwin Clinton T., O'Connor George T., Myers Richard H., Gottlieb Daniel J. Genetic loci influencing lung function: a genome-wide scan in the Framingham Study. Am J Respir Crit Care Med. 2002 Mar 15;165(6):795–799. doi: 10.1164/ajrccm.165.6.2102057. [DOI] [PubMed] [Google Scholar]
  24. Kalsheker N., Hayes K., Weidinger S., Graham A. What is Pi (proteinase inhibitor) null or PiQO?: a problem highlighted by the alpha 1 antitrypsin Mheerlen mutation. J Med Genet. 1992 Jan;29(1):27–29. doi: 10.1136/jmg.29.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lai E. C., Kao F. T., Law M. L., Woo S. L. Assignment of the alpha 1-antitrypsin gene and a sequence-related gene to human chromosome 14 by molecular hybridization. Am J Hum Genet. 1983 May;35(3):385–392. [PMC free article] [PubMed] [Google Scholar]
  26. Larsson C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z. Acta Med Scand. 1978;204(5):345–351. doi: 10.1111/j.0954-6820.1978.tb08452.x. [DOI] [PubMed] [Google Scholar]
  27. Lewis J. H., Iammarino R. M., Spero J. A., Hasiba U. Antithrombin Pittsburgh: an alpha1-antitrypsin variant causing hemorrhagic disease. Blood. 1978 Jan;51(1):129–137. [PubMed] [Google Scholar]
  28. Long G. L., Chandra T., Woo S. L., Davie E. W., Kurachi K. Complete sequence of the cDNA for human alpha 1-antitrypsin and the gene for the S variant. Biochemistry. 1984 Oct 9;23(21):4828–4837. doi: 10.1021/bi00316a003. [DOI] [PubMed] [Google Scholar]
  29. Luisetti M., Seersholm N. Alpha1-antitrypsin deficiency. 1: epidemiology of alpha1-antitrypsin deficiency. Thorax. 2004 Feb;59(2):164–169. doi: 10.1136/thorax.2003.006494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mahadeva R., Lomas D. A. Genetics and respiratory disease. 2. Alpha 1-antitrypsin deficiency, cirrhosis and emphysema. Thorax. 1998 Jun;53(6):501–505. doi: 10.1136/thx.53.6.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Malhotra Alka, Peiffer Andy P., Ryujin Darin T., Elsner Tami, Kanner Richard E., Leppert Mark F., Hasstedt Sandra J. Further evidence for the role of genes on chromosome 2 and chromosome 5 in the inheritance of pulmonary function. Am J Respir Crit Care Med. 2003 Jun 5;168(5):556–561. doi: 10.1164/rccm.200303-410OC. [DOI] [PubMed] [Google Scholar]
  32. Martin N. G., Clark P., Ofulue A. F., Eaves L. J., Corey L. A., Nance W. E. Does the PI polymorphism alone control alpha-1-antitrypsin expression? Am J Hum Genet. 1987 Mar;40(3):267–277. [PMC free article] [PubMed] [Google Scholar]
  33. Novoradovsky A., Brantly M. L., Waclawiw M. A., Chaudhary P. P., Ihara H., Qi L., Eissa N. T., Barnes P. M., Gabriele K. M., Ehrmantraut M. E. Endothelial nitric oxide synthase as a potential susceptibility gene in the pathogenesis of emphysema in alpha1-antitrypsin deficiency. Am J Respir Cell Mol Biol. 1999 Mar;20(3):441–447. doi: 10.1165/ajrcmb.20.3.3144. [DOI] [PubMed] [Google Scholar]
  34. Ogushi F., Fells G. A., Hubbard R. C., Straus S. D., Crystal R. G. Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase. J Clin Invest. 1987 Nov;80(5):1366–1374. doi: 10.1172/JCI113214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Owen M. C., Brennan S. O., Lewis J. H., Carrell R. W. Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder. N Engl J Med. 1983 Sep 22;309(12):694–698. doi: 10.1056/NEJM198309223091203. [DOI] [PubMed] [Google Scholar]
  36. Palmer Lyle J., Celedón Juan C., Chapman Harold A., Speizer Frank E., Weiss Scott T., Silverman Edwin K. Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. Hum Mol Genet. 2003 May 15;12(10):1199–1210. doi: 10.1093/hmg/ddg125. [DOI] [PubMed] [Google Scholar]
  37. Piitulainen E., Tornling G., Eriksson S. Effect of age and occupational exposure to airway irritants on lung function in non-smoking individuals with alpha 1-antitrypsin deficiency (PiZZ). Thorax. 1997 Mar;52(3):244–248. doi: 10.1136/thx.52.3.244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Riva A., Kohane I. S. SNPper: retrieval and analysis of human SNPs. Bioinformatics. 2002 Dec;18(12):1681–1685. doi: 10.1093/bioinformatics/18.12.1681. [DOI] [PubMed] [Google Scholar]
  39. Sandford A. J., Chagani T., Weir T. D., Connett J. E., Anthonisen N. R., Paré P. D. Susceptibility genes for rapid decline of lung function in the lung health study. Am J Respir Crit Care Med. 2001 Feb;163(2):469–473. doi: 10.1164/ajrccm.163.2.2006158. [DOI] [PubMed] [Google Scholar]
  40. Schapira M., Ramus M. A., Jallat S., Carvallo D., Courtney M. Recombinant alpha 1-antitrypsin Pittsburgh (Met 358----Arg) is a potent inhibitor of plasma kallikrein and activated factor XII fragment. J Clin Invest. 1986 Feb;77(2):635–637. doi: 10.1172/JCI112347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schroeder W. T., Miller M. F., Woo S. L., Saunders G. F. Chromosomal localization of the human alpha 1-antitrypsin gene (PI) to 14q31-32. Am J Hum Genet. 1985 Sep;37(5):868–872. [PMC free article] [PubMed] [Google Scholar]
  42. Scott C. F., Carrell R. W., Glaser C. B., Kueppers F., Lewis J. H., Colman R. W. Alpha-1-antitrypsin-Pittsburgh. A potent inhibitor of human plasma factor XIa, kallikrein, and factor XIIf. J Clin Invest. 1986 Feb;77(2):631–634. doi: 10.1172/JCI112346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Seersholm N., Kok-Jensen A. Intermediate alpha 1-antitrypsin deficiency PiSZ: a risk factor for pulmonary emphysema? Respir Med. 1998 Feb;92(2):241–245. doi: 10.1016/s0954-6111(98)90102-0. [DOI] [PubMed] [Google Scholar]
  44. Seersholm N., Wilcke J. T., Kok-Jensen A., Dirksen A. Risk of hospital admission for obstructive pulmonary disease in alpha(1)-antitrypsin heterozygotes of phenotype PiMZ. Am J Respir Crit Care Med. 2000 Jan;161(1):81–84. doi: 10.1164/ajrccm.161.1.9812131. [DOI] [PubMed] [Google Scholar]
  45. Seyama K., Nukiwa T., Souma S., Shimizu K., Kira S. Alpha 1-antitrypsin-deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan. Status of alpha 1-antitrypsin deficiency in Japan. Am J Respir Crit Care Med. 1995 Dec;152(6 Pt 1):2119–2126. doi: 10.1164/ajrccm.152.6.8520784. [DOI] [PubMed] [Google Scholar]
  46. Seyama K., Nukiwa T., Takabe K., Takahashi H., Miyake K., Kira S. Siiyama (serine 53 (TCC) to phenylalanine 53 (TTC)). A new alpha 1-antitrypsin-deficient variant with mutation on a predicted conserved residue of the serpin backbone. J Biol Chem. 1991 Jul 5;266(19):12627–12632. [PubMed] [Google Scholar]
  47. Sifers R. N., Brashears-Macatee S., Kidd V. J., Muensch H., Woo S. L. A frameshift mutation results in a truncated alpha 1-antitrypsin that is retained within the rough endoplasmic reticulum. J Biol Chem. 1988 May 25;263(15):7330–7335. [PubMed] [Google Scholar]
  48. Silverman E. K., Pierce J. A., Province M. A., Rao D. C., Campbell E. J. Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates. Ann Intern Med. 1989 Dec 15;111(12):982–991. doi: 10.7326/0003-4819-111-12-982. [DOI] [PubMed] [Google Scholar]
  49. Silverman E. K., Province M. A., Campbell E. J., Pierce J. A., Rao D. C. Family study of alpha 1-antitrypsin deficiency: effects of cigarette smoking, measured genotype, and their interaction on pulmonary function and biochemical traits. Genet Epidemiol. 1992;9(5):317–331. doi: 10.1002/gepi.1370090504. [DOI] [PubMed] [Google Scholar]
  50. Silverman E. K., Province M. A., Campbell E. J., Pierce J. A., Rao D. C. Variability of pulmonary function in alpha-1-antitrypsin deficiency: residual family resemblance beyond the effect of the Pi locus. Hum Hered. 1990;40(6):340–355. doi: 10.1159/000153958. [DOI] [PubMed] [Google Scholar]
  51. Silverman E. K., Province M. A., Rao D. C., Pierce J. A., Campbell E. J. A family study of the variability of pulmonary function in alpha 1-antitrypsin deficiency. Quantitative phenotypes. Am Rev Respir Dis. 1990 Nov;142(5):1015–1021. doi: 10.1164/ajrccm/142.5.1015. [DOI] [PubMed] [Google Scholar]
  52. Silverman Edwin K., Mosley Jonathan D., Palmer Lyle J., Barth Matthew, Senter Jody M., Brown Alison, Drazen Jeffrey M., Kwiatkowski David J., Chapman Harold A., Campbell Edward J. Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes. Hum Mol Genet. 2002 Mar 15;11(6):623–632. doi: 10.1093/hmg/11.6.623. [DOI] [PubMed] [Google Scholar]
  53. Silverman Edwin K., Palmer Lyle J., Mosley Jonathan D., Barth Matthew, Senter Jody M., Brown Alison, Drazen Jeffrey M., Kwiatkowski David J., Chapman Harold A., Campbell Edward J. Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet. 2002 Mar 25;70(5):1229–1239. doi: 10.1086/340316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Sugiura T., Masuzawa Y., Nakagawa Y., Waku K. Transacylation of lyso platelet-activating factor and other lysophospholipids by macrophage microsomes. Distinct donor and acceptor selectivities. J Biol Chem. 1987 Jan 25;262(3):1199–1205. [PubMed] [Google Scholar]
  55. Takahashi H., Crystal R. G. Alpha 1-antitrypsin Null(isola di procida): an alpha 1-antitrypsin deficiency allele caused by deletion of all alpha 1-antitrypsin coding exons. Am J Hum Genet. 1990 Sep;47(3):403–413. [PMC free article] [PubMed] [Google Scholar]
  56. Takahashi H., Nukiwa T., Satoh K., Ogushi F., Brantly M., Fells G., Stier L., Courtney M., Crystal R. G. Characterization of the gene and protein of the alpha 1-antitrypsin "deficiency" allele Mprocida. J Biol Chem. 1988 Oct 25;263(30):15528–15534. [PubMed] [Google Scholar]
  57. Tobin M. J., Cook P. J., Hutchison D. C. Alpha 1 antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. A survey by the British Thoracic Association. Br J Dis Chest. 1983 Jan;77(1):14–27. doi: 10.1016/0007-0971(83)90002-5. [DOI] [PubMed] [Google Scholar]
  58. Travis J., Salvesen G. S. Human plasma proteinase inhibitors. Annu Rev Biochem. 1983;52:655–709. doi: 10.1146/annurev.bi.52.070183.003255. [DOI] [PubMed] [Google Scholar]
  59. Turino G. M., Barker A. F., Brantly M. L., Cohen A. B., Connelly R. P., Crystal R. G., Eden E., Schluchter M. D., Stoller J. K. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. 1996 Dec;154(6 Pt 1):1718–1725. doi: 10.1164/ajrccm.154.6.8970361. [DOI] [PubMed] [Google Scholar]
  60. Turleau C., de Grouchy J., Chavin-Colin F., Dore F., Seger J., Dautzenberg M. D., Arthuis M., Jeanson C. Two patients with interstitial del (14q), one with features of Holt-Oram syndrome. Exclusion mapping of PI (alpha-1-antitrypsin). Ann Genet. 1984;27(4):237–240. [PubMed] [Google Scholar]
  61. Yamamoto Y., Sawa R., Okamoto N., Matsui A., Yanagisawa M., Ikemoto S. Deletion 14q(q24.3 to q32.1) syndrome: significance of peculiar facial appearance in its diagnosis, and deletion mapping of Pi(alpha 1-antitrypsin). Hum Genet. 1986 Oct;74(2):190–192. doi: 10.1007/BF00282092. [DOI] [PubMed] [Google Scholar]
  62. de Serres Frederick J. Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest. 2002 Nov;122(5):1818–1829. doi: 10.1378/chest.122.5.1818. [DOI] [PubMed] [Google Scholar]

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