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. 1998 Dec;53(12):1022–1024. doi: 10.1136/thx.53.12.1022

Alpha-1 antitrypsin deficiency alleles and severe cystic fibrosis lung disease

R Mahadeva 1, S Stewart 1, D Bilton 1, D Lomas 1
PMCID: PMC1745129  PMID: 10195072

Abstract

BACKGROUND—Alpha-1 antitrypsin (α1-AT) is the most abundant proteinase inhibitor within the lung. We have recently reported the surprising observation that cystic fibrosis patients with mild to moderate deficiency of α1-antitrypsin have significantly better pulmonary function than non-deficient patients. This study may have been biased as it did not include the most severely affected patients who have died in childhood or those who have undergone orthotopic lung transplantation. The prevalence of α1-antitrypsin deficiency alleles in this most severely affected group of patients with cystic fibrosis was therefore assessed.
METHODS—DNA was obtained from neonatal blood spots from children with cystic fibrosis who had died from pulmonary disease and from formalin fixed lung tissue from transplanted cystic fibrosis patients. The common S and Z deficiency alleles of α1-AT were sought by amplification mutagenesis of the appropriate region of the α1-AT gene followed by restriction enzyme digestion with Xmn I and Taq I, respectively.
RESULTS—Seventy nine patients were identified (seven dead, 72 transplanted). Two patients (2.5%) were heterozygous for the Z allele of α1-AT and four (5.1%) were heterozygous for the S allele. This is not significantly different from the incidence in the normal population of 4% and 8% for the S and Z alleles, respectively.
CONCLUSIONS—These data support previous findings that deficiency of α1-AT is not associated with more severe pulmonary disease in cystic fibrosis and may be associated with milder lung disease. Further work is needed to clarify the mechanisms underlying the progressive lung damage in cystic fibrosis.



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Selected References

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  1. Andresen B. S., Knudsen I., Jensen P. K., Rasmussen K., Gregersen N. Two novel nonradioactive polymerase chain reaction-based assays of dried blood spots, genomic DNA, or whole cells for fast, reliable detection of Z and S mutations in the alpha 1-antitrypsin gene. Clin Chem. 1992 Oct;38(10):2100–2107. [PubMed] [Google Scholar]
  2. Belaaouaj A., McCarthy R., Baumann M., Gao Z., Ley T. J., Abraham S. N., Shapiro S. D. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat Med. 1998 May;4(5):615–618. doi: 10.1038/nm0598-615. [DOI] [PubMed] [Google Scholar]
  3. Carrell R. W. Alpha 1-antitrypsin, emphysema and smoking. N Z Med J. 1984 May 23;97(756):327–328. [PubMed] [Google Scholar]
  4. Colp C., Pappas J., Moran D., Lieberman J. Variants of alpha 1-antitrypsin in Puerto Rican children with asthma. Chest. 1993 Mar;103(3):812–815. doi: 10.1378/chest.103.3.812. [DOI] [PubMed] [Google Scholar]
  5. Cook P. J. Genetic aspects of the Pi system. Postgrad Med J. 1974 Jun;50(584):362–364. doi: 10.1136/pgmj.50.584.362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Döring G., Goldstein W., Botzenhart K., Kharazmi A., Schiøtz P. O., Høiby N., Dasgupta M. Elastase from polymorphonuclear leucocytes: a regulatory enzyme in immune complex disease. Clin Exp Immunol. 1986 Jun;64(3):597–605. [PMC free article] [PubMed] [Google Scholar]
  7. Döring G., Krogh-Johansen H., Weidinger S., Høiby N. Allotypes of alpha 1-antitrypsin in patients with cystic fibrosis, homozygous and heterozygous for deltaF508. Pediatr Pulmonol. 1994 Jul;18(1):3–7. doi: 10.1002/ppul.1950180104. [DOI] [PubMed] [Google Scholar]
  8. Döring G. The role of neutrophil elastase in chronic inflammation. Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 2):S114–S117. doi: 10.1164/ajrccm/150.6_Pt_2.S114. [DOI] [PubMed] [Google Scholar]
  9. Fick R. B., Jr, Naegel G. P., Squier S. U., Wood R. E., Gee J. B., Reynolds H. Y. Proteins of the cystic fibrosis respiratory tract. Fragmented immunoglobulin G opsonic antibody causing defective opsonophagocytosis. J Clin Invest. 1984 Jul;74(1):236–248. doi: 10.1172/JCI111407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Geddes D. M., Webley M., Brewerton D. A., Turton C. W., Turner-Warwick M., Murphy A. H., Ward A. M. alpha 1-antitrypsin phenotypes in fibrosing alveolitis and rheumatoid arthritis. Lancet. 1977 Nov 19;2(8047):1049–1051. doi: 10.1016/s0140-6736(77)91883-9. [DOI] [PubMed] [Google Scholar]
  11. Goldstein W., Döring G. Lysosomal enzymes from polymorphonuclear leukocytes and proteinase inhibitors in patients with cystic fibrosis. Am Rev Respir Dis. 1986 Jul;134(1):49–56. doi: 10.1164/arrd.1986.134.1.49. [DOI] [PubMed] [Google Scholar]
  12. Hubbard R., Baoku Y., Kalsheker N., Britton J., Johnston I. Alpha1-antitrypsin phenotypes in patients with cryptogenic fibrosing alveolitis: a case-control study. Eur Respir J. 1997 Dec;10(12):2881–2883. doi: 10.1183/09031936.97.10122881. [DOI] [PubMed] [Google Scholar]
  13. King M. A., Stone J. A., Diaz P. T., Mueller C. F., Becker W. J., Gadek J. E. Alpha 1-antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology. 1996 Apr;199(1):137–141. doi: 10.1148/radiology.199.1.8633137. [DOI] [PubMed] [Google Scholar]
  14. Mahadeva R., Westerbeek R. C., Perry D. J., Lovegrove J. U., Whitehouse D. B., Carroll N. R., Ross-Russell R. I., Webb A. K., Bilton D., Lomas D. A. Alpha1-antitrypsin deficiency alleles and the Taq-I G-->A allele in cystic fibrosis lung disease. Eur Respir J. 1998 Apr;11(4):873–879. doi: 10.1183/09031936.98.11040873. [DOI] [PubMed] [Google Scholar]
  15. Smallman L. A., Hill S. L., Stockley R. A. Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax. 1984 Sep;39(9):663–667. doi: 10.1136/thx.39.9.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sommerhoff C. P., Nadel J. A., Basbaum C. B., Caughey G. H. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J Clin Invest. 1990 Mar;85(3):682–689. doi: 10.1172/JCI114492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Suter S., Schaad U. B., Morgenthaler J. J., Chevallier I., Schnebli H. P. Fibronectin-cleaving activity in bronchial secretions of patients with cystic fibrosis. J Infect Dis. 1988 Jul;158(1):89–100. doi: 10.1093/infdis/158.1.89. [DOI] [PubMed] [Google Scholar]
  18. Suter S., Schaad U. B., Tegner H., Ohlsson K., Desgrandchamps D., Waldvogel F. A. Levels of free granulocyte elastase in bronchial secretions from patients with cystic fibrosis: effect of antimicrobial treatment against Pseudomonas aeruginosa. J Infect Dis. 1986 May;153(5):902–909. doi: 10.1093/infdis/153.5.902. [DOI] [PubMed] [Google Scholar]
  19. Trevani A. S., Andonegui G., Giordano M., Nociari M., Fontán P., Dran G., Geffner J. R. Neutrophil apoptosis induced by proteolytic enzymes. Lab Invest. 1996 Mar;74(3):711–721. [PubMed] [Google Scholar]

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