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Published ahead of print on April 14, 2003, doi:10.1165/rcmb.2002-0271OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 3, September 2003, 390-396

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Submitted on November 26, 2002
Revised on April 8, 2003

ALPHA-1-ANTITRYPSIN DEFICIENCY ALLELES IN CYSTIC FIBROSIS LUNG DISEASE

Despina D Frangolias1*, Jian Ruan2, Pearce J Wilcox2, A. George F Davidson3, Lawrence T Wong3, Yves Berthiaume4, Rosamund Hennessey5, Andreas P Freitag5, Linda Pedder2, Mary Corey6, Neil Sweezey6, Julian Zielenski6, Elizabeth Tullis7, and Andrew J Sandford1

1 Medicine, University of British Columbia, Vancouver, British Columbia, Canada; McDonald Research Laboratories / iCAPTURE Centre, Saint Paul's Hospital, Vancouver, British Columbia, Canada, 2 Medicine, University of British Columbia, Vancouver, British Columbia, Canada, 3 Medicine/Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Division of Infectious Diseases, B.C. Children's Hospital, Vancouver, British Columbia, Canada, 4 Medicine, Universite de Montreal and Centre de Recherche Hotel-Dieu du Chum, Montreal, Quebec, Canada, 5 Medicine, McMaster University & Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada, 6 Medicine, University of Toronto, Toronto, Ontario, Canada; Medicine, Universite de Montreal and Centre de Recherche Hotel-Dieu du Chum, Montreal, Quebec, Canada, 7 Medicine, University of Toronto, Toronto, Ontario, Canada; St. Michael's Hospital, Toronto, Ontario, Canada

* To whom correspondence should be addressed. E-mail: Dfrangolias{at}mrl.ubc.ca.

Cystic fibrosis transmembrane conductance regulator (CFTR) genotype does not explain the heterogeneity observed in CF pulmonary disease severity. Modifier genes are implicated for this heterogeneity. Alpha-1-antitrypsin ({alpha}1-AT) is one of the few antiproteases capable of inactivating neutrophil elastase. We investigated whether {alpha}1-AT alleles (Z, S deficiency alleles and the 3' G1237{Rightarrow}A mutation) were associated with increased disease severity and the {alpha}1-AT acute phase response during pulmonary exacerbations. This was a multicenter Canadian study. 716 CF patients (age range=5.0-63.6 years) were genotyped for the Z, S and G1237{Rightarrow}A polymorphisms of the {alpha}1-AT gene. Stable and acute levels of {alpha}1-AT were measured on 31 adult CF patients and were correlated to clinical parameters. There were 69, 13 and 18 CF patients who were MS, SS and MZ, respectively. There were 95 and 7 CF patients heterozygous or homozygous for the A1237 allele, respectively. {alpha}1-AT genotype did not predict pulmonary disease severity and was not associated with more severe clinical outcome (death or lung transplantation) or age of onset of Pseudomonas aeruginosa infection. BMI was a significant predictor of {alpha}1-AT levels during exacerbations. {alpha}1-AT genotype is not a major contributor to the variability of pulmonary disease severity in CF.




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