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Published ahead of print on April 14, 2003, doi:10.1165/rcmb.2002-0271OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 390-396, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0271OC

{alpha}1-Antitrypsin Deficiency Alleles in Cystic Fibrosis Lung Disease

Despina D. Frangolias, Jian Ruan, Pearce J. Wilcox, A. George F. Davidson, Lawrence T. K. Wong, Yves Berthiaume, Rosamund Hennessey, Andreas Freitag, Linda Pedder, Mary Corey, Neil Sweezey, Julian Zielenski, Elizabeth Tullis and Andrew J. Sandford

McDonald Research Laboratories/iCAPTURE Centre, and Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, B.C. Children's Hospital, Vancouver, British Columbia; Department of Medicine, Universite de Montreal and Centre de Recherche Hotel-Dieu du Chum, Montreal, Quebec; McMaster University & Hamilton Health Sciences Corp., Hamilton; and Hospital for Sick Children, and St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada

Address correspondence to: Despina Daisy Frangolias, McDonald Research Laboratories/iCAPTURE Centre, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Room 292, Vancouver, BC, V6Z 1Y6 Canada. E-mail: Dfrangolias{at}mrl.ubc.ca

Cystic fibrosis (CF) 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->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. Seven hundred sixteen patients with CF (age range, 5.0–63.6 yr) were genotyped for the Z, S, and G1237->A polymorphisms of the {alpha}1-AT gene. Stable and acute levels of {alpha}1-AT were measured on 31 adult patients with CF and were correlated to clinical parameters. There were 69, 13, and 18 patients with CF who were MS, SS, and MZ, respectively. There were 95 and 7 patients with CF 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. Body mass index 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.

Abbreviations: {alpha}1-antitrypsin, {alpha}1-AT • analysis of variance, ANOVA • bronchoalveolar lavage fluid, BALF • body mass index, BMI • cystic fibrosis, CF • cystic fibrosis transmembrane conductance regulator, CFTR • chronic obstructive pulmonary disease, COPD • forced expiratory volume in 1 s, FEV1 • forced vital capacity, FVC • neutrophil elastase, NE • polymerase chain reaction, PCR • percent of predicted FEV1, %predFEV1 • percent of predicted FVC, %predFVC • Schwachman-Kulczycki, S-K




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