title: Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease.
abstract: 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. alpha1-antitrypsin (alpha1-AT) is one of the few antiproteases capable of inactivating neutrophil elastase. We investigated whether alpha1-AT alleles (Z, S deficiency alleles and the 3' G1237-->A mutation) were associated with increased disease severity and the alpha1-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 alpha1-AT gene. Stable and acute levels of alpha1-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. alpha1-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 alpha1-AT levels during exacerbations. alpha1-AT genotype is not a major contributor to the variability of pulmonary disease severity in CF.
authors.affiliation: McDonald Research Laboratories/iCAPTURE Centre, Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, B.C. Children's Hospital, Vancouver, Canada. Dfrangolias@mrl.ubc.ca
authors.forename: Despina D
authors.initials: DD
authors.lastname: Frangolias
authors.forename: Jian
authors.initials: J
authors.lastname: Ruan
authors.forename: Pearce J
authors.initials: PJ
authors.lastname: Wilcox
authors.forename: A George F
authors.initials: AG
authors.lastname: Davidson
authors.forename: Lawrence T K
authors.initials: LT
authors.lastname: Wong
authors.forename: Yves
authors.initials: Y
authors.lastname: Berthiaume
authors.forename: Rosamund
authors.initials: R
authors.lastname: Hennessey
authors.forename: Andreas
authors.initials: A
authors.lastname: Freitag
authors.forename: Linda
authors.initials: L
authors.lastname: Pedder
authors.forename: Mary
authors.initials: M
authors.lastname: Corey
authors.forename: Neil
authors.initials: N
authors.lastname: Sweezey
authors.forename: Julian
authors.initials: J
authors.lastname: Zielenski
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tullis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sandford
mesh_terms: D000210:Acute-Phase Reaction; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008171:Lung Diseases / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics*
chemical_list: D000515:alpha 1-Antitrypsin