title: Association of improved pulmonary phenotype in Irish cystic fibrosis patients with a 3' enhancer polymorphism in alpha-1-antitrypsin.
abstract: Modifier genes other than CFTR are thought to influence lung disease phenotype in cystic fibrosis (CF). In this study, we investigated the relationship between a polymorphism (1237 G --> A) in the 3' enhancer region of the alpha-1-antitrypsin (AAT) gene and pulmonary disease severity in 320 CF patients recruited from two independent adult referral centers in Ireland, and evaluated the in vivo effect of the polymorphism on AAT levels during acute infection. When corrected for confounding variables, the polymorphism was found to make a small but significant contribution to variance in percent predicted forced expired volume in 1 sec (FEV1) (1.1%, P = 0.05), with possession of the A allele being associated with better pulmonary function (AA/AG genotype: percent predicted FEV1, 70.8 +/- 3.9; GG genotype: percent predicted FEV1, 62.0 +/- 1.4). As would be expected of a modifier effect, the influence of the polymorphism was more marked in patient groups traditionally associated with more severe lung disease, contributing 3.2% (P = 0.033) to the variance in percent predicted FEV1 in patients homozygous for DF508, 3.3% (P = 0.007) to those infected with Pseudomonas aeruginosa, and 3% (P = 0.024) in female patients. In each instance, a positive association between possession of the A variant and higher percent predicted FEV1 was observed. We did not, however, find any evidence that possession of the A allele effected upregulation of AAT during acute infection in vivo. This lack of a demonstrable functional effect in vivo suggests that the polymorphism is a marker for a modifying effect on pulmonary phenotype in the Irish CF population by a mechanism that is yet to be explained.
authors.affiliation: Respiratory Research Group, Department of Medicine, Queen's University of Belfast, Belfast, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Courtney
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Plant
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Jackie
authors.initials: J
authors.lastname: Rendall
authors.forename: Charles
authors.initials: C
authors.lastname: Gallagher
authors.forename: Madeleine
authors.initials: M
authors.lastname: Ennis
authors.forename: Noor
authors.initials: N
authors.lastname: Kalsheker
authors.forename: Stuart
authors.initials: S
authors.lastname: Elborn
authors.forename: Clare M
authors.initials: CM
authors.lastname: O'Connor
mesh_terms: D000328:Adult; D001424:Bacterial Infections / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007494:Ireland; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012737:Sex Factors; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator