Published ahead of print on May 11, 2006, doi:10.1164/rccm.200508-1281OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200508-1281OC
Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung DiseaseDivision of Pulmonary and Critical Care Medicine, and Department of Environmental and Occupational Health Sciences and Center for Ecogenetics and Environmental Health, University of Washington, Seattle, Washington; and UBC McDonald Research Laboratories/iCAPTURE Center, Vancouver, British Columbia, Canada Correspondence and requests for reprints should be addressed to Terrance J. Kavanagh, Ph.D., Department of Environmental and Occupational Health Sciences, University of Washington Mail Box 354695, Seattle, WA 98195. E-mail: tjkav{at}u.washington.edu Background: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury. Objectives: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease. Methods: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype. Measurements and Main Results: A total of 440 subjects with CF participated in the study (51% male; mean [± SD] age, 26 ± 11 yr; mean FEV1, 62 ± 28% predicted). In the total population, there was a trend toward an association between GCLC genotypes and CF lung disease (linear regression coefficient [SEM], 1.68 [1.0]; p = 0.097). In the stratified analysis, there was a highly significant association between GCLC genotype and CF lung function in subjects with a milder CFTR genotype (linear regression coefficient [SEM], 5.5 (1.7); p = 0.001). Conclusions: In patients with CF with a milder CFTR genotype, there is a strong association between functional polymorphisms of the GCLC gene and CF lung disease severity.
Key Words: CFTR genotype • glutathione • modifier genes This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
