Variants in the glutamate-cysteine-ligase gene are associated with cystic fibrosis lung disease.
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.


OBJECTIVE
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.


RESULTS
A total of 440 subjects with CF participated in the study (51% male; mean [+/- SD] age, 26 +/- 11 yr; mean FEV(1), 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.
McKone
Edward F
EF
Department of Environmental and Occupational Health Sciences, University of Washington Mail Box 354695, Seattle, WA 98195, USA.
Shao
Jing
J
Frangolias
Daisy D
DD
Keener
Cassie L
CL
Shephard
Cynthia A
CA
Farin
Federico M
FM
Tonelli
Mark R
MR
Pare
Peter D
PD
Sandford
Andrew J
AJ
Aitken
Moira L
ML
Kavanagh
Terrance J
TJ
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005260:Female; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005721:Glutamate-Cysteine Ligase