Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

Abstract

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

Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of γ-glutamylcysteine ligase

“…Several studies have suggested that the GAG repeat polymorphism in GCLC may have a functional significance based on its association with disease risk/severity [21,27,28] and intracellular GSH levels [18]. We hypothesized that the GAG polymorphism in GCLC will affect GSH biosynthetic capacity in cells and will be reflected by differences in GCL activity and GSH levels in blood of healthy adults.…”

Recent advances in genetic predisposition to clinical acute lung injury

“…Marzec and coworkers (63) performed resequencing to scan the entire coding region, and the proximal 1 kb of the promoter and genotyping was performed on two promoter SNPs (Ϫ617 and Ϫ651); they subsequently found that patients who were ho-mozygous for the Ϫ617 minor "A" allele had a significantly higher risk for developing ALI after major trauma relative to patients with the wild type (Ϫ617 CC). Although this is a relatively new group of candidate genes in the field of lung injury genetic epidemiology, there has been a tremendous number of genetic associations between genes associated with defense against oxidant stress and other complex lung diseases, including glutathione synthesis-related genes [e.g., GCLC and cystic fibrosis (65)] and superoxide dismutase (SOD) genes [e.g., SOD3 and COPD (98)]. Recent work by Arcaroli et al (8) confirmed the association between haplotypes in extracellular superoxide dismutase 3 gene (SOD3 or EC-SOD) and mortality in patients with infection-associated ALI, and another report suggested that the A-1221C variant of the NAD(P)H: quinine oxidoreductase 1 (NQO1), a phase II antioxidant gene, conferred higher risk for trauma-associated ALI (78).…”

Strategies for Identifying Modifier Genes in Cystic Fibrosis

“…These have included, among many, ␣ 1 -antitrypsin (SERPINA1) (34), ␤ 2 -adrenergic receptor (ADRB2) (35), glutathione S-transferase (GSTM1) (36), nitric oxide synthase 3 (NOS3) (37), tumor necrosis factor (TNF) (38), and gluatamate-cysteine-ligase (GCLC) (39). All have been identified in these studies as potentially modifying pulmonary phenotype in CF.…”