Lung function loss, smoking, vitamin C intake, and polymorphisms of the glutamate-cysteine ligase genes.
BACKGROUND
Smoking-induced oxidative stress contributes to chronic obstructive pulmonary disease, a lung disease characterized by low lung function and increasing mortality worldwide. The counterbalance for this effect may be provided by, for example, increased intake of the antioxidant vitamin C or endogenously acting antioxidant enzymes like glutamate-cysteine ligase (GCL), which is responsible for glutathione biosynthesis.


OBJECTIVE
To investigate associations of functional polymorphisms in GCL subunits (GCLM and GCLC) with lung function level and its longitudinal course, with vitamin C and smoking habits as potential interactive factors.


METHODS
Two independent general population samples (Doetinchem, n = 1,152, and Vlagtwedde-Vlaardingen, n = 1,390) with multiple lung function (FEV(1), VC) measurements were genotyped for three polymorphisms (C[-129]T, C[-588]T, and a trinucleotide GAG repeat [TNR]) in the subunits of GCL. Genetic effects on lung function level and decline were estimated using linear regression and linear mixed effect models adjusted for confounders. Findings were further investigated for interactions with vitamin C intake in the Doetinchem cohort.


RESULTS
GCLC polymorphisms were significantly associated with lower lung function levels in interaction with pack-years smoked in both cohorts. TNR variants in GCLC were associated with accelerated FEV(1) decline in both cohorts in interaction with pack-years. All significant effects were specifically present in subjects within the lowest tertile of vitamin C intake.


CONCLUSIONS
GCLC is a novel susceptibility gene for low level of lung function in two independent populations. We provide suggestive evidence that this occurs due to an interaction between GCLC polymorphisms, smoking, and low vitamin C intake, which all contribute to the oxidative burden.
Siedlinski
Mateusz
M
Department of Epidemiology, University Medical Center Groningen, E3.29, PO Box 196, 9700 AD Groningen, The Netherlands.
Postma
Dirkje S
DS
van Diemen
Cleo C
CC
Blokstra
Anneke
A
Smit
Henriette A
HA
Boezen
H Marike
HM
D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume; D020022:Genetic Predisposition to Disease; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects*; D018911:Trinucleotide Repeats
D000975:Antioxidants; D005721:Glutamate-Cysteine Ligase; D001205:Ascorbic Acid