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Published ahead of print on April 17, 2008, doi:10.1164/rccm.200711-1749OC
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American Journal of Respiratory and Critical Care Medicine Vol 178. pp. 13-19, (2008)
© 2008 American Thoracic Society
doi: 10.1164/rccm.200711-1749OC

Original Article

Lung Function Loss, Smoking, Vitamin C Intake, and Polymorphisms of the Glutamate-Cysteine Ligase Genes

Mateusz Siedlinski1, Dirkje S. Postma2, Cleo C. van Diemen1, Anneke Blokstra3, Henriette A. Smit3 and H. Marike Boezen1

1 Department of Epidemiology and 2 Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and 3 Centre for Prevention and Health Services Research, National Institute of Public Health and the Environment, Bilthoven, The Netherlands

Correspondence and requests for reprints should be addressed to H. M. Boezen, Ph.D., Department of Epidemiology, University Medical Center Groningen, E3.29, P.O. Box 196, 9700 AD Groningen, The Netherlands. E-mail: h.m.boezen{at}epi.umcg.nl

Rationale: 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.

Objectives: 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 (FEV1, 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.

Measurements and Main 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 FEV1 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.

Key Words: GCLC • GCLM • polymorphism • chronic obstructive pulmonary disease • oxidative stress


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
Cigarette smoke enhances the level of oxidative burden in the lung and thus contributes to the loss of lung function. Glutathione and vitamin C are major antioxidants that protect lungs against smoking-induced oxidative stress.

What This Study Adds to the Field
The current study shows that polymorphisms in the glutamate-cysteine ligase, essential for glutathione synthesis, interact with vitamin C intake and smoking and thus contribute to lung function loss.

 



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