Superoxide dismutases, lung function and bronchial responsiveness in a general population

M. Siedlinski, C. C. van Diemen, D. S. Postma, J. M. Vonk, H. M. Boezen
European Respiratory Journal 2009 33: 986-992; DOI: 10.1183/09031936.00171507

Abstract

Oxidative stress is an important causative factor in the onset and progression of smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD). Superoxide dismutases (SODs) can prevent an increase in oxidative burden.

A total of 1,390 subjects from the prospective Vlagtwedde–Vlaardingen cohort were genotyped for two single nucleotide polymorphisms (SNPs) in SOD2 and four SNPs in SOD3, which were further analysed for associations with the presence of bronchial hyperresponsiveness (BHR; provocative concentration causing a 10% fall in the forced expiratory volume in one second (FEV1; PC10 ≤8 mg·mL−1 of histamine), COPD (defined as Global Initiative for Chronic Obstructive Lung Disease stage II or higher), lung function level and the longitudinal course of FEV1.

The intronic C5774T SNP of SOD2 was significantly associated with the presence of COPD and BHR in the total population. The T/T genotype for this polymorphism and the Val/Val genotype for the SOD2 Ala16Val substitution were risk factors for BHR in individuals without COPD. The SOD3 Arg213Gly substitution was associated with slower FEV1 decline in never-smokers exclusively, and the SOD3 G(−4466)T SNP was associated with a lower vital capacity level.

Both SOD2 polymorphisms are associated with bronchial hyperresponsiveness, a risk factor for chronic obstructive pulmonary disease, while SOD2 C5774T additionally confers a risk for chronic obstructive pulmonary disease in the total population. The current authors furthermore confirm previously reported associations of SOD3 single nucleotide polymorphisms with lung function in the general population.

An imbalance between oxidants and antioxidants is considered to be an important causative factor in the onset and progression of chronic obstructive pulmonary disease (COPD) 1, 2. A key molecule in the regulatory process of oxidative stress is the superoxide anion, which is inhaled through cigarette smoke and additionally generated during numerous cellular reactions 3. The free superoxide anion is a substrate for the synthesis of highly reactive oxygen species, which can damage epithelial cells, impair epithelial ciliary function, alter expression of cellular adhesion molecules, and increase airway smooth muscle contraction in response to histamine and other stimuli in both in vitro and in vivo models 4. Therefore, impaired superoxide metabolism may contribute to the development of bronchial hyperresponsiveness (BHR) and the subsequent onset of COPD 5, 6. Indeed, it has previously been shown that patients with COPD have increased production of the superoxide anion by blood leukocytes, which is associated with more severe hyperresponsiveness 7. However, this cross-sectional study did not elucidate whether the increased production of superoxide anions was the cause or consequence of BHR and COPD 7. To date, studies on the relationship between superoxide anions and the development of both COPD and BHR in the general population are lacking.

The family of superoxide dismutases (SODs) is the only enzymatic system able to degrade a superoxide anion 8. Impairment of the mitochondrial SOD (SOD2) activity was related to asthma pathophysiology 9, and extracellular SOD (SOD3) was shown to protect lungs against oxidant-mediated injury 10, 11. Therefore, it is of interest to investigate whether single nucleotide polymorphisms (SNPs) in these SOD genes contribute to the development of BHR and/or COPD. SOD2 contains one prevalent nonsynonymous SNP, i.e. Ala16Val, which is localised in a protein signal sequence, and thus possibly has a functional role 12–14. This substitution has been associated with a higher lung cancer risk in Caucasians 15–17 but not with the presence of COPD in Caucasian and Chinese smokers 18, 19. SOD3 contains three nonsynonymous SNPs, i.e. Ala40Thr, Phe131Cys and Arg213Gly. The Arg213Gly substitution has been associated with elevated SOD3 levels in human plasma 20 and with protection against COPD development in Caucasians 18, 21, whereas Ala40Thr and Phe131Cys have not yet been studied in this context. Recently, in the Copenhagen City Heart Study 22, it has been shown that the rs8192288 SNP in the SOD3 5′-untranslated region is associated with lower forced vital capacity in two large Danish cohorts and constitutes a risk for more frequent COPD hospitalisation.

The present study links the well-known risk factors for COPD development, i.e. BHR and smoking, with polymorphisms located in genes involved in response to oxidative stress, a key manifestation in COPD pathogenesis. Furthermore, it aims to broaden the knowledge on candidate SOD3 SNPs with respect to (the course of) lung function and it provides new insight into the SOD2 role in this context.

METHODS

Subjects

A total of 1,390 subjects of the Vlagtwedde–Vlaardingen cohort who participated in the previous 1989–1990 survey 23 were included in the present study. This general population-based cohort of Caucasian individuals of Dutch descent started in 1965 and has been followed up for 25 yrs 23–25. Standardised forced expiratory volume in one second (FEV1) and vital capacity (VC) measurements were performed every 3 yrs (see online supplementary material for details) 26. The present study’s protocol was approved by the local university hospital medical ethics committee and all participants gave their written informed consent.

DNA extraction and genotyping

The online supplementary material provides a description of DNA extraction and the genotyping protocol. Six SNPs in two SOD genes were genotyped, i.e. Ala16Val (rs4880) and C5774T (rs2842958) in SOD2, and Ala40Thr (rs2536512), Arg213Gly (rs1799895), G(-4466)T (rs8192288), and Phe131Cys 27 in SOD3.

The C5774T SNP was included to enable tagging of SOD2 haplotypes, as described previously 28.

Presence of COPD and BHR phenotype

The present authors identified subjects with COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, i.e. an FEV1/VC <70% and an FEV1 <80% predicted (% pred; GOLD stage II or higher) at the last survey 29.

Bronchial responsiveness to histamine (the 30-s method) was assessed in a random subsample of the total cohort, as described previously 25. BHR at the last survey was expressed dichotomously, i.e. as a provocative concentration causing a 10% fall in the FEV1 (PC10) ≤8 mg·mL−1 histamine.

Statistical analysis

Differences in prevalence of rare alleles of SNPs between subjects with and without COPD or BHR were tested using the Chi-squared test and logistic regression. Additionally, the present authors performed all mentioned analyses stratified according to smoking habits (never- and ever-smokers), as the SOD effects were expected to depend on smoking habits. For two SOD3 SNPs, it was not possible to estimate the odds ratios for COPD and BHR for the homozygous mutant genotype due either to the lack of Arg213Gly or to the low number of G(-4466)T (n = 3) subjects.

In order to disentangle the phenotypes for COPD and BHR, subjects were classified into four phenotypic groups according to the presence of COPD and/or BHR (i.e. “COPD-/BHR-”, “COPD-/BHR+”, “COPD+/BHR-” and “COPD+/BHR+”). Multinomial logistic regression, adjusted for pack-yrs of smoking, was performed separately for all SNPs, with the four phenotypic groups as dependent variables. These analyses allowed prediction of whether subjects with certain genotypes were more likely to develop a COPD phenotype or a BHR phenotype.

Linear regression analysis (adjusted for sex, height, age and pack-yrs of smoking) was used to test whether the FEV1 or VC level differed between SOD genotypes at the last survey 23. Linear mixed effect models were used to estimate longitudinal changes in lung function in the total cohort, as well as in the ever- and never-smokers subgroups (see online supplementary material for details) 30.

Haplotype analysis was performed (see online supplementary material for details) 31, 32. The remaining statistical analyses were performed and p-values <0.05 were considered to be significant (using two-tailed tests).

RESULTS

Study population and distribution of SOD SNPs

The study population characteristics and genotype frequencies are shown in table 1⇓. All SNPs were distributed according to the Hardy–Weinberg equilibrium in the total population and were not correlated with each other (r2<0.27 for any SNP pair). The Phe131Cys substitution in SOD3 was not present in the current cohort. No homozygote mutants were found for the Arg213Gly SNP in SOD3 in the present population. Three and five haplotypes were identified in SOD2 and SOD3, respectively, occurring with a frequency >1% in the total population (table S4 in the online supplementary material).

View this table:
Table 1—

Characteristics of the sample of the Vlagtwedde–Vlaardingen cohort investigated at the last survey

SOD SNPs and the presence of COPD

The SOD2 C5774T SNP was significantly associated with COPD in the total population and in ever-smokers (table 2⇓ and table S2 in supplementary material online) but not in never-smokers (data not shown). No significant associations were found for the other investigated SNPs (table 2⇓). The haplotype containing the SOD2 C5774T SNP was associated with significantly higher odds for the presence of COPD (recessive effect; odds ratio (OR) 2.1 (95% confidence interval (CI) 1.1–4.0), p = 0.02), compared with the wild type haplotype (table S4 in the online supplementary material).

View this table:
Table 2—

The presence of chronic obstructive pulmonary disease(COPD) bronchial hyperresponsiveness (BHR) in the total population and in ever-smokers, respectively, according to superoxide dismutase (SOD) single nucleotide polymorphisms (SNPs)

SOD SNPs and the presence of BHR

The SOD2 C5774T SNP was significantly associated with the presence of BHR in the random subgroup of the total population (n = 409/1,390; table 2⇑ and table S3 in online supplementary material). Mutant homozygotes had a significantly higher risk of having BHR compared with wild types. The Ala16Val substitution in SOD2 was borderline significantly associated with BHR (p = 0.07 for mutant versus wild type homozygotes; table 2⇑). Stratified analyses according to smoking showed no significant associations for these two SNPs. The haplotype containing the mutant allele of C5774T SNP was associated with an increased risk for BHR, as compared with the wild type haplotype (additive effect; OR 1.7 (95% CI 1.1–2.6), p = 0.01; table S4 in the online supplementary material).

The Ala40Thr SNP was significantly associated with BHR only in never-smokers (OR (95% CI) for the presence of BHR Ala/Thr versus Ala/Ala 2.84 (1.08–7.48), and for Thr/Thr versus Ala/Ala 14.40 (2.92–71.08) adjusted for FEV1 % pred), but not in the total population and not in ever-smokers (table 2⇑).

SOD SNPs and the presence of COPD and/or BHR phenotype

A total of 213 subjects had neither COPD nor BHR (COPD-/BHR-), 154 subjects had COPD-/BHR+, six subjects had COPD+/BHR-, and 36 subjects had COPD+/BHR+. Subjects with the homozygous Ala16Val substitution in SOD2 were most likely to be COPD-/BHR+ (OR 2.1 (95% CI 1.1–3.8) for the Val/Val variant compared with Ala/Ala), indicating that the Ala16Val substitution was predictive for the presence of BHR and not for COPD or their combination. Likewise, subjects with the homozygous mutant SOD2 C5774T SNP were most likely to have COPD-/BHR+ (3.1 (95% CI 1.03–9.51) for the homozygous mutant variant compared with the wild type). Haplotype analysis revealed that the only haplotype containing mutant alleles of both SOD2 SNPs showed a significantly increased OR (for an additive effect, 1.7 (95% CI 1.2–2.6); p = 0.01) for BHR in non-COPD subjects as compared with the wild type haplotype. The polymorphisms in the SOD3 gene were not associated with any of the four phenotypic outcome groups.

SOD SNPs and the level of FEV1 or VC

No significant differences between the SOD genotypes in relation to the level of FEV1 or VC were observed in the total population (see table S5 in the online supplementary material) or in the never- or ever-smoker subgroups (data not shown). Subjects homozygous for the G(-4466)T SNP in SOD3 had borderline significantly lower VC (regression coefficient B (se) -532.2 mL (292.0); p = 0.068), but not FEV1, compared with the homozygous wild-type group (fig. 1⇓). There were no homozygous SOD3 G(-4466)T SNP subjects in the never-smokers. In ever-smokers that were homozygous for the SOD3 G(-4466)T SNP, the current authors observed an effect size (i.e. -533.2 mL (301.2), p = 0.077) that was similar to that in the total cohort.

Fig. 1—
Fig. 1—

Adjusted means of a) the level of forced expiratory volume in one second (FEV1) and b) vital capacity (VC) according to the superoxide dismutase 3 G(-4466)T genotypes in the total population. Boxes and whiskers present means and confidence intervals, respectively. #: p = 0.21; : p = 0.60; +: p = 0.46; §: p = 0.50; ƒ: p = 0.09; ##: p = 0.07. G/G subjects n = 1,236, G/T n = 119 and T/T n = 3.

SOD SNPs and longitudinal change in FEV1

The annual FEV1 decline was similar in all genotype subgroups of the investigated SNPs (see table S6 in the online supplementary material). Stratification according to smoking habits revealed that the SOD3 Arg213Gly substitution was associated with slower FEV1 decline in never-smokers, e.g. 9.3 mL less decline per yr in carriers of the Arg/Gly genotype compared with the wild type (fig. 2⇓). The other SNPs were not associated with excess FEV1 decline in stratified analyses.

Fig. 2—
Fig. 2—

Adjusted means for the annual change in forced expiratory volume in one second (FEV1) for the superoxide dismutase (SOD)3 Arg213Gly genotypes in the total population and according to smoking habits. Boxes and whiskers present means and confidence intervals, respectively. •: total cohort; ○: ever-smokers; ▪: never-smokers. #: p = 0.14; : p = 0.45; +: p = 0.03. G/G subjects n = 1,236, G/T n = 119 and T/T n = 3.

DISCUSSION

Of all human tissues, the lungs are most directly and particularly exposed to noxious free radicals. Tobacco smoke and environmental air pollution are the major sources of these particles. Therefore, the redox balance regulation can be an important factor for the development of BHR, excess decline in lung function and development of COPD. The current authors have shown that SOD2, containing the mutant allele of the C5774T SNP, is a risk factor for BHR in the general population. Exclusively in subjects who had smoked, COPD was more prevalent in carriers of two copies of this mutant allele compared with wild type carriers. The SOD3 Arg213Gly substitution that has previously been shown to be protective for COPD 18, 21, was associated with slower FEV1 decline in never-smokers only. Additionally, the current study confirms a recently observed negative association of the G(-4466)T SOD3 SNP with lung VC level in the general population 22.

The present finding is of interest, as SOD2 dysfunction and inactivation has been recently described ex vivo in bronchial epithelial cells derived from airways of asthmatic patients 9. This confirms the importance of SOD2 in lung homeostasis, where reactive oxygen species can impair epithelial ciliary function and increase airway smooth muscle contraction in response to histamine 4, which may contribute to the development of BHR. The present data suggest that this may also be the case in COPD.

At the last survey 23, it was found that the mutant homozygosity of the SOD2 SNP (C5774T), located in intron 3, is a risk factor for the presence of COPD and BHR in the total population. Although the role of SNPs localised in introns is not clear yet, it is known that they may affect alternative splicing processes 33, 34, which result in different amino acid sequences in mature proteins. The main difference between the SOD2 isoforms is the presence of an additional exon within the third intron 35, but the implication with respect to putative differences in activity between both isoforms is as yet unknown. It is indeed confirmed that the formation SOD2 isoforms may depend on genetic variations, as this has been shown in vitro for a polymorphism (single base-pair deletion) that is prevalent in African-Americans 36. However, that specific study 36 concluded that other (cis-acting)factors are necessary for switching between two isoforms in vivo. Thus it is also possible that C5774T SNP is in high linkage disequilibrium with other functional SNPs, which are actually responsible for the associations presently observed.

Theoretically, the Ala16Val substitution could also be of importance, as in vitro studies have shown impaired transport of Val16-SOD2 to the mitochondrion 12, 13, and lower mitochondrial SOD2 activity in leukocytes for the Val/Val genotype as compared with the other genotypes 14. An association of the Ala16Val SNP was not found neither with the presence of COPD nor with lung function decline, which is in concordance with results of two previous studies performed 18, 19.

Bronchial responsiveness may be modulated by superoxide anion production 7 and BHR is a known risk factor for COPD development 5, 6. Therefore, impaired superoxide radical detoxification, caused by loss of SOD2 function, may increase the level of BHR and affect the development of COPD. Remarkably, subjects with homozygous variants of the SOD2 Ala16Val substitution or the SOD2 C5774T SNP showed increased ORs for having “pure BHR”, which suggests it is indeed the phenotype BHR that is associated with these SOD2 SNPs, and the relationship that the present authors have found between C5774T SNP and COPD is driven by the association with BHR. Out of two mutant SOD2 haplotypes, only the one containing the mutant allele of the C5774T SNP was associated with increased risk for BHR as compared with the wild type haplotype, which implies that this SNP, rather than Ala16Val substitution, is associated with the presence of BHR.

Juul et al. 21 have shown both prospectively and cross-sectionally a lower risk for COPD for the SOD3 Arg213Gly SNP heterozygotes compared with the wild type. This has been confirmed by another cross-sectional study 18. The underlying mechanism of these associations may be explained by reduced proteolytic processing of mutated SOD3 protein 37 and a higher SOD3 level in blood plasma due to lower affinity to heparan sulphate in the extracellular matrix 20, 38. The present authors additionally found that the protective effect of this SNP on longitudinal FEV1 change appears in never-smokers. Therefore, the present authors hypothesise that there are other antioxidant-related genetic factors that additionally contribute to the FEV1 change in smokers. Recently, in the Copenhagen City Heart Study, Dahl et al. 22 reported that the G(-4466)T (rs8192288) SNP, and particularly the homozygote mutant genotype, in SOD3 constitutes a risk factor for a low level of forced vital capacity and more frequent COPD hospitalisation. Interestingly, in the present study, the same SNP was borderline significantly associated with low lung VC level, with a relatively large effect size. However, only three subjects were identified as carrying the risk (homozygous mutant) genotype and therefore it was impossible to either detect likely associations with FEV1 decline or estimate the OR for COPD presence.

There are some limitations to the present study. It is conceivable that the low prevalence of the C5774T SNP in SOD2 and especially of G(-4466)T and Arg213Gly in SOD3 may have negatively affected the power of the present study. Therefore, associations with BHR, FEV1 decline or with COPD in the general population or in ever-smokers may have been impossible to detect. Another study limitation is the fact that the Vlagtwedde–Vlaardingen cohort is a unique prospective study with measurements of both BHR and FEV1 at several time-points over 25 yrs. Therefore, it is not possible to check for replication of the present findings in another prospective cohort in order to reduce type I error (false positives). Additionally, p-values were not corrected for multiple comparisons.

In summary, it can be concluded that superoxide dismutase 2 is an antioxidant enzyme in which variations in DNA sequence can play a role in the development of bronchial hyperresponsiveness. By showing the protective effect of the Arg213Gly single nucleotide polymorphism in SOD3 on the course of forced expiratory volume in one second in never-smokers, another piece of the puzzle of the role of this substitution in pulmonary disease is added. Additionally, supportive evidence for an association of G(-4466)T (rs8192288) SOD3 single nucleotide polymorphism with the level of vital capacity in the general population is provided. Further studies are needed to confirm the possible role of SOD single nucleotide polymorphisms in chronic obstructive pulmonary disease and bronchial hyperresponsiveness, and additional functional studies are warranted.

Support statement

This study was supported by a grant from: the Dutch Asthma Foundation (grant 3.2.02.51); University of Groningen, Groningen, The Netherlands; and Graduate School for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen.

Statement of interest

None declared.

Footnotes

  • Received December 19, 2007.
  • Accepted December 16, 2008.

References

  1. ↵
    Kinnula VL. Focus on antioxidant enzymes and antioxidant strategies in smoking related airway diseases. Thorax 2005;60:693–700.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Domej W, Foldes-Papp Z, Flogel E, Haditsch B. Chronic obstructive pulmonary disease and oxidative stress. Curr Pharm Biotechnol 2006;7:117–123.
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    Tsuchiya M, Thompson DF, Suzuki YJ, Cross CE, Packer L. Superoxide formed from cigarette smoke impairs polymorphonuclear leukocyte active oxygen generation activity. Arch Biochem Biophys 1992;299:30–37.
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    Henricks PA, Nijkamp FP. Reactive oxygen species as mediators in asthma. Pulm Pharmacol Ther 2001;14:409–420.
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    Postma DS, Boezen HM. Rationale for the Dutch hypothesis. Allergy and airway hyperresponsiveness as genetic factors and their interaction with environment in the development of asthma and COPD. Chest 2004;126: Suppl. 2 96S–104S.
    OpenUrlCrossRefPubMed
  6. ↵
    Brutsche MH, Downs SH, Schindler C, et al. Bronchial hyperresponsiveness and the development of asthma and COPD in asymptomatic individuals: SAPALDIA cohort study. Thorax 2006;61:671–677.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Postma DS, Renkema TE, Noordhoek JA, Faber H, Sluiter HJ, Kauffman H. Association between nonspecific bronchial hyperreactivity and superoxide anion production by polymorphonuclear leukocytes in chronic air-flow obstruction. Am Rev Respir Dis 1988;137:57–61.
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    Fridovich I. Superoxide anion radical (O2-·), superoxide dismutases, and related matters. J Biol Chem 1997;272:18515–18517.
    OpenUrlFREE Full Text
  9. ↵
    Comhair SA, Xu W, Ghosh S, et al. Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity. Am J Pathol 2005;166:663–674.
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    Carlsson LM, Jonsson J, Edlund T, Marklund SL. Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Natl Acad Sci USA 1995;92:6264–6268.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Folz RJ, Abushamaa AM, Suliman HB. Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia. J Clin Invest 1999;103:1055–1066.
    OpenUrlPubMedWeb of Science
  12. ↵
    Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics 2003;13:145–157.
    OpenUrlCrossRefPubMedWeb of Science
  13. ↵
    Sutton A, Imbert A, Igoudjil A, et al. The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharmacogenet Genomics 2005;15:311–319.
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    Fujimoto H, Taguchi J, Imai Y, et al. Manganese superoxide dismutase polymorphism affects the oxidized low-density lipoprotein-induced apoptosis of macrophages and coronary artery disease. Eur Heart J 2008;29:1267–1274.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Liu G, Zhou W, Wang LI, et al. MPO and SOD2 polymorphisms, gender, and the risk of non-small cell lung carcinoma. Cancer Lett 2004;214:69–79.
    OpenUrlCrossRefPubMedWeb of Science
  16. Wang LI, Miller DP, Sai Y, et al. Manganese superoxide dismutase alanine-to-valine polymorphism at codon 16 and lung cancer risk. J Natl Cancer Inst 2001;93:1818–1821.
    OpenUrlFREE Full Text
  17. ↵
    Wang LI, Neuberg D, Christiani DC. Asbestos exposure, manganese superoxide dismutase (MnSOD) genotype, and lung cancer risk. J Occup Environ Med 2004;46:556–564.
    OpenUrlPubMedWeb of Science
  18. ↵
    Young RP, Hopkins R, Black PN, et al. Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function. Thorax 2006;61:394–399.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Mak JC, Ho SP, Yu WC, et al. Polymorphisms and functional activity in superoxide dismutase and catalase genes in smokers with COPD. Eur Respir J 2007;30:684–690.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Sandstrom J, Nilsson P, Karlsson K, Marklund SL. 10-fold increase in human plasma extracellular superoxide dismutase content caused by a mutation in heparin-binding domain. J Biol Chem 1994;269:19163–19166.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Juul K, Tybjaerg-Hansen A, Marklund S, Lange P, Nordestgaard BG. Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:858–864.
    OpenUrlCrossRefPubMedWeb of Science
  22. ↵
    Dahl M, Bowler RP, Juul K, Crapo JD, Levy S, Nordestgaard BG. Superoxide dismutase 3 polymorphism associated with reduced lung function in two large populations. Am J Respir Crit Care Med 2008;178:906–912.
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Schouten JP, Boezen HM. A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population. Am J Respir Crit Care Med 2005;172:329–333.
    OpenUrlCrossRefPubMedWeb of Science
  24. van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Nolte IM, Boezen HM. Decorin and TGF-beta1 polymorphisms and development of COPD in a general population. Respir Res 2006;7:89
    OpenUrlCrossRefPubMed
  25. ↵
    Rijcken B, Schouten JP, Mensinga TT, Weiss ST, De VK, Van der LR. Factors associated with bronchial responsiveness to histamine in a population sample of adults. Am Rev Respir Dis 1993;147:1447–1453.
    OpenUrlCrossRefPubMedWeb of Science
  26. ↵
    Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J 1993;6: Suppl. 16 5–40.
    OpenUrlFREE Full Text
  27. ↵
    Campo S, Sardo AM, Campo GM, et al. Extracellular superoxide dismutase (EC-SOD) gene mutations screening in a sample of Mediterranean population. Mutat Res 2005;578:143–148.
    OpenUrlPubMedWeb of Science
  28. ↵
    Cebrian A, Pharoah PD, Ahmed S, et al. Tagging single-nucleotide polymorphisms in antioxidant defense enzymes and susceptibility to breast cancer. Cancer Res 2006;66:1225–1233.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2006. www.goldcopd.org Date last updated: November 2008. Date last accessed: March 3, 2009
  30. ↵
    R Development Core Team (2007). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. www.R-project.org Date last updated: December 2008. Date last accessed: March 3, 2009
  31. ↵
    Lin DY, Zeng D, Millikan R. Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in association studies. Genet Epidemiol 2005;29:299–312.
    OpenUrlCrossRefPubMedWeb of Science
  32. ↵
    Zeng D, Lin DY, Avery CL, North KE, Bray MS. Efficient semiparametric estimation of haplotype-disease associations in case-cohort and nested case-control studies. Biostatistics 2006;7:486–502.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    von Ahsen N, Oellerich M. The intronic prothrombin 19911A>G polymorphism influences splicing efficiency and modulates effects of the 20210G>A polymorphism on mRNA amount and expression in a stable reporter gene assay system. Blood 2004;103:586–593.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383–391.
    OpenUrlCrossRefPubMedWeb of Science
  35. ↵
    Hubbard T, Barker D, Birney E, et al. The Ensembl genome database project. Nucleic Acids Res 2002;30:38–41.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Shao J, Chen L, Marrs B, et al. SOD2 polymorphisms: unmasking the effect of polymorphism on splicing. BMC Med Genet 2007;8:7
    OpenUrlCrossRefPubMed
  37. ↵
    Bowler RP, Nicks M, Olsen DA, et al. Furin proteolytically processes the heparin-binding region of extracellular superoxide dismutase. J Biol Chem 2002;277:16505–16511.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Folz RJ, Peno-Green L, Crapo JD. Identification of a homozygous missense mutation (Arg to Gly) in the critical binding region of the human EC-SOD gene (SOD3) and its association with dramatically increased serum enzyme levels. Hum Mol Genet 1994;3:2251–2254.
    OpenUrlFREE Full Text
Back to top
View this article with LENS
Email
Print
Citation Tools

Superoxide dismutases, lung function and bronchial responsiveness in a general population
M. Siedlinski, C. C. van Diemen, D. S. Postma, J. M. Vonk, H. M. Boezen
European Respiratory Journal May 2009, 33 (5) 986-992; DOI: 10.1183/09031936.00171507
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To