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. 2004 Feb;59(2):116–119. doi: 10.1136/thorax.2003.005611

Two functional variants of the superoxide dismutase genes in Finnish families with asthma

V Kinnula 1, S Lehtonen 1, P Koistinen 1, S Kakko 1, M Savolainen 1, J Kere 1, V Ollikainen 1, T Laitinen 1
PMCID: PMC1746944  PMID: 14760150

Abstract

Background: Functional polymorphisms in the genes encoding superoxide dismutases (SOD)—that is, superoxide scavenging antioxidant enzymes—may play an important role in the development of inflammatory airway diseases such as asthma.

Methods: The allele frequencies of two missense polymorphisms of SOD genes (Ala16Val in MnSOD (SOD2) and Arg213Gly in ECSOD (SOD3)) were investigated in Finnish patients with asthma and compared with family based controls. Both variants have been shown to be functionally interesting in the lung. The polymorphism at the exon–intron 3 boundary of a third SOD, CuZnSOD (SOD1), was also included in the analysis.

Results: None of the SOD genetic variants studied appeared to be major genetic regulators in the development of asthma. We could exclude all models of inheritance that increased the risk of asthma more than 1.2 fold for MnSOD*Val (frequency of allele 0.74 in the population) and more than 6.6 fold for ECSOD*Gly213 (frequency of allele 0.03 in the population) compared with non-carriers. For the intronic polymorphism in CuZnSOD, a relative risk of more than 3.3 (frequency of allele 0.10 in the population) could be excluded.

Conclusions: It is highly unlikely that the functionally important genetic variants Ala16Val and Arg213Gly of SODs play a major role in the genetic susceptibility of asthma.

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Selected References

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  1. Carlsson L. M., Jonsson J., Edlund T., Marklund S. L. Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6264–6268. doi: 10.1073/pnas.92.14.6264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Comhair S. A., Bhathena P. R., Dweik R. A., Kavuru M., Erzurum S. C. Rapid loss of superoxide dismutase activity during antigen-induced asthmatic response. Lancet. 2000 Feb 19;355(9204):624–624. doi: 10.1016/S0140-6736(99)04736-4. [DOI] [PubMed] [Google Scholar]
  3. Folz R. J., Abushamaa A. M., Suliman H. B. Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia. J Clin Invest. 1999 Apr;103(7):1055–1066. doi: 10.1172/JCI3816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Folz R. J., Crapo J. D., Peno-Green L. A. Elevated levels of extracellular superoxide dismutase in chronic lung disease and characterization of genetic variants. Chest. 1997 Jun;111(6 Suppl):74S–74S. doi: 10.1378/chest.111.6_supplement.74s. [DOI] [PubMed] [Google Scholar]
  5. Folz R. J., Peno-Green L., Crapo J. D. 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 Dec;3(12):2251–2254. doi: 10.1093/hmg/3.12.2251. [DOI] [PubMed] [Google Scholar]
  6. Forsberg L., de Faire U., Morgenstern R. Oxidative stress, human genetic variation, and disease. Arch Biochem Biophys. 2001 May 1;389(1):84–93. doi: 10.1006/abbi.2001.2295. [DOI] [PubMed] [Google Scholar]
  7. Hiroi S., Harada H., Nishi H., Satoh M., Nagai R., Kimura A. Polymorphisms in the SOD2 and HLA-DRB1 genes are associated with nonfamilial idiopathic dilated cardiomyopathy in Japanese. Biochem Biophys Res Commun. 1999 Aug 2;261(2):332–339. doi: 10.1006/bbrc.1999.1036. [DOI] [PubMed] [Google Scholar]
  8. Ho Y. S., Gargano M., Cao J., Bronson R. T., Heimler I., Hutz R. J. Reduced fertility in female mice lacking copper-zinc superoxide dismutase. J Biol Chem. 1998 Mar 27;273(13):7765–7769. doi: 10.1074/jbc.273.13.7765. [DOI] [PubMed] [Google Scholar]
  9. Kauppi P., Laitinen L. A., Laitinen H., Kere J., Laitinen T. Verification of self-reported asthma and allergy in subjects and their family members volunteering for gene mapping studies. Respir Med. 1998 Nov;92(11):1281–1288. doi: 10.1016/s0954-6111(98)90229-3. [DOI] [PubMed] [Google Scholar]
  10. Kere J. Human population genetics: lessons from Finland. Annu Rev Genomics Hum Genet. 2001;2:103–128. doi: 10.1146/annurev.genom.2.1.103. [DOI] [PubMed] [Google Scholar]
  11. Kharitonov S. A., Barnes P. J. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med. 2001 Jun;163(7):1693–1722. doi: 10.1164/ajrccm.163.7.2009041. [DOI] [PubMed] [Google Scholar]
  12. Kinnula V. L., Yankaskas J. R., Chang L., Virtanen I., Linnala A., Kang B. H., Crapo J. D. Primary and immortalized (BEAS 2B) human bronchial epithelial cells have significant antioxidative capacity in vitro. Am J Respir Cell Mol Biol. 1994 Nov;11(5):568–576. doi: 10.1165/ajrcmb.11.5.7946385. [DOI] [PubMed] [Google Scholar]
  13. Laitinen T., Daly M. J., Rioux J. D., Kauppi P., Laprise C., Petäys T., Green T., Cargill M., Haahtela T., Lander E. S. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Nat Genet. 2001 May;28(1):87–91. doi: 10.1038/ng0501-87. [DOI] [PubMed] [Google Scholar]
  14. Laitinen T., Kauppi P., Ignatius J., Ruotsalainen T., Daly M. J., Käriäinen H., Kruglyak L., Laitinen H., de la Chapelle A., Lander E. S. Genetic control of serum IgE levels and asthma: linkage and linkage disequilibrium studies in an isolated population. Hum Mol Genet. 1997 Nov;6(12):2069–2076. doi: 10.1093/hmg/6.12.2069. [DOI] [PubMed] [Google Scholar]
  15. Lakari E., Päkkö P., Kinnula V. L. Manganese superoxide dismutase, but not CuZn superoxide dismutase, is highly expressed in the granulomas of pulmonary sarcoidosis and extrinsic allergic alveolitis. Am J Respir Crit Care Med. 1998 Aug;158(2):589–596. doi: 10.1164/ajrccm.158.2.9711059. [DOI] [PubMed] [Google Scholar]
  16. Li Y., Huang T. T., Carlson E. J., Melov S., Ursell P. C., Olson J. L., Noble L. J., Yoshimura M. P., Berger C., Chan P. H. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet. 1995 Dec;11(4):376–381. doi: 10.1038/ng1295-376. [DOI] [PubMed] [Google Scholar]
  17. Marklund S. L., Nilsson P., Israelsson K., Schampi I., Peltonen M., Asplund K. Two variants of extracellular-superoxide dismutase: relationship to cardiovascular risk factors in an unselected middle-aged population. J Intern Med. 1997 Jul;242(1):5–14. doi: 10.1046/j.1365-2796.1997.00160.x. [DOI] [PubMed] [Google Scholar]
  18. Mitrunen K., Sillanpä P., Kataja V., Eskelinen M., Kosma V. M., Benhamou S., Uusitupa M., Hirvonen A. Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis. 2001 May;22(5):827–829. doi: 10.1093/carcin/22.5.827. [DOI] [PubMed] [Google Scholar]
  19. Oury T. D., Chang L. Y., Marklund S. L., Day B. J., Crapo J. D. Immunocytochemical localization of extracellular superoxide dismutase in human lung. Lab Invest. 1994 Jun;70(6):889–898. [PubMed] [Google Scholar]
  20. Rosenblum J. S., Gilula N. B., Lerner R. A. On signal sequence polymorphisms and diseases of distribution. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4471–4473. doi: 10.1073/pnas.93.9.4471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sandström J., Nilsson P., Karlsson K., Marklund S. L. 10-fold increase in human plasma extracellular superoxide dismutase content caused by a mutation in heparin-binding domain. J Biol Chem. 1994 Jul 22;269(29):19163–19166. [PubMed] [Google Scholar]
  22. Shimoda-Matsubayashi S., Matsumine H., Kobayashi T., Nakagawa-Hattori Y., Shimizu Y., Mizuno Y. Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease. Biochem Biophys Res Commun. 1996 Sep 13;226(2):561–565. doi: 10.1006/bbrc.1996.1394. [DOI] [PubMed] [Google Scholar]
  23. Tsan M. F. Superoxide dismutase and pulmonary oxygen toxicity: lessons from transgenic and knockout mice (Review). Int J Mol Med. 2001 Jan;7(1):13–19. doi: 10.3892/ijmm.7.1.13. [DOI] [PubMed] [Google Scholar]
  24. Ukkola O., Erkkilä P. H., Savolainen M. J., Kesäniemi Y. A. Lack of association between polymorphisms of catalase, copper-zinc superoxide dismutase (SOD), extracellular SOD and endothelial nitric oxide synthase genes and macroangiopathy in patients with type 2 diabetes mellitus. J Intern Med. 2001 May;249(5):451–459. doi: 10.1046/j.1365-2796.2001.00828.x. [DOI] [PubMed] [Google Scholar]
  25. Van Landeghem G. F., Tabatabaie P., Beckman G., Beckman L., Andersen P. M. Manganese-containing superoxide dismutase signal sequence polymorphism associated with sporadic motor neuron disease. Eur J Neurol. 1999 Nov;6(6):639–644. doi: 10.1046/j.1468-1331.1999.660639.x. [DOI] [PubMed] [Google Scholar]
  26. Wang L. I., Miller D. P., Sai Y., Liu G., Su L., Wain J. C., Lynch T. J., Christiani D. C. Manganese superoxide dismutase alanine-to-valine polymorphism at codon 16 and lung cancer risk. J Natl Cancer Inst. 2001 Dec 5;93(23):1818–1821. doi: 10.1093/jnci/93.23.1818. [DOI] [PubMed] [Google Scholar]
  27. Weisiger R. A., Fridovich I. Mitochondrial superoxide simutase. Site of synthesis and intramitochondrial localization. J Biol Chem. 1973 Jul 10;248(13):4793–4796. [PubMed] [Google Scholar]
  28. White C. W., Avraham K. B., Shanley P. F., Groner Y. Transgenic mice with expression of elevated levels of copper-zinc superoxide dismutase in the lungs are resistant to pulmonary oxygen toxicity. J Clin Invest. 1991 Jun;87(6):2162–2168. doi: 10.1172/JCI115249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Zelko Igor N., Mariani Thomas J., Folz Rodney J. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002 Aug 1;33(3):337–349. doi: 10.1016/s0891-5849(02)00905-x. [DOI] [PubMed] [Google Scholar]

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