Journal of Applied Genetics

, Volume 51, Issue 3, pp 323–330

Prostaglandin-endoperoxide synthase genesCOX1 andCOX2 — novel modifiers of disease severity in cystic fibrosis patients

  • K. Czerska
  • A. Sobczyńska-Tomaszewska
  • D. Sands
  • A. Nowakowska
  • D. Bąk
  • K. Wertheim
  • J. Poznański
  • J. Zielenski
  • A. Norek
  • J. Bal
Original Article

Abstract

Cystic fibrosis (CF) is one of the most common autosomal recessive diseases among Caucasians caused by a mutation in theCFTR gene. However, the clinical outcome of CF pulmonary disease varies remarkably even in patients with the sameCFTR genotype. This has led to a search for genetic modifiers located outside theCFTR gene. The aim of this study was to evaluate the effect of functional variants in prostaglandin-endoperoxide synthase genes (COX1 andCOX2) on the severity of lung disease in CF patients. To the best of our knowledge, it is the first time when analysis ofCOX1 andCOX2 as potential CF modifiers is provided. The study included 94 CF patients homozygous for F508del mutation ofCFTR. To compare their clinical condition, several parameters were recorded, e.g. a unique clinical score: disease severity status (DSS). To analyse the effect of non-CFTR genetic polymorphisms on the clinical course of CF patients, the whole coding region ofCOX1 and selectedCOX2 polymorphisms were analysed. Statistical analysis of genotype-phenotype associations revealed a relationship between the heterozygosity status of identified polymorphisms and better lung function. These results mainly concernCOX2 polymorphisms: −765G>C and 8473T>C. TheCOX1 andCOX2 polymorphisms reducing COX protein levels had a positive effect on all analysed clinical parameters. This suggests an important role of these genes as protective modifiers of pulmonary disease in CF patients, due to inhibition of arachidonic acid conversion into prostaglandins, which probably reduces the inflammatory process.

Keywords

COX1 COX2 cystic fibrosis lung disease gene modifiers 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Boyle MP, 2007. Strategies for identifying modifier genes in cystic fibrosis. Proc Am Thorac Soc 4:52–57.PubMedCrossRefGoogle Scholar
  2. Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, Canzian F, 2004. Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25:229–235.PubMedCrossRefGoogle Scholar
  3. Clayton A, Knox AJ, 2006. COX-2: a link between airway inflammation and disordered chloride secretion in cystic fibrosis? Thorax 61:552–553.PubMedCrossRefGoogle Scholar
  4. Cutting GR, 2005. Modifier genetics: cystic fibrosis. Annu Rev Genomics Hum Genet 6:237–260.PubMedCrossRefGoogle Scholar
  5. Davies J, Alton E, Griesenbach U, 2005. Cystic fibrosis modifier genes. J R Soc Med 98 Suppl 45:47–54.Google Scholar
  6. Davies JC, Griesenbach U, Alton E, 2005. Modifier genes in cystic fibrosis. Pediatr Pulmonol 39:383–391.PubMedCrossRefGoogle Scholar
  7. Davis PB, 2001. Cystic fibrosis. Pediatr Rev 22:257–264.PubMedCrossRefGoogle Scholar
  8. Drumm ML, 2001. Modifier genes and variation in cystic fibrosis. Respir Res 2:125–128.PubMedCrossRefGoogle Scholar
  9. Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, et al. 2005; Gene Modifier Study Group. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 353:1443–1453.PubMedCrossRefGoogle Scholar
  10. Fritsche E, Baek SJ, King LM, Zeldin DC, Eling TE, Bell DA, 2001. Functional characterization of cyclooxygenase-2 polymorphisms. J Pharmacol Exp Ther 299:468–476.PubMedGoogle Scholar
  11. Haston CK, Hudson TJ, 2005. Finding genetic modifiers of cystic fibrosis. N Engl J Med 353:1509–1511.PubMedCrossRefGoogle Scholar
  12. Hollox EJ, Davies J, Griesenbach U, Burgess J, Alton EW, Armour JA, 2005. Beta-defensin genomic copy number is not a modifier locus for cystic fibrosis. J Negat Results Biomed 4:9–13.PubMedCrossRefGoogle Scholar
  13. Hull J, Thomson AH, 1998. Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis. Thorax 53:1018–1021.PubMedCrossRefGoogle Scholar
  14. Katz SL, Strug LJ, Coates AL, Corey M, 2004. Disease severity in siblings with cystic fibrosis. Pediatr Pulmonol 37:407–412.PubMedCrossRefGoogle Scholar
  15. Knowles MR, 2006. Gene modifiers of lung disease. Curr Opin Pulm Med 12:416–421.PubMedCrossRefGoogle Scholar
  16. Konstan MW, Byard PJ, Hoppel CL, Davis PB, 1995. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 332:848–854.PubMedCrossRefGoogle Scholar
  17. Konstan MW, Schluchter MD, Xue W, Davis PB, 2007. Clinical use of Ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med 176:1084–1089.PubMedCrossRefGoogle Scholar
  18. Maree AO, Curtin RJ, Chubb A, Dolan C, Cox D, O’Brien J, et al. 2005. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 3:2340–2345.PubMedCrossRefGoogle Scholar
  19. Martin CP, Talbert RL, 2005. Aspirin resistance: an evaluation of current evidence and measurement methods. Pharmacotherapy 25:942–953.PubMedCrossRefGoogle Scholar
  20. Merlo CA, Boyle MP, 2003. Modifier genes in cystic fibrosis lung disease. J Lab Clin Med 141:237–241.PubMedCrossRefGoogle Scholar
  21. Miller SA, Dykes DD, Polesky HF, 1988. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215.PubMedCrossRefGoogle Scholar
  22. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE, Laurent GJ, 2002. Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. 22:1631–1636.Google Scholar
  23. Roca-Ferrer J, Pujols L, Gartner S, Moreno A, Pumarola F, Mullol J, et al. 2006. Upregulation of COX-1 and COX-2 in nasal polyps in cystic fibrosis. Thorax 61:592–596.PubMedCrossRefGoogle Scholar
  24. Salvatore F, Scudiero O, Castaldo G, 2002. Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes. 111:88–95.Google Scholar
  25. Sanak M, Szczeklik W, Szczeklik A, 2005. Association of COX-2 gene haplotypes with prostaglandin production in bronchial asthma. J Allergy Clin Immunol 116:221–223.PubMedCrossRefGoogle Scholar
  26. Slieker MG, Sanders EA, Rijkers GT, Ruven HJ, van der Ent CK, 2005. Disease modifying genes in cystic fibrosis. J Cyst Fibros 4 Suppl 2:7–13.CrossRefGoogle Scholar
  27. Sorensen M, Autrup H, Tjonneland A, Overvad K, Raaschou-Nielsen O, 2005. A genetic polymorphism in prostaglandin synthase 2 (8473, T→C) and the risk of lung cancer.Cancer Lett 226(1):49–54.PubMedCrossRefGoogle Scholar
  28. Szczeklik A, Sanak M, 2002. The role of COX-1 and COX-2 in asthma pathogenesis and its significance in the use of selective inhibitors. Clin Exp All 32:339–342.CrossRefGoogle Scholar
  29. Szczeklik W, Sanak M, Szczeklik A, 2004. Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma. J Allergy Clin Immunol 114:248–253.PubMedCrossRefGoogle Scholar
  30. Ulrich CM, Bigler J, Sibert J, Greene EA, Sparks R, Carlson CS, Potter JD, 2002. Cyclooxygenase 1 (COX1) polymorphisms in African-American and Caucasian populations. Hum Mutat 20(5):409–410.PubMedCrossRefGoogle Scholar
  31. Ulrich CM, Bigler J, Sparks R, Whitton J, Sibert JG, Goode EL, et al. 2004. Polymorphisms in PTGS1 (=COX-1) and risk of colorectal polyps. Cancer Epidemiol Biomarkers Prev 13:889–893.PubMedGoogle Scholar
  32. Vanscoy LL, Blackman SM, Collaco JM, Bowers A, Lai T, Naughton K, et al. 2007. Heritability of lung disease severity in cystic fibrosis. Am J Respir Crit Care Med, 175:1036–1043.PubMedCrossRefGoogle Scholar
  33. Welsh MJ, Smith AE, 1995. Cystic fibrosis. Sci Am 273:52–59.PubMedCrossRefGoogle Scholar
  34. Wine JJ, 1999: The genesis of cystic fibrosis lung disease. J Clin Invest 103:309–312.PubMedCrossRefGoogle Scholar
  35. Yarden J, Radojkovic D, De Boeck K, Macek M Jr, Zemkova D, Vavrova V, et al. 2005. Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype. 60: 320–325.Google Scholar
  36. Zielenski J, Tsui LC, 1995. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 29:777–807.PubMedCrossRefGoogle Scholar

Copyright information

© Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2010

Authors and Affiliations

  • K. Czerska
    • 1
    • 2
  • A. Sobczyńska-Tomaszewska
    • 1
  • D. Sands
    • 3
  • A. Nowakowska
    • 3
  • D. Bąk
    • 1
    • 2
  • K. Wertheim
    • 1
  • J. Poznański
    • 4
  • J. Zielenski
    • 5
  • A. Norek
    • 1
  • J. Bal
    • 1
  1. 1.Department of Medical GeneticsInstitute of Mother and ChildWarsawPoland
  2. 2.Postgraduate School of Molecular MedicineWarsawPoland
  3. 3.Department of PaediatricsInstitute of Mother and ChildWarsawPoland
  4. 4.Department of BiophysicsInstitute of Biochemistry and BiophysicsWarsawPoland
  5. 5.Program in Genetics and Genome BiologyHospital for Sick ChildrenTorontoCanada

Personalised recommendations