Cyclooxygenase-2 (COX-2) polymorphisms and risk of inflammatory bowel disease in a Scottish and Danish case–control study
Corresponding Author
Vibeke Andersen PhD
Medical Department, Viborg Regional Hospital, Viborg, Denmark
Medical Department, Regional Hospital Viborg, Heibergs Allé 4, DK-8800 Viborg, DenmarkSearch for more papers by this authorElaine Nimmo PhD
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorHenrik B. Krarup PhD
Department of Clinical Biochemistry, Aarhus University Hospital, Aalborg, Denmark
Search for more papers by this authorHazel Drummond BSc
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorJane Christensen MSc
Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark
Search for more papers by this authorGwo-tzer Ho PhD
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorMette Østergaard PhD
Medical Department, Viborg Regional Hospital, Viborg, Denmark
Biochemical Department, Viborg Regional Hospital, Viborg, Denmark
Search for more papers by this authorAnja Ernst PhD
Department of Clinical Biochemistry, Aarhus University Hospital, Aalborg, Denmark
Search for more papers by this authorCharlie Lees Prof
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorBent A. Jacobsen PhD
Department of Medical Gastroenterology, Aarhus University Hospital, Aalborg, Denmark
Search for more papers by this authorJack Satsangi Prof
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorUlla Vogel Prof
National Food Institute, Technical University of Denmark, DK-2860 Søborg, Denmark
Institute for Science, Systems and Models, University of Roskilde, Denmark
National Research Centre for the Working Environment, Copenhagen, Denmark
Search for more papers by this authorCorresponding Author
Vibeke Andersen PhD
Medical Department, Viborg Regional Hospital, Viborg, Denmark
Medical Department, Regional Hospital Viborg, Heibergs Allé 4, DK-8800 Viborg, DenmarkSearch for more papers by this authorElaine Nimmo PhD
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorHenrik B. Krarup PhD
Department of Clinical Biochemistry, Aarhus University Hospital, Aalborg, Denmark
Search for more papers by this authorHazel Drummond BSc
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorJane Christensen MSc
Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark
Search for more papers by this authorGwo-tzer Ho PhD
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorMette Østergaard PhD
Medical Department, Viborg Regional Hospital, Viborg, Denmark
Biochemical Department, Viborg Regional Hospital, Viborg, Denmark
Search for more papers by this authorAnja Ernst PhD
Department of Clinical Biochemistry, Aarhus University Hospital, Aalborg, Denmark
Search for more papers by this authorCharlie Lees Prof
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorBent A. Jacobsen PhD
Department of Medical Gastroenterology, Aarhus University Hospital, Aalborg, Denmark
Search for more papers by this authorJack Satsangi Prof
Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, UK
Search for more papers by this authorUlla Vogel Prof
National Food Institute, Technical University of Denmark, DK-2860 Søborg, Denmark
Institute for Science, Systems and Models, University of Roskilde, Denmark
National Research Centre for the Working Environment, Copenhagen, Denmark
Search for more papers by this authorAbstract
Background:
Inflammatory bowel diseases (IBDs) are a result of interactions between luminal pathogens and the intestinal immune response. Cyclooxygenase-2 (COX-2) plays a key role in the regulation of the inflammatory response upon stimulation by luminal pathogens via Toll-like receptors.
Methods:
Genotypes of the COX-2/PTGS2/PGHS2 A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) polymorphisms were assessed in a Scottish and Danish case–control study including 732 Crohn's disease (CD) cases, 973 ulcerative colitis (UC) cases, and 1157 healthy controls using logistic regression.
Results:
Carriers of the COX-2 A-1195G variant allele had increased risk of UC (odds ratio [OR], 95% confidence interval [CI] = 1.25 [1.02–1.54], P = 0.03) and of both UC and IBD among never smokers (OR [95% CI] = 1.47 [1.11–1.96], P = 0.01 and OR [95% CI] = 1.37 [1.06–1.77], P = 0.02, respectively). Furthermore, this variant genotype was associated with increased risk of diagnosis of UC before age 40 years and with extensive UC (OR [95% CI] = 1.34 [1.11–1.62], P = 0.002 and OR [95% CI] = 1.32 [1.03–1.69], P = 0.03, respectively).
Conclusions:
COX-2 A-1195G polymorphism was associated with the risk of UC, especially among never-smokers, suggesting that low activity of COX-2 may predispose to UC. Our results suggest that inclusion of smoking status may be essential for the evaluation of the role of genetic predisposition to IBD. (Inflamm Bowel Dis 2011)
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| IBD_21440_sm_supptable2A.doc66.5 KB | Supporting Table 2A: Odds Ratios for the COX-2 Gene Polymorphisms in the Scottish and Danish Crohns Disease (CD) Study Groups. Statistical Analyses Included Subjects Where all Information Was Available |
| IBD_21440_sm_supptable2B.doc63.5 KB | Supporting Table 2B: Odds Ratios for the COX-2 Gene Polymorphisms in the Scottish and Danish Ulcerative Colitis (UC) Study Groups. Statistical Analyses Included Subjects Where all Information was Available |
| IBD_21440_sm_supptable3A.doc57.5 KB | Supporting Table 3A: Odds Ratios (OR) for COX-2 Genotypes in Scottish and Danish Patients with Crohns Disease (CD) Dependent on their Smoking Habit at the Time of Diagnosis. Statistical Analyses Included Subjects Where all Information was Available |
| IBD_21440_sm_supptable3B.doc56 KB | Supporting Table 3B: Odds Ratios (OR) for COX-2 Genotypes in Scottish and Danish Patients with Ulcerative Colitis Dependent on their Smoking Habit at the Time of Diagnosis. Statistical Analyses Included Subjects Where all Information was Available |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Andersen V, Ernst A, Christensen J, et al. The polymorphism rs3024505 proximal to IL-10 is associated with risk of ulcerative colitis and Crohns disease in a Danish case-control study. BMC Med Genet. 2010; 11: 82.
- 2 Lees CW, Satsangi J. Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. Expert Rev Gastroenterol Hepatol. 2009; 3: 513–534.
- 3 Ernst A, Andersen V, Ostergaard M, et al. Genetic variants of glutathione S-transferases mu, theta, and pi display no susceptibility to inflammatory bowel disease in the Danish population. Scand J Gastroenterol. 2010 [Epub ahead of print].
- 4 Duerr RH. Update on the genetics of inflammatory bowel disease. J Clin Gastroenterol. 2003; 37: 358–367.
- 5 Brant SR, Shugart YY. Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology, and present status of the field. Inflamm Bowel Dis. 2004; 10: 300–311.
- 6 Economou M, Pappas G. New global map of Crohn's disease: Genetic, environmental, and socioeconomic correlations. Inflamm Bowel Dis. 2008; 14: 709–720.
- 7 Jacobsen BA, Fallingborg J, Rasmussen HH, et al. Increase in incidence and prevalence of inflammatory bowel disease in northern Denmark: a population-based study, 1978–2002. Eur J Gastroenterol Hepatol. 2006; 18: 601–606.
- 8 Ernst A, Jacobsen B, Ostergaard M, et al. Mutations in CARD15 and smoking confer susceptibility to Crohn's disease in the Danish population. Scand J Gastroenterol. 2007; 42: 1445–1451.
- 9 Hugot JP, Zaccaria I, Cavanaugh J, et al. Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol. 2007; 102: 1259–1267.
- 10 Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007; 369: 1627–1640.
- 11 Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007; 117: 514–521.
- 12 Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007; 448: 427–434.
- 13 Fukata M, Chen A, Klepper A, et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine. Gastroenterology. 2006; 131: 862–877.
- 14 Tsatsanis C, Androulidaki A, Venihaki M, et al. Signalling networks regulating cyclooxygenase-2. Int J Biochem Cell Biol. 2006; 38: 1654–1661.
- 15 Scher JU, Pillinger MH. The anti-inflammatory effects of prostaglandins. J Investig Med. 2009; 57: 703–708.
- 16 Wallace JL. COX-2: a pivotal enzyme in mucosal protection and resolution of inflammation. Sci World J. 2006; 6: 577–588.
- 17 Sheibanie AF, Yen JH, Khayrullina T, et al. The proinflammatory effect of prostaglandin E2 in experimental inflammatory bowel disease is mediated through the IL-23—>IL-17 axis. J Immunol. 2007; 178: 8138–8147.
- 18 Karmeli F, Cohen P, Rachmilewitz D. Cyclo-oxygenase-2 inhibitors ameliorate the severity of experimental colitis in rats. Eur J Gastroenterol Hepatol. 2000; 12: 223–231.
- 19 Reuter BK, Asfaha S, Buret A, et al. Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest. 1996; 98: 2076–2085.
- 20 Okayama M, Hayashi S, Aoi Y, et al. Aggravation by selective COX-1 and COX-2 inhibitors of dextran sulfate sodium (DSS)-induced colon lesions in rats. Dig Dis Sci. 2007; 52: 2095–2103.
- 21 Kapoor M, Kojima F, Yang L, et al. Sequential induction of pro- and anti-inflammatory prostaglandins and peroxisome proliferators-activated receptor-gamma during normal wound healing: a time course study. Prostaglandins Leukot Essent Fatty Acids. 2007; 76: 103–112.
- 22 Rajakariar R, Yaqoob MM, Gilroy DW. COX-2 in inflammation and resolution. Mol Interv. 2006; 6: 199–207.
- 23 Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology. 1997; 112: 387–397.
- 24 Hendel J, Nielsen OH. Expression of cyclooxygenase-2 mRNA in active inflammatory bowel disease. Am J Gastroenterol. 1997; 92: 1170–1173.
- 25 Singer II, Kawka DW, Schloemann S, et al. Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology. 1998; 115: 297–306.
- 26 Zhang X, Miao X, Tan W, et al. Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology. 2005; 129: 565–576.
- 27 Vogel U, Christensen J, Wallin H, et al. Polymorphisms in COX-2, NSAID use and risk of basal cell carcinoma in a prospective study of Danes. Mutat Res. 2007; 617: 138–146.
- 28 Andersen V, Ostergaard M, Christensen J, et al. Polymorphisms in the xenobiotic transporter multidrug resistance 1 (MDR1) gene and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study. BMC Cancer. 2009; 9: 407.
- 29 Sanak M, Szczeklik W, Szczeklik A. Association of COX-2 gene haplotypes with prostaglandins production in bronchial asthma. J Allergy Clin Immunol. 2005; 116: 221–223.
- 30 Cox DG, Crusius JB, Peeters PH, et al. Haplotype of prostaglandin synthase 2/cyclooxygenase 2 is involved in the susceptibility to inflammatory bowel disease. World J Gastroenterol. 2005; 11: 6003–6008.
- 31 Ostergaard M, Ernst A, Labouriau R, et al. Cyclooxygenase-2, multidrug resistance 1, and breast cancer resistance protein gene polymorphisms and inflammatory bowel disease in the Danish population. Scand J Gastroenterol. 2009; 44: 65–73.
- 32 Hermann M, Krum H, Ruschitzka F. To the heart of the matter: coxibs, smoking, and cardiovascular risk. Circulation. 2005; 112: 941–945.
- 33 Moraitis D, Du B, De Lorenzo MS, et al. Levels of cyclooxygenase-2 are increased in the oral mucosa of smokers: evidence for the role of epidermal growth factor receptor and its ligands. Cancer Res. 2005; 65: 664–670.
- 34 Badawi AF, Habib SL, Mohammed MA, et al. Influence of cigarette smoking on prostaglandin synthesis and cyclooxygenase-2 gene expression in human urinary bladder cancer. Cancer Invest. 2002; 20: 651–656.
- 35 Mahid SS, Minor KS, Soto RE, et al. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc. 2006; 81: 1462–1471.
- 36 Aldhous MC, Drummond HE, Anderson N, et al. Does cigarette smoking influence the phenotype of Crohn's disease? Analysis using the Montreal classification. Am J Gastroenterol. 2007; 102: 577–588.
- 37 Aldhous MC, Drummond HE, Anderson N, et al. Smoking habit and load influence age at diagnosis and disease extent in ulcerative colitis. Am J Gastroenterol. 2007; 102: 589–597.
- 38 Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002; 347: 417–429.
- 39 Campa D, Zienolddiny S, Maggini V, et al. Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis. 2004; 25: 229–235.
- 40 Greenland S. Dose-response and trend analysis in epidemiology: alternatives to categorical analysis. Epidemiology. 1995; 6: 356–365.
- 41 Vogel U, Christensen J, Wallin H, et al. Polymorphisms in COX-2, NSAID use and risk of basal cell carcinoma in a prospective study of Danes. Mutat Res. 2007; 617: 138–146.
- 42 Vogel U, Christensen J, Wallin H, et al. Polymorphisms in genes involved in the inflammatory response and interaction with NSAID use or smoking in relation to lung cancer risk in a prospective study. Mutat Res. 2008; 639: 89–100.
- 43 Hakansson A, Bergman O, Chrapkowska C, et al. Cyclooxygenase-2 polymorphisms in Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet. 2007; 144B: 367–369.
- 44 Hedelin M, Chang ET, Wiklund F, et al. Association of frequent consumption of fatty fish with prostate cancer risk is modified by COX-2 polymorphism. Int J Cancer. 2007; 120: 398–405.
- 45HapMap: Rs689466:http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=689466. 2010.
- 46 Dossus L, Kaaks R, Canzian F, et al. PTGS2 and IL6 Genetic Variation and Risk of Breast and Prostate Cancer: results from the Breast and Prostate Cancer Cohort Consortium (BPC3). Carcinogenesis. 2010; 31: 455–461.
- 47 Siezen CL, van Leeuwen AI, Kram NR, et al. Colorectal adenoma risk is modified by the interplay between polymorphisms in arachidonic acid pathway genes and fish consumption. Carcinogenesis. 2005; 26: 449–457.
- 48 Siezen CL, Bueno-de-Mesquita HB, Peeters PH, et al. Polymorphisms in the genes involved in the arachidonic acid-pathway, fish consumption and the risk of colorectal cancer. Int J Cancer. 2006; 119: 297–303.
- 49 Ulrich CM, Whitton J, Yu JH, et al. PTGS2 (COX-2)-765G > C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs. Cancer Epidemiol Biomarkers Prev. 2005; 14: 616–619.
- 50 Gao J, Ke Q, Ma HX, et al. Functional polymorphisms in the cyclooxygenase 2 (COX-2) gene and risk of breast cancer in a Chinese population. J Toxicol Environ Health A. 2007; 70: 908–915.
- 51 Tan W, Wu J, Zhang X, et al. Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer. Carcinogenesis. 2007; 28: 1197–1201.
- 52 McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2004; CD004722.
- 53 Arnott ID, Nimmo ER, Drummond HE, et al. NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe? Genes Immun. 2004; 5: 417–425.
- 54 Genetic Power Calculator; http://pngu.mgh.harvard.edu/≈purcell/gpc/cc2.html. 2009.
