Türk toplumundaki inflammatuar bağırsak hastalığının hastalık mekanizmasında COX-2 gen varyantlarının rolü

Yıl 2018, , 45 - 48, 24.04.2018

Elif Sinem İplik , Resul Kahraman , Barış Ertuğrul Gonca Candan Arzu Ergen Bedia Çakmakoğlu

https://doi.org/10.25000/acem.416012

Öz

Amaç: İnflamatuar
bağırsak hastalığı, gastrointestinal sistemde etiolojisi tam olarak bilinmeyen
bir hastalık grubu olup, Crohn hastalığı ve ülseratif kolit olmak üzere iki
önemli tipe ayrılmaktadır. COX-2 kolon kanserinin de dahil olduğu karsinogenez
prosesinde rolü olan ve tümör gelişimine katkı sağlayan bir mediatördür. Aynı
zamanda, inflamasyon meydana geldiğinde kolonik mukoza üzerindeki stabiliteyi
değiştirdiği bilinmektedir. Bu amaçla, çalışmamızda inflamatuar barsak
hastalığı ile COX-2 ilişkisinin Türk kökenli kişiler üzerinde araştırılması
amaçlanmıştır.

Yöntemler: Çalışmaya 42 Crohn ve 64
ülseratif kolitli
hasta olmak üzere toplam 106 hasta)
ve 121 sağlıklı kontrol dahil edilmiştir. COX-2 -765G→C ve COX-2 -1195A→G gen varyantları polimeraz zincir reaksiyonu ve
restriksiyon parça uzunluk polimorfizmi teknikleri kullanılarak analiz
edilmiştir.

Bulgular:
COX-2-1195A→G gen varyantı AA taşıyıcılarının istatistiksel olarak hasta
grubunda (Crohn hastalığı için p=0,008 ve ülseratif kolit için p=0,001) kontrol
grubuna göre yüksek bulunmuştur. Buna karşılık olarak AG genotipi ve G
taşıyıcıları da kontrol grubunda anlamlı olarak yüksek bulunmuştur (Crohn
hastalığı: p=0,005 AG için ve p= 0,008 G
için; ülseratif kolit: p=0,001 AG için ve p=0,001G için).

Sonuç: Çalışmada Türk kökenli kişiler
üzerinde, inflamatuar bağırsak hastalığı ve COX-2 arasındaki ilişkiye dair COX-2-1195A→G AA
taşıyıcıları gibi önemli
ve araştırılması gerekli soruları beraberinde getiren bulgular elde edilmiştir.
Hasta sayısının arttırılarak ek çalışmalar ile hastalık patogonezindeki rolünün
tam olarak araştırılması gerektiği düşünülmektedir. 

Anahtar Kelimeler

COX-2, gen varyantları, Crohn, ülseratif kolit

The role of COX-2 gene variants on the disease mechanism of inflammatory bowel disease in a Turkish population

Öz

Aim: Inflammatory
bowel disease has two major types: Crohn’s disease and ulcerative colitis that
occur in the gastrointestinal tract with unknown etiology. COX-2 has important
role on carcinogenesis process including colon cancer supporting the tumor
growth. COX-2 was also known due to its ability to change homeostasis on
colonic mucosa in inflammatory cells on patients who have inflammatory bowel
disease.  In this study, we have aimed to
find a linkage between inflammatory bowel disease and COX-2 in a Turkish population.

Methods:A total of 106 patients,42 with Crohn’s disease
and 64 with ulcerative
colitis and 121 healthy control subjects were
included the study. Gene
variants of COX-2-765G→C and COX-2-1195A→G were analyzed
by polymerase chain reaction and restriction fragment length polymorphism
techniques.

Results: The
results demonstrated that COX-2-1195A→G gene variants AA carriers were
statistically found in high level on patients with both ulcerative colitis
(p=0,001) and Crohn’s disease (p=0.008). In contrast, AG genotype and G carriers
were statistically found higher in control group (Crohn’s disease, p=0.005
for AG and p= 0.008 for G; ulcerative colitis, p=0.001 for AG and p=0.001 for
G).

Conclusion: In this research, we have
observed important and questionable results between inflammatory bowel disease and COX-2, especially COX-2-1195A→G gene variants AA carriers in a Turkish population.
Researches need to focus on their local roles on inflammatory bowel disease pathogenesis with large sample size.

Anahtar Kelimeler

COX-2, gene variants, Crohn’s disease, Ulcerative Colitis

Kaynakça

• 1. Sleizenger & Fordtran’s, Gastrointestinal and Liver Disease 7th Edition, Saunders Elsevier, Philadelphia .Volume I, pp. 2005–67.
• 2. Peña-Sánchez JN, Lix LM, Teare GF, Li W, Fowler SA, Jones JL. Impact of an Integrated Model of Care on Outcomes of Patients With Inflammatory Bowel Diseases: Evidence From a Population-Based Study. J Crohns Colitis. 2017;11:1471-9.
• 3. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001; 48(4): 526–535.
• 4. Higashi D, Futami K, Ishibashi Y, Egawa Y, Maekawa T, Matsui T, Iwashita A, et al. Clinical course of colorectal cancer in patients with ulcerative colitis. Anticancer Res. 2011;31:2499–504.
• 5. Lesage S, Zouali H, Cézard JP, Colombel JF, Belaiche J, Almer S, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002;70:845-57.
• 6. Olén O, Askling J, Sachs MC, Frumento P, Neovius M, Smedby KE, et al. Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014. BMJ. 2017;20:358:j3951.
• 7. Jewel Samadder N, Valentine JF, Guthery S, Singh H, Bernstein CN, Wan Y, et al. Colorectal Cancer in Inflammatory Bowel Diseases: A Population-Based Study in Utah. Dig Dis Sci. 2017;62:2126-32
• 8. Luo C, Zhang H. The Role of Proinflammatory Pathways in the Pathogenesis of Colitis-Associated Colorectal Cancer. Mediators Inflamm. 2017;2017:5126048.
• 9. Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004;126:451–9.
• 10. Wang R, Leong RW. Primary sclerosing cholangitis as an independent risk factor for colorectal cancer in the context of inflammatory bowel disease: a review of the literature. World Journal of Gastroenterology. 2014;20:8783–8789.
• 11. Watanabe T, Konishi T, Kishimoto J, Kotake K, Muto T, Sugihara K, et al. Ulcerative colitis-associated colorectal cancer shows a poorer survival than sporadic colorectal cancer: a nationwide Japanese study. Inflamm Bowel Dis. 2011;17:802–8.
• 12. Zhang X, Miao X, Tan W, Ning B, Liu Z, Hong Y. Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology. 2005;129:565–76.
• 13. Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a populationbased study. Cancer. 2001;91:854-62.
• 14. Goldacre MJ, Wotton CJ, Yeates D, Seagroatt V, Jewell D. Cancer in patients with ulcerative colitis, Crohn’s disease and coeliac disease: record linkage study. Eur J Gastroenterol Hepatol. 2008;20:297-304.
• 15. Beaugerie L, Svrcek M, Seksik P, Bouvier AM, Simon T, Allez M, et al. CESAME Study Group. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology. 2013;145:166-175.e8.
• 16. Askling J, Dickman PW, Karlén P, Broström O, Lapidus A, Löfberg R,et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology. 2001;120:1356-62.
• 17. Thompson PA, Ashbeck EL, Roe DJ, Fales L, Buckmeier J, Wang F, et al. Celecoxib for the Prevention of Colorectal Adenomas: Results of a Suspended Randomized Controlled Trial. J Natl Cancer Inst. 2016;108:pii:djw151.
• 18. Li P, Wu H, Zhang H, Shi Y, Xu J, Ye Y, et al. Aspirin use after diagnosis but not prediagnosis improves established colorectal cancer survival: a meta-analysis. Gut. 2015;64:1419-25.
• 19. Connell W, Leong RW, Walsh A, Kamm M, Kench J, What should be the protocol to manage indefinite dysplasia in IBD? http://wiki.cancer.org.au/australiawiki/index.php?oldid=17938, 2012.
• 20. Singer II, Kawka DW, Schloemann S, Tessner T, Riehl T, Stenson WF, Cyclooxygenase 2 is induced in colonicepithelial cells in inflammatory bowel disease. Gastroenterology. 1998;115:297–306.
• 21. Smythe EM, Burke A, FitzGerald GA. Lipid-derived autacoids: eicosanoids and platelet-activating factor. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, edited by Brunton LL, Lazo JS, Parker KL. New York: McGraw-Hill, 2005, p. 653–670.
• 22. Patrignani P, Panara MR, Sciulli MG, Santini G, Renda G, Patrono C. Differential inhibition of human prostaglandin endoperoxide synthase- 1 and -2 by nonsteroidal anti-inflammatory drugs. J Physiol Pharmacol. 1997;48:623–631.
• 23. Vane JR, Botting RM. New insights into the mode of action of antiinflammatory drugs. Inflamm Res. 1995;44:1–10.
• 24. Needleman P, Isakson PC. The discovery and function of COX-2. J Rheumatol. 1997;49:6–8.
• 25. Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growthand ulcer healing. Nat Med. 1999;5:1418–23.
• 26. Hatazawa R, Tanaka A, Tanigami M, Amagase K, Kato S, Ashida Y, Takeuchi K. Cyclooxygenase-2/prostaglandin E2 accelerates the healing of gastric ulcers via EP4 receptors. Am J Physiol Gastrointest Liver Physiol. 2007;293:G788–G797.
• 27. Mizuno H, Sakamoto C, Matsuda K, Wada K, Uchida T, Noguchi H, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology. 1997;112:387–97.
• 28. Ukawa H, Yamakuni H, Kato S, Takeuchi K. Effects of cyclooxygenase- 2 selective and nitric oxide-releasing nonsteroidal antiinflammatory drugs on mucosal ulcerogenic and healing responses of the stomach. DigDis Sci. 1998;43:2003–11.
• 29. Andersen V, Nimmo E, Krarup HB, Drummond H, Christensen J, Ho GT, et al. Cyclooxygenase-2 (COX-2) polymorphisms and risk of inflammatory bowel disease in a Scottish and Danish case-control study. Inflamm Bowel Dis. 2011;17:937-46.
• 30. Zhang CX, Guo LK, Guo XF. Interaction between the polymorphisms of cyclooxygenase-2-1195G/A,MnSOD9Ala/val genes and the high-fat diets and its correlation with ulcerative colitis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2015;37: 37-43.
• 31. de Vries HS, te Morsche RH, van Oijen MG, Nagtegaal ID, Peters WH, de Jong DJ.The functional -765G→C polymorphism of the COX-2 gene may reduce the risk of developing crohn's disease. PLoS One. 2010;5:e15011.
• 32. Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 1999;18:7908-16.
• 33. Zhu W, Wei BB, Shan X, Liu P. 765G[C and 8473T[Cpolymorphisms of COX-2 and cancer risk: a meta-analysis based on 33 case–control studies. Mol Biol Rep. 2009;37:277–288.
• 34. Watanabe J, Lin JA, Narasimha AJ, Shahbazian A, Ishikawa T, Martin MG, et al. Novel anti-inflammatory functions for endothelial and myeloid cyclooxygenase-2 in a new mouse model of Crohn’s disease. Am J Physiol Gastrointest Liver Physiol. 2010;298:G842–G850.