A.V. TKACHEV, L.S. MKRTCHIAN, K.E. MAZOVKA, A.S. MAKARENKO, A.M. ASLANOV

Rostov State Medical University,  Rostov-on-Don

 Contact details:

Tkachev A.V. — MD, Professor, Head of the Department of Propaedeutics of Internal Diseases

Address: 29 Nakhichevanskiy per., Russian Federation, Rostov-on-Don, tel.: +7-918-557-11-73, e-mail: tkachev@aaanet.ru

The article presents a review of modern literature on progress in the study of genetic factors predisposing to the development of inflammatory bowel disease (IBD). The research data of the recent years are summarized, which are related to genome-wide associations study (GWAS): gene-coding changes, direct violations by the neighboring zones of transcription factor links, and specific tissue epigenetic mechanisms; features of genes polymorphism are described for the territories of the Russian Federation. Many studies indicate the possibility of genetic variants that can be the basis for determining the mechanisms of the disease and, in the future, using genetic studies in the differential diagnosis of IBD, predicting the character and severity of the disease, and personalized medication treatment. However, it is necessary to remember that the presence of a genetic predisposition does not indicate the presence of a disease. This in turn emphasizes the influence of other factors on the development of IBD, such as environmental factors, nutritional characters, the influence of microbiota, which opens future direction for further studies of the interaction of the above factors and the practical use of the results.

Key words: ulcerative colitis, Crohn’s disease, inflammatory bowel disease, genes polymorphism.

REFERENCES

1. Khalif I.L., Loranskaya I.D. Vospalitel’nye zabolevaniya kishechnika (nespetsificheskiy yazvennyy kolit i bolezn’ Krona): klinika, diagnostika, lechenie [Inflammatory bowel diseases (ulcerative colitis and Crohn’s disease): clinical presentation, diagnosis, treatment]. Moscow: Miklosh, 2004. 88 p.
2. Gastroenterologiya: natsional’noe rukovodstvo, pod red. V.T. Ivashkina, T.L. Lapinoy [Gastroenterology: national guidelines, ed. V.T. Ivashkin, T.L. Lapina]. Moscow: GEOTAR Media, 2008. 754 p.
3. Livzan M.A., Makeykina M.A. Ulcerative colitis: genetics of the immune response. Klin. perspektivy gastroenterol., gepatol, 2012, no. 1, pp. 28–33 (in Russ.).
4. Orholm M., Munkholm P., Langholz E. et al. Familial occurence of inflammatory bowel disease. N. Engl. J. Med, 1991, vol. 324, pp. 84–88.
5. Hugot J-P., Chamaiilard M., Zouali H. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature, 2001, vol. 411, pp. 599–603.
6. Ogura Y., Bonen D.K., Inohara N. et al. A frameshift mutation in Nod2 associated with susceptibility to Crohn’s disease. Nature, 2001, vol. 411, pp. 603–606.
7. Duerr R.H., Taylor K.D., Brant S.R. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science, 2006, vol. 314, pp. 1461–1463.
8. Huang H., Fang M., Jostins L., Umićević Mirkov et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature, 2017, Jul 13, vol. 547 (7662), pp. 173–178. DOI: 10.1038/nature22969. Epub 2017 Jun 28
9. Jostins L., Ripke S., Weersma R.K. et al. Hostmicrobe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 2012, vol. 491, pp. 119–124.
10. Zhang H., Massey D., Tremelling M., Parkes M. Genetics of inflammatory bowel disease: clues to pathogenesis. British Medical Bulletin, 2008, vol. 87, pp. 17–30.
11. Michelsen K.S., Thomas L.S., Taylor K.D. et al. IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein. PLoS One, 2009, r. 4719.
12. Ferwerda B., McCall M.V.B., Verheijen K., Kullberg B.J. Functional Consequences of Toll-like Receptor 4 Polymorphisms. MOL MED, 2008, vol. 14, no. 14 (5–6), pp. 46–52.
13. Cho J.H., Weaver C.T. The genetics of inflammatory bowel disease. Gastroenterology, 2007, vol. 133 (4), pp. 1327–1339.
14. Komarov F.I., Osadchuk A.M., Osadchuk M.A., Kvetnoy I.M. Nespetsificheskiy yazvennyy kolit [Nonspecific ulcerative colitis]. Moscow: OOO «Meditsinskoe informatsionnoe agentstvo», 2008. 256 p.
15. Kaser A., Lee A-H., Franke A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell, 2008, vol. 134, pp. 743–756.
16. Matsuzawa J., Sugimura K., Matsuda Y., Takazoe M, Ishizuka K., Mochizuki T., Seki S., Yoneyama O., Bannnai H., Suzuki K., Honma T., Asakura H. Association between K469E allele of intercellular adhesion molecule 1 gene and inflammatory bowel disease in a Japanese population. Gut,2003, vol. 52 (1), pp. 75–78.
17. Livzan M.A., Makeykina M.A. Inflammatory bowel diseases: modern aspects of diagnosis and treatment. Consilium Medicum. Pril.: Gastroenterologiya, 2010, pp. 60–65 (in Russ.).
18. Vavricka S.R., Rogler G., Gantenbein C., Spoerri M., PrinzVavricka M., Navarini A.A., French L.E., Safroneeva E., Fournier N., Straumann A., Froehlich F., Fried M., Michetti P., Seibold F., Lakatos P.L., Peyrin-Biroulet L., Schoepfer A.M. Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort. Inflamm. Bowel Dis, 2015, vol. 21 (8), pp. 1794–1800.
19. Bernstein C.N., Blanchard J.F., Rawsthorne P., Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am. J. Gastroenterol,2001, vol. 96 (4), pp. 1116–1122.
20. Geng X., Biancone L., Dai H.H., Lin J.J., Yoshizaki N., Dasgupta A., Pallone F., Das K.M. Tropomyosin isoforms in intestinal mucosa: production of autoantibodies to tropomyosin isoforms in ulcerative colitis. Gastroenterology, 1998, vol. 114 (5), pp. 912–922.
21. Biancone L., Mandal A., Yang H., Dasgupta T., Paoluzi A.O., Marcheggiano A., Paoluzi P., Pallone F., Das K.M. Production of immunoglobulin G and G1 antibodies to cytoskeletal protein by lamina propria cells in ulcerative colitis. Gastroenterology, 1995, vol. 109 (1), pp. 3–12.
22. Van Sommeren S., Janse M., Karjalainen J., Fehrmann R., Franke L., Fu J., Weersma R.K. Extraintestinal manifestations and complications in inflammatory bowel disease: from shared genetics to shared biological pathways. Inflamm. Bowel Dis, 2014, vol. 20 (6), pp. 987–994.
23. Ott C., Scholmerich J. Extraintestinal manifestations and complications in IBD. Nat. Rev.. Gastroenterol. Hepatol, 2013, vol. 10 (10), pp. 585–595.
24. Silverberg M., Mirea L., Bull S., Murphy J., Steinhart A., Greenberg G., McLeod R., Cohen Z., Wade J., Siminovitch K. A population- and family-based study of Canadian families reveals association of HLA DRB1*0103 with colonic involvement in inflammatory bowel disease. Inflamm Bowel Dis, 2003, vol. 9 (1), pp. 1–9.
25. Brikos C., O’Neill L.A. Signaling of toll-like receptors. Handb. Exp. Pharmacol, 2008, vol. 183, pp. 21–50.
26. Nasykhova Yu.A. Molekulyarno-geneticheskie aspekty razvitiya vospalitel’nykh zabolevaniy kishechnika: bolezni Krona i yazvennogo kolita: avtoref. dis… kand. biol. nauk [Molecular genetic aspects of the development of inflammatory bowel diseases: Crohn’s disease and ulcerative colitis. Synopsis of dis. PhD biol. sciences ]. Saint Petersburg, 2012.
27. Kharitonov A.G. Kliniko-geneticheskie i immunologicheskie kharakteristiki razlichnykh variantov techeniya yazvennogo kolita: avtoref. diss…. kand. med. nauk [Clinical-genetic and immunological characteristics of various variants of the course of ulcerative colitis. Synopsis of dis. PhD med. sciences]. Saint Petersburg, 2013.
28. Valuyskikh E.Yu., Svetlova I.O., Kurilovich S.A. et al. Polymorphism of genes regulators of inflammation in Crohn’s disease and ulcerative colitis. Byulleten’ SO RAMN, 2009, vol. 2, no. 136, pp. 81–89 (in Russ.).
29. Livzan M.A., Makeykina M.A. Prognostic factors of the course of ulcerative colitis. EiKG, 2013, no. 8, pp. 17–23 (in Russ.).
30. Von Stein P., Lofberg R., Kuznetsov N.V. et al. Multigene analysis can discriminate between ulcerative colitis, Crohn’s disease, and irritable bowel syndrome. Gastroenterology, 2008, vol. 134, pp. 1869–1881.
31. Arijs I., Li K., Toedter G. et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut, 2009, vol. 58, pp. 1612–1619.
32. Cleynen I., Mahachie John J.M., Henckaerts L. et al. Molecular reclassification of Crohn’s disease by cluster analysis of genetic variants. PLoS. One, 2010, vol. 5, pp. e12952.
33. Medzhitov R., Horng T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol, 2009, vol. 9, pp. 692–703.
34. Scarpa M., Stylianou E. Epigenetics: Concepts and relevance to IBD pathogenesis. Inflamm. Bowel Dis, 2012, vol. 18, pp. 1982–1996.
35. Rebane A., Akdis C.A. MicroRNAs: Essential players in the regulation of inflammation. J. AllergyClin. Immunol, 2013, vol. 132, pp. 15–26.
36. Baulina N.M., Kulakova O.G., Favorova O.O. MicroRNAs: role in the development of autoimmune inflammation. Astanaturae, 2016. vol. 8 (1/28), pp. 23-36 (In Russian)
37. Coskun M., Bjerrum J.T., Seidelin J.B. et al. MicroRNAs in inflammatory bowel disease-pathogenesis, diagnostics and therapeutics. World J. Gastroenterol, 2012, vol. 18, pp. 4629–4634.
38. Takagi T., Naito Y., Mizushima K. et al. Increased expression of microRNA in the inflamed colonic mucosa of patients with active ulcerative colitis. J. Gastroenterol. Hepatol, 2010, vol. 25 (1), pp. 129–133.
39. Iborra M., Bernuzzi F., Correale C. et al. Identification of serum and tissue micro-RNA expression profiles in different stages of inflammatory bowel disease Clinical & Experemental immunology, 2013, vol. 173 (2), pp. 250–258.
40. Tomankova T., Petrek M., Gallo J. et al. MicroRNAs: emerging regulators of immune-mediated diseases. Scand. J. Immunol, 2011, vol. 75 (2), pp. 129–141.
41. Sovalkin V.I., Bikbavova G.R., Emel’yanova Yu.A. Modern view of the pathogenesis and laboratory diagnosis of ulcerative colitis (literature review). Arkhiv vnutrenney meditsiny, 2017, vol. 7, no. 4, pp. 252–259 (in Russ.).
42. Wang M.H., Fiocchi C., Ripke S. et al. A novel approach to detect cumulative genetic effects and genetic interactions in Crohn’s disease. Inflamm. Bowel Dis, 2013, vol. 19, pp. 1799–1808.
43. Wang M.H., Fiocchi C., Zhu X. et al. Gene-gene and gene-environment interactions in ulcerative colitis. Hum. Genet, 2014, vol. 133 (5), pp. 547–558.