Genetic and epigenetic re-programming in the progression of inflammatory bowel disease: A comprehensive review

Abstract

Inflammatory Bowel Disease (IBD) is portrayed as deleterious and redundant condition. Its point-by-point progression is as yet indistinct, albeit accessible proof proposes that perplexing cooperation between inherited tendencies, ecological variable elements, and contorted and heartless responses are the causes behind the advancement of IBD. Late disclosures concerning its innate characteristics have offered a huge effect on the muddled genetic reason, be that as it may, the perceived innate legacy. The components shed light on the overall contrast in malady. It is bit by bit uncovering itself. It is discernible to say, the epigenetic parts can interpose in the association between genetic characteristics and conditions, leading to accepting an essential job in the progression of the ailment. This review encompasses the late inherited and epigenetic disclosures and jobs in IBD, with consideration regarding epigenetic changes noteworthiness in ineptitude because of illness, development, conduct, and colorectal malignant growth (CRC) and its inert capacity translational applications.

References

1. A. Kaser, S. Zeissig, and R. S. Blumberg, "Inflammatory bowel disease," (in eng), Annual review of immunology, vol. 28, pp. 573-621, 2010, doi: 10.1146/annurev-immunol-030409-101225.
2. H. Zhang, Z. Zeng, A. Mukherjee, and B. Shen, "Molecular diagnosis and classification of inflammatory bowel disease," (in eng), Expert review of molecular diagnostics, vol. 18, no. 10, pp. 867-886, Oct 2018, doi: 10.1080/14737159.2018.1516549.
3. N. T. Ventham, N. A. Kennedy, E. R. Nimmo, and J. Satsangi, "Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics," (in eng), Gastroenterology, vol. 145, no. 2, pp. 293-308, Aug 2013, doi: 10.1053/j.gastro.2013.05.050.
4. K. Aleksandrova, B. Romero-Mosquera, and V. Hernandez, "Diet, Gut Microbiome and Epigenetics: Emerging Links with Inflammatory Bowel Diseases and Prospects for Management and Prevention," (in eng), Nutrients, vol. 9, no. 9, Aug 30 2017, doi: 10.3390/nu9090962.
5. G. G. Kaplan and S. C. Ng, "Understanding and Preventing the Global Increase of Inflammatory Bowel Disease," (in eng), Gastroenterology, vol. 152, no. 2, pp. 313-321.e2, Feb 2017, doi: 10.1053/j.gastro.2016.10.020.
6. P. S. Karatzas, M. Gazouli, M. Safioleas, and G. J. Mantzaris, "DNA methylation changes in inflammatory bowel disease," (in eng), Annals of gastroenterology, vol. 27, no. 2, pp. 125-132, 2014.
7. J. S. Levine and R. Burakoff, "Extraintestinal manifestations of inflammatory bowel disease," Gastroenterology & hepatology, vol. 7, no. 4, p. 235, 2011.
8. W. Li, "Precision medicine: to cure and relieve more," Precision Clinical Medicine, vol. 1, no. 1, pp. 3-4, 2018, doi: 10.1093/pcmedi/pby002 %J Precision Clinical Medicine.
9. S. M. Weissman, "Personalized medicine: a new horizon for medical therapy," Precision Clinical Medicine, vol. 1, no. 1, pp. 1-2, 2018, doi: 10.1093/pcmedi/pby001 %J Precision Clinical Medicine.
10. J. Satsangi, D. P. Jewell, W. M. Rosenberg, and J. I. Bell, "Genetics of inflammatory bowel disease," (in eng), Gut, vol. 35, no. 5, pp. 696-700, May 1994, doi: 10.1136/gut.35.5.696.
11. J. Halfvarson, L. Bodin, C. Tysk, E. Lindberg, and G. Järnerot, "Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics," (in eng), Gastroenterology, vol. 124, no. 7, pp. 1767-73, Jun 2003, doi: 10.1016/s0016-5085(03)00385-8.
12. T. Ahmad, J. Satsangi, D. McGovern, M. Bunce, and D. P. Jewell, "Review article: the genetics of inflammatory bowel disease," (in eng), Alimentary pharmacology & therapeutics, vol. 15, no. 6, pp. 731-48, Jun 2001, doi: 10.1046/j.1365-2036.2001.00981.x.
13. K. L. Helbig et al., "A case-only study of gene-environment interaction between genetic susceptibility variants in NOD2 and cigarette smoking in Crohn's disease aetiology," (in eng), BMC medical genetics, vol. 13, p. 14, Mar 14 2012, doi: 10.1186/1471-2350-13-14.
14. D. Ellinghaus et al., "Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies," (in eng), Gastroenterology, vol. 145, no. 2, pp. 339-47, Aug 2013, doi: 10.1053/j.gastro.2013.04.040.
15. J. Z. Liu et al., "Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations," (in eng), Nature genetics, vol. 47, no. 9, pp. 979-986, Sep 2015, doi: 10.1038/ng.3359.
16. K. M. de Lange et al., "Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease," (in eng), Nature genetics, vol. 49, no. 2, pp. 256-261, Feb 2017, doi: 10.1038/ng.3760.
17. H. Huang et al., "Histone H3 trimethylation at lysine 36 guides m(6)A RNA modification co-transcriptionally," (in eng), Nature, vol. 567, no. 7748, pp. 414-419, Mar 2019, doi: 10.1038/s41586-019-1016-7.
18. A. Jeltsch, J. Broche, and P. Bashtrykov, "Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes," (in eng), Genes, vol. 9, no. 11, Nov 21 2018, doi: 10.3390/genes9110566.
19. L. Li, K. Fu, W. Zhou, and M. Snyder, "Applying circulating tumor DNA methylation in the diagnosis of lung cancer," Precision Clinical Medicine, vol. 2, no. 1, pp. 45-56, 2019, doi: 10.1093/pcmedi/pbz003 %J Precision Clinical Medicine.
20. A. Portela and M. Esteller, "Epigenetic modifications and human disease," (in eng), Nature biotechnology, vol. 28, no. 10, pp. 1057-68, Oct 2010, doi: 10.1038/nbt.1685.
21. W. Y. Tang and S. M. Ho, "Epigenetic reprogramming and imprinting in origins of disease," (in eng), Reviews in endocrine & metabolic disorders, vol. 8, no. 2, pp. 173-82, Jun 2007, doi: 10.1007/s11154-007-9042-4.
22. T. Tahara et al., "Effect of MDR1 gene promoter methylation in patients with ulcerative colitis," (in eng), International journal of molecular medicine, vol. 23, no. 4, pp. 521-7, Apr 2009, doi: 10.3892/ijmm_00000160.
23. E. McDermott et al., "DNA Methylation Profiling in Inflammatory Bowel Disease Provides New Insights into Disease Pathogenesis," (in eng), Journal of Crohn's & colitis, vol. 10, no. 1, pp. 77-86, Jan 2016, doi: 10.1093/ecco-jcc/jjv176.
24. K. Kang, J. H. Bae, K. Han, E. S. Kim, T. O. Kim, and J. M. Yi, "A Genome-Wide Methylation Approach Identifies a New Hypermethylated Gene Panel in Ulcerative Colitis," (in eng), International journal of molecular sciences, vol. 17, no. 8, Aug 9 2016, doi: 10.3390/ijms17081291.
25. J. Cooke et al., "Mucosal genome-wide methylation changes in inflammatory bowel disease," (in eng), Inflammatory bowel diseases, vol. 18, no. 11, pp. 2128-37, Nov 2012, doi: 10.1002/ibd.22942.
26. T. Gutschner and S. Diederichs, "The hallmarks of cancer: a long non-coding RNA point of view," (in eng), RNA biology, vol. 9, no. 6, pp. 703-19, Jun 2012, doi: 10.4161/rna.20481.
27. Y. Dong et al., "Non-coding RNA-linked epigenetic regulation in cardiac hypertrophy," (in eng), International journal of biological sciences, vol. 14, no. 9, pp. 1133-1141, 2018, doi: 10.7150/ijbs.26215.
28. J. Wehkamp et al., "NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression," (in eng), Gut, vol. 53, no. 11, pp. 1658-64, Nov 2004, doi: 10.1136/gut.2003.032805.
29. J. E. Wilusz, H. Sunwoo, and D. L. Spector, "Long noncoding RNAs: functional surprises from the RNA world," (in eng), Genes & development, vol. 23, no. 13, pp. 1494-504, Jul 1 2009, doi: 10.1101/gad.1800909.
30. J. Winter, S. Jung, S. Keller, R. I. Gregory, and S. Diederichs, "Many roads to maturity: microRNA biogenesis pathways and their regulation," (in eng), Nature cell biology, vol. 11, no. 3, pp. 228-34, Mar 2009, doi: 10.1038/ncb0309-228.
31. R. Kalla et al., "MicroRNAs: new players in IBD," (in eng), Gut, vol. 64, no. 3, pp. 504-17, Mar 2015, doi: 10.1136/gutjnl-2014-307891.
32. Z. Zeng, A. Mukherjee, and H. Zhang, "From Genetics to Epigenetics, Roles of Epigenetics in Inflammatory Bowel Disease," (in eng), Frontiers in genetics, vol. 10, p. 1017, 2019, doi: 10.3389/fgene.2019.01017.
33. Z. Rahman, M. R. Bazaz, T. Pasam, M. S. Kumar, and M. P. Dandekar, "Importance of biological clock epigenetics in the manifestation of polycystic ovary syndrome," Biological Sciences, vol. 1, no. 1, pp. 67-81, 2021.
34. C. Ling and T. Rönn, "Epigenetics in Human Obesity and Type 2 Diabetes," (in eng), Cell Metab, vol. 29, no. 5, pp. 1028-1044, 2019, doi: 10.1016/j.cmet.2019.03.009.
35. S. Sharma, T. K. Kelly, and P. A. Jones, "Epigenetics in cancer," (in eng), Carcinogenesis, vol. 31, no. 1, pp. 27-36, 2010, doi: 10.1093/carcin/bgp220.
36. N. Jawad, N. Direkze, and S. J. Leedham, "Inflammatory bowel disease and colon cancer," (in eng), Recent Results Cancer Res, vol. 185, pp. 99-115, 2011, doi: 10.1007/978-3-642-03503-6_6.
37. D. E. Handy, R. Castro, and J. Loscalzo, "Epigenetic modifications: basic mechanisms and role in cardiovascular disease," (in eng), Circulation, vol. 123, no. 19, pp. 2145-2156, 2011, doi: 10.1161/CIRCULATIONAHA.110.956839.
38. J. Satsangi, M. S. Silverberg, S. Vermeire, and J. F. Colombel, "The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications," (in eng), Gut, vol. 55, no. 6, pp. 749-53, Jun 2006, doi: 10.1136/gut.2005.082909.
39. A. T. Adams et al., "Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci," (in eng), Inflammatory bowel diseases, vol. 20, no. 10, pp. 1784-93, Oct 2014, doi: 10.1097/mib.0000000000000179.
40. Y. Dai, G. Pei, Z. Zhao, and P. Jia, "A Convergent Study of Genetic Variants Associated With Crohn’s Disease: Evidence From GWAS, Gene Expression, Methylation, eQTL and TWAS," (in English), Frontiers in genetics, Original Research vol. 10, 2019-April-09 2019, doi: 10.3389/fgene.2019.00318.
41. K. J. Howell et al., "DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome," (in eng), Gastroenterology, vol. 154, no. 3, pp. 585-598, Feb 2018, doi: 10.1053/j.gastro.2017.10.007.
42. W. J. Locke et al., "DNA Methylation Cancer Biomarkers: Translation to the Clinic," (in eng), Frontiers in genetics, vol. 10, pp. 1150-1150, 2019, doi: 10.3389/fgene.2019.01150.
43. P. W. Laird, "The power and the promise of DNA methylation markers," (in eng), Nature reviews. Cancer, vol. 3, no. 4, pp. 253-66, Apr 2003, doi: 10.1038/nrc1045.
44. J. R. Raut, Z. Guan, P. Schrotz-King, and H. Brenner, "Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review," Clinical Epigenetics, vol. 12, no. 1, p. 122, 2020/08/10 2020, doi: 10.1186/s13148-020-00904-7.
45. J. M. Whyte, J. J. Ellis, M. A. Brown, and T. J. Kenna, "Best practices in DNA methylation: lessons from inflammatory bowel disease, psoriasis and ankylosing spondylitis," Arthritis Research & Therapy, vol. 21, no. 1, p. 133, 2019/06/03 2019, doi: 10.1186/s13075-019-1922-y.
46. A. Raine, E. Manlig, P. Wahlberg, A. C. Syvänen, and J. Nordlund, "SPlinted Ligation Adapter Tagging (SPLAT), a novel library preparation method for whole genome bisulphite sequencing," (in eng), Nucleic acids research, vol. 45, no. 6, p. e36, Apr 7 2017, doi: 10.1093/nar/gkw1110.
47. O. Taryma-Leśniak, K. E. Sokolowska, and T. K. Wojdacz, "Current status of development of methylation biomarkers for in vitro diagnostic IVD applications," Clinical Epigenetics, vol. 12, no. 1, p. 100, 2020/07/06 2020, doi: 10.1186/s13148-020-00886-6.
48. K. Fisher and J. Lin, "MicroRNA in inflammatory bowel disease: Translational research and clinical implication," (in eng), World journal of gastroenterology, vol. 21, no. 43, pp. 12274-82, Nov 21 2015, doi: 10.3748/wjg.v21.i43.12274.
49. F. Wu et al., "Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn's disease," (in eng), Inflammatory bowel diseases, vol. 17, no. 1, pp. 241-50, Jan 2011, doi: 10.1002/ibd.21450.
50. C. G. Chapman and J. Pekow, "The emerging role of miRNAs in inflammatory bowel disease: a review," (in eng), Therapeutic advances in gastroenterology, vol. 8, no. 1, pp. 4-22, Jan 2015, doi: 10.1177/1756283x14547360.
51. M. Coskun, J. T. Bjerrum, J. B. Seidelin, J. T. Troelsen, J. Olsen, and O. H. Nielsen, "miR-20b, miR-98, miR-125b-1*, and let-7e* as new potential diagnostic biomarkers in ulcerative colitis," (in eng), World journal of gastroenterology, vol. 19, no. 27, pp. 4289-99, Jul 21 2013, doi: 10.3748/wjg.v19.i27.4289.
52. A. M. Zahm, M. Thayu, N. J. Hand, A. Horner, M. B. Leonard, and J. R. Friedman, "Circulating microRNA is a biomarker of pediatric Crohn disease," (in eng), Journal of pediatric gastroenterology and nutrition, vol. 53, no. 1, pp. 26-33, Jul 2011, doi: 10.1097/MPG.0b013e31822200cc.
53. J. S. Schaefer et al., "MicroRNA signatures differentiate Crohn's disease from ulcerative colitis," (in eng), BMC immunology, vol. 16, p. 5, Feb 10 2015, doi: 10.1186/s12865-015-0069-0.
54. U. Christerson, A. V. Keita, J. D. Söderholm, and C. Gustafson-Svärd, "Potential role of protease-activated receptor-2-stimulated activation of cytosolic phospholipase A(2) in intestinal myofibroblast proliferation: Implications for stricture formation in Crohn's disease," (in eng), Journal of Crohn's & colitis, vol. 3, no. 1, pp. 15-24, Feb 2009, doi: 10.1016/j.crohns.2008.10.002.
55. C. W. Lees, J. C. Barrett, M. Parkes, and J. Satsangi, "New IBD genetics: common pathways with other diseases," (in eng), Gut, vol. 60, no. 12, pp. 1739-53, Dec 2011, doi: 10.1136/gut.2009.199679.
56. T. Jess et al., "Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark," (in eng), Inflammatory bowel diseases, vol. 13, no. 4, pp. 481-9, Apr 2007, doi: 10.1002/ibd.20036.
57. F. Magro et al., "Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders," (in eng), Journal of Crohn's & colitis, vol. 11, no. 6, pp. 649-670, Jun 1 2017, doi: 10.1093/ecco-jcc/jjx008.
58. S. Saito et al., "DNA methylation of colon mucosa in ulcerative colitis patients: correlation with inflammatory status," (in eng), Inflammatory bowel diseases, vol. 17, no. 9, pp. 1955-65, Sep 2011, doi: 10.1002/ibd.21573.
59. A. Barnicle, C. Seoighe, J. M. Greally, A. Golden, and L. J. Egan, "Inflammation-associated DNA methylation patterns in epithelium of ulcerative colitis," (in eng), Epigenetics, vol. 12, no. 8, pp. 591-606, Aug 2017, doi: 10.1080/15592294.2017.1334023.
60. T. Lobatón et al., "Relationship between methylation and colonic inflammation in inflammatory bowel disease," (in eng), World journal of gastroenterology, vol. 20, no. 30, pp. 10591-8, Aug 14 2014, doi: 10.3748/wjg.v20.i30.10591.
61. N. J. Gould, K. L. Davidson, C. U. Nwokolo, and R. P. Arasaradnam, "A systematic review of the role of DNA methylation on inflammatory genes in ulcerative colitis," (in eng), Epigenomics, vol. 8, no. 5, pp. 667-84, May 2016, doi: 10.2217/epi-2016-0006.
62. Z. Lin et al., "Identification of disease-associated DNA methylation in B cells from Crohn's disease and ulcerative colitis patients," (in eng), Digestive diseases and sciences, vol. 57, no. 12, pp. 3145-53, Dec 2012, doi: 10.1007/s10620-012-2288-z.
63. J. Hanna, G. S. Hossain, and J. Kocerha, "The Potential for microRNA Therapeutics and Clinical Research," (in English), Frontiers in genetics, Mini Review vol. 10, 2019-May-16 2019, doi: 10.3389/fgene.2019.00478.
64. F. E. Ahmed et al., "Diagnostic microRNA markers to screen for sporadic human colon cancer in stool: I. Proof of principle," (in eng), Cancer Genomics Proteomics, vol. 10, no. 3, pp. 93-113, May-Jun 2013.
65. M. Iborra et al., "Identification of serum and tissue micro-RNA expression profiles in different stages of inflammatory bowel disease," (in eng), Clinical and experimental immunology, vol. 173, no. 2, pp. 250-8, Aug 2013, doi: 10.1111/cei.12104.
66. G. Koukos et al., "MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis," (in eng), Gastroenterology, vol. 145, no. 4, pp. 842-52.e2, Oct 2013, doi: 10.1053/j.gastro.2013.07.001.
67. G. W. Krissansen et al., "Overexpression of miR-595 and miR-1246 in the sera of patients with active forms of inflammatory bowel disease," (in eng), Inflammatory bowel diseases, vol. 21, no. 3, pp. 520-30, Mar 2015, doi: 10.1097/mib.0000000000000285.
68. H. Wang et al., "Circulating MicroRNA223 is a New Biomarker for Inflammatory Bowel Disease," (in eng), Medicine, vol. 95, no. 5, p. e2703, Feb 2016, doi: 10.1097/md.0000000000002703.
69. F. Gomollón et al., "3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 1: Diagnosis and Medical Management," (in eng), Journal of Crohn's & colitis, vol. 11, no. 1, pp. 3-25, Jan 2017, doi: 10.1093/ecco-jcc/jjw168.
70. T. Tahara et al., "Promoter methylation of protease-activated receptor (PAR2) is associated with severe clinical phenotypes of ulcerative colitis (UC)," (in eng), Clinical and experimental medicine, vol. 9, no. 2, pp. 125-30, Jun 2009, doi: 10.1007/s10238-008-0025-x.
71. N. Benderska et al., "miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis," (in eng), Inflammatory bowel diseases, vol. 21, no. 9, pp. 2039-51, Sep 2015, doi: 10.1097/mib.0000000000000453.
72. J. R. Pekow et al., "miR-143 and miR-145 are downregulated in ulcerative colitis: putative regulators of inflammation and protooncogenes," (in eng), Inflammatory bowel diseases, vol. 18, no. 1, pp. 94-100, Jan 2012, doi: 10.1002/ibd.21742.
73. K. Ludwig et al., "PDCD4/miR-21 dysregulation in inflammatory bowel disease-associated carcinogenesis," (in eng), Virchows Archiv : an international journal of pathology, vol. 462, no. 1, pp. 57-63, Jan 2013, doi: 10.1007/s00428-012-1345-5.
74. A. E. M’Koma, "The multifactorial etiopathogeneses interplay of inflammatory bowel disease: an overview," Gastrointestinal Disorders, vol. 1, no. 1, pp. 75-105, 2018.
75. S. Fiorucci et al., "Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis," (in eng), Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13936-41, Nov 20 2001, doi: 10.1073/pnas.241377298.
76. N. Cenac et al., "Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2," (in eng), The American journal of pathology, vol. 161, no. 5, pp. 1903-15, Nov 2002, doi: 10.1016/s0002-9440(10)64466-5.
77. O. Brenner et al., "Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia," (in eng), Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 45, pp. 16016-21, Nov 9 2004, doi: 10.1073/pnas.0407180101.
78. M. M. Garrity-Park, E. V. Loftus, Jr., S. C. Bryant, and T. C. Smyrk, "A Biomarker Panel to Detect Synchronous Neoplasm in Non-neoplastic Surveillance Biopsies from Patients with Ulcerative Colitis," (in eng), Inflammatory bowel diseases, vol. 22, no. 7, pp. 1568-74, Jul 2016, doi: 10.1097/mib.0000000000000789.
79. M. M. Garrity-Park, E. V. Loftus, Jr., W. J. Sandborn, S. C. Bryant, and T. C. Smyrk, "Methylation status of genes in non-neoplastic mucosa from patients with ulcerative colitis-associated colorectal cancer," (in eng), The American journal of gastroenterology, vol. 105, no. 7, pp. 1610-9, Jul 2010, doi: 10.1038/ajg.2010.22.
80. S. Brand, "Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease," (in eng), Gut, vol. 58, no. 8, pp. 1152-67, Aug 2009, doi: 10.1136/gut.2008.163667.
81. J. Wan, L. Xia, W. Xu, and N. Lu, "Expression and Function of miR-155 in Diseases of the Gastrointestinal Tract," (in eng), International journal of molecular sciences, vol. 17, no. 5, May 11 2016, doi: 10.3390/ijms17050709.
82. S. Moein, M. Vaghari-Tabari, D. Qujeq, M. Majidinia, S. M. Nabavi, and B. Yousefi, "MiRNAs and inflammatory bowel disease: An interesting new story," (in eng), Journal of cellular physiology, vol. 234, no. 4, pp. 3277-3293, Apr 2019, doi: 10.1002/jcp.27173.
83. M. Lucafò et al., "Pharmacogenetics of treatments for inflammatory bowel disease," (in eng), Expert opinion on drug metabolism & toxicology, vol. 14, no. 12, pp. 1209-1223, Dec 2018, doi: 10.1080/17425255.2018.1551876.
84. B. J. Kullberg et al., "Crohn's disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli," (in eng), Immunology, vol. 123, no. 4, pp. 600-5, Apr 2008, doi: 10.1111/j.1365-2567.2007.02735.x.
85. E. Voss, J. Wehkamp, K. Wehkamp, E. F. Stange, J. M. Schröder, and J. Harder, "NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2," (in eng), The Journal of biological chemistry, vol. 281, no. 4, pp. 2005-11, Jan 27 2006, doi: 10.1074/jbc.M511044200.
86. J. C. Chow, D. W. Young, D. T. Golenbock, W. J. Christ, and F. Gusovsky, "Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction," (in eng), The Journal of biological chemistry, vol. 274, no. 16, pp. 10689-92, Apr 16 1999, doi: 10.1074/jbc.274.16.10689.
87. Z. J. Lu et al., "MicroRNA-155 promotes the pathogenesis of experimental colitis by repressing SHIP-1 expression," (in eng), World journal of gastroenterology, vol. 23, no. 6, pp. 976-985, Feb 14 2017, doi: 10.3748/wjg.v23.i6.976.
88. C. He et al., "miR-301a promotes intestinal mucosal inflammation through induction of IL-17A and TNF-α in IBD," (in eng), Gut, vol. 65, no. 12, pp. 1938-1950, Dec 2016, doi: 10.1136/gutjnl-2015-309389.
89. A. Latiano et al., "The association of MYO9B gene in Italian patients with inflammatory bowel diseases," (in eng), Alimentary pharmacology & therapeutics, vol. 27, no. 3, pp. 241-8, Feb 1 2008, doi: 10.1111/j.1365-2036.2007.03551.x.
90. J. C. Barrett et al., "Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region," (in eng), Nature genetics, vol. 41, no. 12, pp. 1330-4, Dec 2009, doi: 10.1038/ng.483.
91. V. M. Wolters et al., "Replication of genetic variation in the MYO9B gene in Crohn's disease," (in eng), Human immunology, vol. 72, no. 7, pp. 592-7, Jul 2011, doi: 10.1016/j.humimm.2011.03.025.
92. P. Azarschab, R. Porschen, M. Gregor, N. Blin, and K. Holzmann, "Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis," (in eng), Genes Chromosomes Cancer, vol. 35, no. 2, pp. 121-6, Oct 2002, doi: 10.1002/gcc.10101.
93. C. M. Panwala, J. C. Jones, and J. L. Viney, "A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis," (in eng), Journal of immunology (Baltimore, Md. : 1950), vol. 161, no. 10, pp. 5733-44, Nov 15 1998. [Online]. Available: https://www.jimmunol.org/content/jimmunol/161/10/5733.full.pdf.
94. G. T. Ho, D. R. Gaya, and J. Satsangi, "Multidrug resistance (MDR1) gene in inflammatory bowel disease: a key player?," (in eng), Inflammatory bowel diseases, vol. 11, no. 11, pp. 1013-9, Nov 2005, doi: 10.1097/01.mib.0000186488.53493.c3.
95. T. Tahara et al., "DNA methylation status of epithelial-mesenchymal transition (EMT)--related genes is associated with severe clinical phenotypes in ulcerative colitis (UC)," (in eng), PloS one, vol. 9, no. 10, p. e107947, 2014, doi: 10.1371/journal.pone.0107947.