Evaluation of ABCB1 Gene Promoter Methylation in Patients with Ulcerative Colitis
-
Hossein Sanjari Moghaddam
,
Golshid Sanati
,
Maryam Sadr
,
Bahareh Mohebbi
,
Mahsa Keshavarz-Fathi
,
Roham Salmanroghani
,
Hassan Salmanroghani
,
Nima Rezaei
Abstract
Background: The pathogenesis of inflammatory bowel disease may be associated with the disruption in
interactions between the immune system and gut flora. Epigenetic mechanisms especially, DNAmethylation
appear to be significant regarding the interaction between the environment and genome. ABCB1 is the
encoding gene for multi-drug resistance protein 1 (MDR1) (P-glycoprotein), which is an important
transmembrane protein responsible for the efflux of cellular molecules from the intestinal wall to the lumen.
Method: In this study, we compared the methylation status of the promoter of ABCB1 in rectal mucosa of
patients with ulcerative colitis (UC) and healthy controls by using the bisulfite conversion system and real-
time quantitative multiplex methylation-specific PCR (QM-MSP).
Results: We demonstrated that the mucosal specimen of 26 UC patients had significantly higher levels of
promoter methylation in comparison to 26 controls.
Conclusion: As the first investigation of Iranian patients with UC, we showed that patients had higher levels
of ABCB1 promoter methylation in their inflammatory rectal mucosa compared to controls. However, this
altered state of methylation did not associate with the characteristics of the patients such as age and sex. Our
findings are a basis for further studies on concurrent assessment of promoter methylation and expression
of ABCB1 in UC.
1. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.
2. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46-54.e42; quiz e30.
3. Shanahan F, Bernstein CN. The evolving epidemiology of inflammatory bowel disease. Curr Opin Gastroenterol. 2009;25(4):301-5.
4. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17.
5. Thia KT, Loftus EV, Jr., Sandborn WJ, Yang SK. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol. 2008;103(12):3167-82.
6. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293(5532):1068-70.
7. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461-3.
8. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39(2):207-11.
9. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39(5):596-604.
10. Yamazaki K, McGovern D, Ragoussis J, Paolucci M, Butler H, Jewell D, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Hum Mol Genet. 2005;14(22):3499-506.
11. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40(8):955-62.
12. Xavier RJ, Rioux JD. Genome-wide association studies: a new window into immune-mediated diseases. Nat Rev Immunol. 2008;8(8):631-43.
13. PETRONIS A, PETRONIENE R. Epigenetics of inflammatory bowel disease. Gut. 2000;47(2):302-06.
14. Maeda O, Ando T, Watanabe O, Ishiguro K, Ohmiya N, Niwa Y, et al. DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: a mini review. Inflammopharmacology. 2006;14(5-6):204-6.
15. Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, et al. Effect of MDR1 gene promoter methylation in patients with ulcerative colitis. Int J Mol Med. 2009;23(4):521-7.
16. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987;84(21):7735-8.
17. Zappe K, Cichna-Markl M. Aberrant DNA Methylation of ABC Transporters in Cancer. Cells. 2020;9(10).
18. Triantafillidis JK, Nasioulas G, Kosmidis PA. Colorectal Cancer and Inflammatory Bowel Disease: Epidemiology, Risk Factors, Mechanisms of Carcinogenesis and Prevention Strategies. Anticancer Res. 2009;29(7):2727.
19. Ho GT, Moodie FM, Satsangi J. Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut. 2003;52(5):759-66.
20. Banner KH, Cattaneo C, Le Net JL, Popovic A, Collins D, Gale JD. Macroscopic, microscopic and biochemical characterisation of spontaneous colitis in a transgenic mouse, deficient in the multiple drug resistance 1a gene. Br J Pharmacol. 2004;143(5):590-8.
21. Kalitsky-Szirtes J, Shayeganpour A, Brocks DR, Piquette-Miller M. Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats. Drug Metab Dispos. 2004;32(1):20-7.
22. Wilk JN, Bilsborough J, Viney JL. The mdr1a-/- mouse model of spontaneous colitis: a relevant and appropriate animal model to study inflammatory bowel disease. Immunol Res. 2005;31(2):151-9.
23. Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, et al. MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet. 2003;73(6):1282-92.
24. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97(7):3473-8.
25. Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J, et al. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology. 2003;124(1):26-33.
26. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nature protocols. 2008;3(6):1101-08.
27. Husseiny MI, Kuroda A, Kaye AN, Nair I, Kandeel F, Ferreri K. Development of a quantitative methylation-specific polymerase chain reaction method for monitoring beta cell death in type 1 diabetes. PloS one. 2012;7(10):e47942.
28. Bird AP, Wolffe AP. Methylation-induced repression--belts, braces, and chromatin. Cell. 1999;99(5):451-4.
29. Petronis A. Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature. 2010;465(7299):721-7.
30. Yi JM, Kim TO. Epigenetic alterations in inflammatory bowel disease and cancer. Intestinal research. 2015;13(2):112-21.
31. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119-24.
32. Kim JM. Antimicrobial proteins in intestine and inflammatory bowel diseases. Intest Res. 2014;12(1):20-33.
33. Gloria L, Cravo M, Pinto A, de Sousa LS, Chaves P, Leitao CN, et al. DNA hypomethylation and proliferative activity are increased in the rectal mucosa of patients with long-standing ulcerative colitis. Cancer. 1996;78(11):2300-6.
34. Hsieh CJ, Klump B, Holzmann K, Borchard F, Gregor M, Porschen R. Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res. 1998;58(17):3942-5.
35. Kuester D, Guenther T, Biesold S, Hartmann A, Bataille F, Ruemmele P, et al. Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma. Pathol Res Pract. 2010;206(9):616-24.
36. Saito S, Kato J, Hiraoka S, Horii J, Suzuki H, Higashi R, et al. DNA methylation of colon mucosa in ulcerative colitis patients: correlation with inflammatory status. Inflamm Bowel Dis. 2011;17(9):1955-65.
37. Azarschab P, Porschen R, Gregor M, Blin N, Holzmann K. Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis. Genes Chromosomes Cancer. 2002;35(2):121-6.
38. Callen DF, Baker E, Simmers RN, Seshadri R, Roninson IB. Localization of the human multiple drug resistance gene, MDR1, to 7q21.1. Hum Genet. 1987;77(2):142-4.
39. Moret-Tatay I, Cerrillo E, Sáez-González E, Hervás D, Iborra M, Sandoval J, et al. Identification of Epigenetic Methylation Signatures With Clinical Value in Crohn's Disease. Clinical and translational gastroenterology. 2019;10(10):e00083-e83.
40. Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet. 1996;14(2):199-202.
41. van Heel DA, Fisher SA, Kirby A, Daly MJ, Rioux JD, Lewis CM. Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet. 2004;13(7):763-70.
42. Ho GT, Nimmo ER, Tenesa A, Fennell J, Drummond H, Mowat C, et al. Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology. 2005;128(2):288-96.
43. Osuga T, Sakaeda T, Nakamura T, Yamada T, Koyama T, Tamura T, et al. MDR1 C3435T polymorphism is predictive of later onset of ulcerative colitis in Japanese. Biol Pharm Bull. 2006;29(2):324-9.
44. Cao Y, Qu C, Chen Y, Li L, Wang X. Association of ABCB1 polymorphisms and ulcerative colitis susceptibility. International journal of clinical and experimental pathology. 2015;8(1):943-47.
45. Englund G, Jacobson A, Rorsman F, Artursson P, Kindmark A, Rönnblom A. Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1). Inflamm Bowel Dis. 2007;13(3):291-7.
46. Yamamoto-Furusho JK, Villeda-Ramírez MA, Fonseca-Camarillo G, Sánchez-Muñoz F, Dominguez-Lopez A, Barreto-Zuñiga R, et al. High Gene Expression of MDR1 (ABCB1) is Associated with Medical Treatment Response and Long-Term Remission in Patients with Ulcerative Colitis. Inflammatory Bowel Diseases. 2010;16(4):541-42.
47. Gupta S, Gollapudi S. P-glycoprotein (MDR 1 gene product) in cells of the immune system: Its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection. J Clin Immunol. 1993;13(5):289-301.
48. Ho GT, Aird RE, Liu B, Boyapati RK, Kennedy NA, Dorward DA, et al. MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunology. 2018;11(1):120-30.
49. Bar F, Bochmann W, Widok A, von Medem K, Pagel R, Hirose M, et al. Mitochondrial gene polymorphisms that protect mice from colitis. Gastroenterology. 2013;145(5):1055-63.e3.
50. Biasi F, Leonarduzzi G, Oteiza PI, Poli G. Inflammatory bowel disease: mechanisms, redox considerations, and therapeutic targets. Antioxidants & redox signaling. 2013;19(14):1711-47.
2. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46-54.e42; quiz e30.
3. Shanahan F, Bernstein CN. The evolving epidemiology of inflammatory bowel disease. Curr Opin Gastroenterol. 2009;25(4):301-5.
4. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17.
5. Thia KT, Loftus EV, Jr., Sandborn WJ, Yang SK. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol. 2008;103(12):3167-82.
6. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293(5532):1068-70.
7. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461-3.
8. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39(2):207-11.
9. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39(5):596-604.
10. Yamazaki K, McGovern D, Ragoussis J, Paolucci M, Butler H, Jewell D, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Hum Mol Genet. 2005;14(22):3499-506.
11. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40(8):955-62.
12. Xavier RJ, Rioux JD. Genome-wide association studies: a new window into immune-mediated diseases. Nat Rev Immunol. 2008;8(8):631-43.
13. PETRONIS A, PETRONIENE R. Epigenetics of inflammatory bowel disease. Gut. 2000;47(2):302-06.
14. Maeda O, Ando T, Watanabe O, Ishiguro K, Ohmiya N, Niwa Y, et al. DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: a mini review. Inflammopharmacology. 2006;14(5-6):204-6.
15. Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, et al. Effect of MDR1 gene promoter methylation in patients with ulcerative colitis. Int J Mol Med. 2009;23(4):521-7.
16. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987;84(21):7735-8.
17. Zappe K, Cichna-Markl M. Aberrant DNA Methylation of ABC Transporters in Cancer. Cells. 2020;9(10).
18. Triantafillidis JK, Nasioulas G, Kosmidis PA. Colorectal Cancer and Inflammatory Bowel Disease: Epidemiology, Risk Factors, Mechanisms of Carcinogenesis and Prevention Strategies. Anticancer Res. 2009;29(7):2727.
19. Ho GT, Moodie FM, Satsangi J. Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut. 2003;52(5):759-66.
20. Banner KH, Cattaneo C, Le Net JL, Popovic A, Collins D, Gale JD. Macroscopic, microscopic and biochemical characterisation of spontaneous colitis in a transgenic mouse, deficient in the multiple drug resistance 1a gene. Br J Pharmacol. 2004;143(5):590-8.
21. Kalitsky-Szirtes J, Shayeganpour A, Brocks DR, Piquette-Miller M. Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats. Drug Metab Dispos. 2004;32(1):20-7.
22. Wilk JN, Bilsborough J, Viney JL. The mdr1a-/- mouse model of spontaneous colitis: a relevant and appropriate animal model to study inflammatory bowel disease. Immunol Res. 2005;31(2):151-9.
23. Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, et al. MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet. 2003;73(6):1282-92.
24. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97(7):3473-8.
25. Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J, et al. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology. 2003;124(1):26-33.
26. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nature protocols. 2008;3(6):1101-08.
27. Husseiny MI, Kuroda A, Kaye AN, Nair I, Kandeel F, Ferreri K. Development of a quantitative methylation-specific polymerase chain reaction method for monitoring beta cell death in type 1 diabetes. PloS one. 2012;7(10):e47942.
28. Bird AP, Wolffe AP. Methylation-induced repression--belts, braces, and chromatin. Cell. 1999;99(5):451-4.
29. Petronis A. Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature. 2010;465(7299):721-7.
30. Yi JM, Kim TO. Epigenetic alterations in inflammatory bowel disease and cancer. Intestinal research. 2015;13(2):112-21.
31. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119-24.
32. Kim JM. Antimicrobial proteins in intestine and inflammatory bowel diseases. Intest Res. 2014;12(1):20-33.
33. Gloria L, Cravo M, Pinto A, de Sousa LS, Chaves P, Leitao CN, et al. DNA hypomethylation and proliferative activity are increased in the rectal mucosa of patients with long-standing ulcerative colitis. Cancer. 1996;78(11):2300-6.
34. Hsieh CJ, Klump B, Holzmann K, Borchard F, Gregor M, Porschen R. Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res. 1998;58(17):3942-5.
35. Kuester D, Guenther T, Biesold S, Hartmann A, Bataille F, Ruemmele P, et al. Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma. Pathol Res Pract. 2010;206(9):616-24.
36. Saito S, Kato J, Hiraoka S, Horii J, Suzuki H, Higashi R, et al. DNA methylation of colon mucosa in ulcerative colitis patients: correlation with inflammatory status. Inflamm Bowel Dis. 2011;17(9):1955-65.
37. Azarschab P, Porschen R, Gregor M, Blin N, Holzmann K. Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis. Genes Chromosomes Cancer. 2002;35(2):121-6.
38. Callen DF, Baker E, Simmers RN, Seshadri R, Roninson IB. Localization of the human multiple drug resistance gene, MDR1, to 7q21.1. Hum Genet. 1987;77(2):142-4.
39. Moret-Tatay I, Cerrillo E, Sáez-González E, Hervás D, Iborra M, Sandoval J, et al. Identification of Epigenetic Methylation Signatures With Clinical Value in Crohn's Disease. Clinical and translational gastroenterology. 2019;10(10):e00083-e83.
40. Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet. 1996;14(2):199-202.
41. van Heel DA, Fisher SA, Kirby A, Daly MJ, Rioux JD, Lewis CM. Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet. 2004;13(7):763-70.
42. Ho GT, Nimmo ER, Tenesa A, Fennell J, Drummond H, Mowat C, et al. Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology. 2005;128(2):288-96.
43. Osuga T, Sakaeda T, Nakamura T, Yamada T, Koyama T, Tamura T, et al. MDR1 C3435T polymorphism is predictive of later onset of ulcerative colitis in Japanese. Biol Pharm Bull. 2006;29(2):324-9.
44. Cao Y, Qu C, Chen Y, Li L, Wang X. Association of ABCB1 polymorphisms and ulcerative colitis susceptibility. International journal of clinical and experimental pathology. 2015;8(1):943-47.
45. Englund G, Jacobson A, Rorsman F, Artursson P, Kindmark A, Rönnblom A. Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1). Inflamm Bowel Dis. 2007;13(3):291-7.
46. Yamamoto-Furusho JK, Villeda-Ramírez MA, Fonseca-Camarillo G, Sánchez-Muñoz F, Dominguez-Lopez A, Barreto-Zuñiga R, et al. High Gene Expression of MDR1 (ABCB1) is Associated with Medical Treatment Response and Long-Term Remission in Patients with Ulcerative Colitis. Inflammatory Bowel Diseases. 2010;16(4):541-42.
47. Gupta S, Gollapudi S. P-glycoprotein (MDR 1 gene product) in cells of the immune system: Its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection. J Clin Immunol. 1993;13(5):289-301.
48. Ho GT, Aird RE, Liu B, Boyapati RK, Kennedy NA, Dorward DA, et al. MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunology. 2018;11(1):120-30.
49. Bar F, Bochmann W, Widok A, von Medem K, Pagel R, Hirose M, et al. Mitochondrial gene polymorphisms that protect mice from colitis. Gastroenterology. 2013;145(5):1055-63.e3.
50. Biasi F, Leonarduzzi G, Oteiza PI, Poli G. Inflammatory bowel disease: mechanisms, redox considerations, and therapeutic targets. Antioxidants & redox signaling. 2013;19(14):1711-47.
| Files | ||
| Issue | Vol 6, No 1 (2023) | |
| Section | Original Article | |
| DOI | https://doi.org/10.18502/igj.v6i1.16340 | |
| Keywords | ||
| ABCB1 Epigenetics Gene Methylation MDR1 Ulcerative Colitis | ||
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How to Cite
1.
Sanjari Moghaddam H, Sanati G, Sadr M, Mohebbi B, Keshavarz-Fathi M, Salmanroghani R, Salmanroghani H, Rezaei N. Evaluation of ABCB1 Gene Promoter Methylation in Patients with Ulcerative Colitis. Immunol Genet J. 2023;6(1):21-27.
