Assessment of the role of EGF +61A/G and EGFR R497K polymorphism in patients with inflammatory bowel disease: A case-control study
Abstract
Aim: Epidermal growth factor (EGF) and epidermal growth factor
receptor (EGFR) play an important role in the regulation of cell growth,
survival, migration, apoptosis, proliferation, and differentiation. We aimed to
investigate the presence of EGF (+61A/G) and EGFR R497Kpolymorphisms in
patients with inflammatory bowel disease (IBD) and their associations with
clinical features of the patients.
Methods: This case-control study included 91 IBD patients (45
Crohn’s disease (CD) patients and 46 ulcerative colitis (UC) patients) and 129
healthy controls (HC). EGF and EGFR were
genotyped by polymerase chain reaction
and restriction fragment length polymorphism techniques to elucidate their
association with clinical outcomes. The disease activity for UC and CD were
assessed by Truelove-Witts index (TW) and Crohn's disease activity index
(CDAI), respectively. The Montreal classification was used for disease
involvement and behavior.
Results: EGFR497 AA genotype was significantly decreased in patients with
UC compared with CD and HC. In addition, the patients with UC who had EGF +61 A
allele had increased risk of moderate and severe disease (p=0.28; OR= 3.13; 95%
CI=0.34-28.73). The patients with CD who had the EGF61 AG genotype were
found to increased risk for the presence of penetrating disease (p=0.14; χ2=5.59; OR=5.00;
95% CI=1.26-19.83). EGF +61 A genotype carriers also had higher CDAI scores
(p=0.19; OR=4.00; 95% CI=0.44-36.14). In addition, A+ carriers were also found
to have higher requirement for anti-TNF treatment (p=0.11; OR=5.0; 95% CI=0.56-44.4).
Conclusion: In this study,
EGFR 497 AA genotype was found to decrease significantly in patients with UC
compared to HC and CD patients. To enlighten the mechanism, further studies with
larger sample groups are needed to clarify the role of the EGF (+61A/G) and
EGFR R497K genes polymorphism, and development of the etiology and pathogenesis
of IBD.
Keywords
EGF61 EGFR497 inflammatory bowel diseases ulcerative colitis Crohn’s disease ulcerative colitis
References
- 29. Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 2003;349:350-7.
- 28. Lu N, Wang L, Cao H, Liu L, Van Kaer L, Washington MK, et al. Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis. J Immunol 2014;192:1013-23.
- 27. Clark JA, Doelle SM, Halpern MD, Saunders TA, Holubec H, Dvorak K, et al. Intestinal barrier failure during experimental necrotizing enterocolitis: protective effect of EGF treatment. Am J Physiol Gastrointest Liver Physiol. 2006;291:G938-49.
- 26. Bedford A, Chen T, Huynh E, Zhu C, Medeiros S, Wey D, et al. Epidermal growth factor containing culture supernatant enhances intestine development of early-weaned pigs in vivo: potential mechanisms involved. J Biotechnol. 2015;196-197:9-19.
- 25. Ménard D, Tremblay E, Ferretti E, Babakissa C, Perron N, Seidman EG, et al. Anti-inflammatory effects of epidermal growth factor on the immature human intestine. Physiol Genomics. 2012;44:268-80.
- 24. Housley RM, Morris CF, Boyle W, Ring B, Biltz R, Tarpley JE, et al. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract. J Clin Invest. 1994;94:1764-77.
- 23. Burrin DG, Petersen Y, Stoll B, Sangild P. Glucagon-like peptide 2: a nutrient-responsive gut growth factor. J Nutr. 2001;131:709-12.
- 22. Geng Y, Li J, Wang F, Li Q, Wang X, Sun L, Li W. Epidermal growth factor promotes proliferation and improves restoration after intestinal ischemia-reperfusion injury in rats. Inflammation. 2013;36:670-9.
- 21. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749-53.
- 20. Dichi I, Burini RC. [Inflammatory bowel disease activity index: clinical and laboratory indicators]. Arq Gastroenterol. 1995;32:121-30.
- 19. Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence-based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis. J Crohns Colitis. 2010;4:7–27
- 18. Moriai T, Kobrin MS, Hope C, Speck L, Korc M. A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci USA. 1994;91:10217-21.
- 17. Zhang W, Park DJ, Lu B, Yang DY, Gordon M, Groshen S, et al. Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. Clin Cancer Res. 2005;11:600-5.
- 16. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215
- 15. Ménard D, Tremblay E, Ferretti E. et al. Anti-inflammatory effects of epidermal growth factor on the immature human intestine. Physiol Genomics. 2012;44(4):268-80.
- 14. Lurje G, Nagashima F, Zhang W. et al. Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab. Clin Cancer Res. 2008;14:7884-95.
- 13. Hisamatsu T, Inoue N, Yajima T, Izumiya M, Ichikawa H, Hibi T. Psychological aspects of inflammatory bowel disease. J Gastroenterol. 2007;42:34-40.
- 12. Moriai T, Kobrin MS, Hope C, Speck L, Korc M. A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci USA. 1994;91:10217-21.
- 11. Wu GY, Hasenberg T, Magdeburg R, Bönninghoff R, Sturm JW, Keese M. Association between EGF, TGF-beta1, VEGF gene polymorphism and colorectal cancer. World J Surg. 2009;33:124-9.
- 10. Shahbazi M, Pravica V, Nasreen N, Fakhoury H, Fryer AA, Strange RC, et al. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet. 2002;359:397-401.
- 9. Spindler KL, Nielsen JN, Ornskov D, Brandslund I, Jakobsen A. Epidermal growth factor (EGF) A61G polymorphism and EGF gene expression in normal colon tissue from patients with colorectal cancer. Acta Oncol. 2007;46:1113-7.
- 8. Chaudhry A, Funa K, Oberg K. Expression of growth factor peptides and their receptors in neuroendocrine tumors of the digestive system. Acta Oncol. 1993;32:107-14.
- 7. Hormi K, Lehy T. Developmental expression of transforming growth factor-alpha and epidermal growth factor receptor proteins in the human pancreas and digestive tract. Cell Tissue Res. 1994;278:439-50.
- 6. Yan F, Cao H, Cover TL, Washington MK, Shi Y, Liu L. Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism. J Clin Invest. 2011;121:2242-53.
- 5. Kondo I, Shimizu N. Mapping of the human gene for epidermal growth factor receptor (EGFR) on the p13 leads to q22 region of chromosome 7. Cytogenet Cell Genet. 1983;35:9-14.
- 4. Tang X, Liu H, Yang S. Li Z, Zhong J, Fang R. Epidermal Growth Factor and Intestinal Barrier Function. Mediators Inflamm. 2016;2016:1927348.
- 3. Scott J, Patterson S, Rall L, Bell GI, Crawford R, Penschow J, Niall H, Coghlan J. The structure and biosynthesis of epidermal growth factor precursor. J Cell Sci. Suppl 1985;3:19-28.
- 2. Dieckgraefe BK, Korzenik JR, Anant S. Growth factors as treatment options for intestinal inflammation. Ann N Y Acad Sci. 2006;1072:300-6.
- 1. Mehta M, Ahmed S, Dryden G. Immunopathophysiology of inflammatory bowel disease: how genetics link barrier dysfunction and innate immunity to inflammation. Innate Immun. 2017;23:497-505.
İnflamatuar bağırsak hastalığında EGF +61A/G ve EGFR R497K polimorfizm rolünün değerlendirilmesi: Bir olgu-kontrol çalışması
Abstract
Amaç: Epidermal büyüme faktörü (EGF) ve
epidermal büyüme faktörü reseptörü (EGFR), hücre büyümesi, canlılığı,
migrasyonu, apoptoz, proliferasyon ve farklılaşmasının düzenlenmesinde önemli
bir rol oynamaktadır. İnflamatuar barsak hastalığı (İBH) olan hastalarda EGF
(+61A/G) ve EGFR R497K polimorfizmlerinin varlığını ve hastalığın klinik
özellikler ile ilişkisini araştırmayı amaçladık.
Yöntemler: Bu vaka kontrol çalışmasında 91
IBD hastası (45 Crohn hastalığı (CD) hastası ve 46 ülseratif kolit (UC) hastası)
ve 129 sağlıklı kontrol (HC) vardı. EGF ve EGFR, polimeraz zincir reaksiyonu ve
restriksiyon fragman uzunluğu polimorfizm teknikleri ile hastalık ve sağlıklı
control grubu genotiplendirildi. Genotiplerin
hastalık ve klinik özellikleri ile ilişkileri incelendi. UC ve CD için
hastalık aktivitesi sırasıyla Truelove-Witts indeksi (TW) ve Crohn hastalığı
aktivite indeksi (CDAI) ile değerlendirildi. Montreal sınıflandırması hastalık
tutulumu ve davranışı için kullanılmıştır.
Bulgular: Ulseratif kolit hastalarında
EGFR497 AA genotipi CD ve HC'ye göre anlamlı olarak azaldığı saptanmıştır. Ek
olarak, EGF +61 A alleli olan UC'li hastalarda orta ve ciddi hastalık riski
artmıştır (p = 0.28; OR = 3.13; % 95 CI = 0.34-28.73). EGF +61 AG genotipine
sahip olan CD'li hastalarda penetran hastalık varlığı açısından artmış risk
bulundu (p = 0.14; χ2 = 5.59; OR = 5.00; % 95 CI = 1.26-19.83). EGF +61 A
alleli taşıyıcılarında daha yüksek CDAI skor riski saptandı (p = 0.19; OR =
4.00; % 95 CI = 0.44-36.14). Ek olarak, CD hastalarında EGF +61 A alleli
taşıyıcılarının anti-TNF tedavi gereksinimi için artmış riske sahip olduğu
bulunmuştur (p = 0.11; OR = 5.0; % 95 CI = 0.56-44.4).
Sonuç: Bu çalışmada, UC'li hastalarda EGFR497
AA genotipinde HC ve CD'li hastalara kıyasla, anlamlı azalma saptandı. EGF +61A
allele sahip hastalarda artmış aktivite riski saptanmıştır. IBD'nin etiyolojisi ve patogenezinde EGF (+
61A / G) ve EGFR R497K gen polimorfizminin rolünü açıklığa kavuşturmak için
daha geniş örnek gruplarıyla daha fazla çalışmaya ihtiyaç vardır.
References
- 29. Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 2003;349:350-7.
- 28. Lu N, Wang L, Cao H, Liu L, Van Kaer L, Washington MK, et al. Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis. J Immunol 2014;192:1013-23.
- 27. Clark JA, Doelle SM, Halpern MD, Saunders TA, Holubec H, Dvorak K, et al. Intestinal barrier failure during experimental necrotizing enterocolitis: protective effect of EGF treatment. Am J Physiol Gastrointest Liver Physiol. 2006;291:G938-49.
- 26. Bedford A, Chen T, Huynh E, Zhu C, Medeiros S, Wey D, et al. Epidermal growth factor containing culture supernatant enhances intestine development of early-weaned pigs in vivo: potential mechanisms involved. J Biotechnol. 2015;196-197:9-19.
- 25. Ménard D, Tremblay E, Ferretti E, Babakissa C, Perron N, Seidman EG, et al. Anti-inflammatory effects of epidermal growth factor on the immature human intestine. Physiol Genomics. 2012;44:268-80.
- 24. Housley RM, Morris CF, Boyle W, Ring B, Biltz R, Tarpley JE, et al. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract. J Clin Invest. 1994;94:1764-77.
- 23. Burrin DG, Petersen Y, Stoll B, Sangild P. Glucagon-like peptide 2: a nutrient-responsive gut growth factor. J Nutr. 2001;131:709-12.
- 22. Geng Y, Li J, Wang F, Li Q, Wang X, Sun L, Li W. Epidermal growth factor promotes proliferation and improves restoration after intestinal ischemia-reperfusion injury in rats. Inflammation. 2013;36:670-9.
- 21. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749-53.
- 20. Dichi I, Burini RC. [Inflammatory bowel disease activity index: clinical and laboratory indicators]. Arq Gastroenterol. 1995;32:121-30.
- 19. Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence-based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis. J Crohns Colitis. 2010;4:7–27
- 18. Moriai T, Kobrin MS, Hope C, Speck L, Korc M. A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci USA. 1994;91:10217-21.
- 17. Zhang W, Park DJ, Lu B, Yang DY, Gordon M, Groshen S, et al. Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. Clin Cancer Res. 2005;11:600-5.
- 16. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215
- 15. Ménard D, Tremblay E, Ferretti E. et al. Anti-inflammatory effects of epidermal growth factor on the immature human intestine. Physiol Genomics. 2012;44(4):268-80.
- 14. Lurje G, Nagashima F, Zhang W. et al. Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab. Clin Cancer Res. 2008;14:7884-95.
- 13. Hisamatsu T, Inoue N, Yajima T, Izumiya M, Ichikawa H, Hibi T. Psychological aspects of inflammatory bowel disease. J Gastroenterol. 2007;42:34-40.
- 12. Moriai T, Kobrin MS, Hope C, Speck L, Korc M. A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci USA. 1994;91:10217-21.
- 11. Wu GY, Hasenberg T, Magdeburg R, Bönninghoff R, Sturm JW, Keese M. Association between EGF, TGF-beta1, VEGF gene polymorphism and colorectal cancer. World J Surg. 2009;33:124-9.
- 10. Shahbazi M, Pravica V, Nasreen N, Fakhoury H, Fryer AA, Strange RC, et al. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet. 2002;359:397-401.
- 9. Spindler KL, Nielsen JN, Ornskov D, Brandslund I, Jakobsen A. Epidermal growth factor (EGF) A61G polymorphism and EGF gene expression in normal colon tissue from patients with colorectal cancer. Acta Oncol. 2007;46:1113-7.
- 8. Chaudhry A, Funa K, Oberg K. Expression of growth factor peptides and their receptors in neuroendocrine tumors of the digestive system. Acta Oncol. 1993;32:107-14.
- 7. Hormi K, Lehy T. Developmental expression of transforming growth factor-alpha and epidermal growth factor receptor proteins in the human pancreas and digestive tract. Cell Tissue Res. 1994;278:439-50.
- 6. Yan F, Cao H, Cover TL, Washington MK, Shi Y, Liu L. Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism. J Clin Invest. 2011;121:2242-53.
- 5. Kondo I, Shimizu N. Mapping of the human gene for epidermal growth factor receptor (EGFR) on the p13 leads to q22 region of chromosome 7. Cytogenet Cell Genet. 1983;35:9-14.
- 4. Tang X, Liu H, Yang S. Li Z, Zhong J, Fang R. Epidermal Growth Factor and Intestinal Barrier Function. Mediators Inflamm. 2016;2016:1927348.
- 3. Scott J, Patterson S, Rall L, Bell GI, Crawford R, Penschow J, Niall H, Coghlan J. The structure and biosynthesis of epidermal growth factor precursor. J Cell Sci. Suppl 1985;3:19-28.
- 2. Dieckgraefe BK, Korzenik JR, Anant S. Growth factors as treatment options for intestinal inflammation. Ann N Y Acad Sci. 2006;1072:300-6.
- 1. Mehta M, Ahmed S, Dryden G. Immunopathophysiology of inflammatory bowel disease: how genetics link barrier dysfunction and innate immunity to inflammation. Innate Immun. 2017;23:497-505.
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Original Research |
| Authors | |
| Publication Date | July 20, 2018 |
| Published in Issue | Year 2018 Volume: 3 Issue: 2 |
