Turkiye Klinikleri Journal of Medical Sciences

.: ORIGINAL RESEARCH
Tekrarlayan Gebelik Kaybı ile İlişkili Apoptotik Ölüm Reseptörü-4 TRAIL Bağlanma Bölgesindeki C626G Polimorfizmi: Vaka-Kontrol Araştırması
C626G Polymorphism in the Apoptotic Death Receptor-4 TRAIL Binding Domain Associated with Recurrent Pregnancy Loss: Case-Control Research
Sevinç SÜRER TEKİNa, Mustafa Ertan AYa, Hüseyin DURUKANb, Kenan ÇEVİKa, Özlem İZCİ AYa, Gurbet DOĞRU ÖZDEMİRa, Ümit KARAKAŞc, Mehmet Emin ERDALa
aMersin Üniversitesi Tıp Fakültesi, Tıbbi Biyoloji ABD, Mersin, TÜRKİYE
bMersin Üniversitesi Tıp Fakültesi, Kadın Hastalıkları ve Doğum ABD, Mersin, TÜRKİYE
cBayburt Üniversitesi Sağlık Hizmetleri Meslek Yüksek Okulu, Bayburt, TÜRKİYE
Turkiye Klinikleri J Med Sci. 2021;41(4):478-84
doi: 10.5336/medsci.2021-83700
Article Language: TR
Full Text
ÖZET
 Amaç: Embriyonik gelişim sürecinde hücrelerde apoptotik dengenin bozulması gebelik kayıplarına neden olabilmektedir. Bu araştırmada, nedeni belirlenemeyen tekrarlayan gebelik kaybı (TGK) ile apoptotik uyarıcı ölüm reseptörü-4 [death receptor-4 (DR-4)] geni polimorfizmleri arasındaki ilişki araştırıldı. Gereç ve Yöntemler: Bu araştırmada, TGK tanısı almış 70 kadın ve kontrol grubu olarak 70 kadından genomik DNA elde edildi. Her 2 gruptaki DR-4 geni 3. ekzonundaki rs6557634 G422A, 4. ekzonundaki rs20575 C626G ve 5. ekzonundaki rs20576 A683C polimorfizmleri polimeraz zincir reaksiyonu-kısıtlayıcı enzim kesimi fragman uzunluk polimorfizmi yöntemi kullanılarak belirlendi. Bulgular: DR-4'ün ekstrasellüler kısmında TRAIL ligand bağlanma bölgesindeki 209. kodonda treoninin arginine değişimi ile sonuçlanan ekzon 4'teki bir missense değişim olan C626G polimorfizminin görülme sıklığının, TGK hastalarında kontrol grubuna göre arttığı saptandı. Araştırılan ekzon 3 ve ekzon 5 polimorfizmleri için TGK ve kontrol grubu arasında istatistiksel fark gözlenmedi. Sonuç: TGK hastalarında saptadığımız DR-4 genindeki missense ekzon 4 polimorfizminin, embriyonik gelişim sürecinde embriyonun uterusa invazyonu ve immünolojik toleransındaki apoptotik dengenin bozulması yoluyla, gebelik kayıplarına neden olabileceğini düşünmekteyiz.

Anahtar Kelimeler: Apoptoz; tekrarlayan gebelik kaybı; TRAIL; ölüm reseptörü-4; polimorfizm
ABSTRACT
 Objective: Disruption of apoptotic balance in cells during embryonic development can lead to pregnancy losses. In this study, the relationship between unexplained recurrent pregnancy loss (RPL) and apoptotic inducing death receptor-4 (DR-4) gene polymorphisms was investigated. Material and Methods: In this study, genomic DNA was obtained from 70 women diagnosed with RPL and 70 women as a control group. The polymorphisms of rs6557634 G422A in the 3rd exon of the DR-4 gene, rs20575 C626G in the 4th exon and rs20576 A683C in the 5th exon were determined in both groups using the polyme rase chain reaction-restriction fragment length polymorphism method. Results: It was determined that the incidence of C626G polymorphism, which is a missense variant in exon 4 resulting in the change of threonine to arginine in the 209th codone in the extracellular TRAIL ligand binding domain of DR-4, increased in RPL cases compared to the controls. For the investigated exon 3 and exon 5 polymorphisms, no statistical difference was observed between the RPL and the control group. Conclusion: We conclude that the missense exon 4 polymorphism in the DR-4 gene, which we detected in patients with RPL, may cause pregnancy losses through the invasion of the embryo to the uterus during embryonic development and the disruption of the apoptotic balance in its immunological tolerance.

Keywords: Apoptosis; recurrent pregnancy loss; TRAIL; death receptor-4; polymorphism
REFERENCES:
  1. Wapner RJ, Lewis D. Genetics and metabolic causes of stillbirth. Semin Perinatol. 2002; 26(1):70-4. [Crossref]  [PubMed] 
  2. ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004. [Crossref]  [PubMed]  [PMC] 
  3. Preston FE, Rosendaal FR, Walker ID, Briët E, Berntorp E, Conard J, et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;348(9032):913-6. [Crossref]  [PubMed] 
  4. Lee RM, Silver RM. Recurrent pregnancy loss: summary and clinical recommendations. Semin Reprod Med. 2000;18(4):433-40. [Crossref]  [PubMed] 
  5. Hong Li Y, Marren A. Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Aust J Gen Pract. 2018;47(7):432-6. [Crossref]  [PubMed] 
  6. Youssef A, Vermeulen N, Lashley EELO, Goddijn M, van der Hoorn MLP. Comparison and appraisal of (inter)national recurrent pregnancy loss guidelines. Reprod Biomed Online. 2019;39(3):497-503. [Crossref]  [PubMed] 
  7. Kidd VJ. Proteolytic activities that mediate apoptosis. Annu Rev Physiol. 1998;60:533-73. [Crossref]  [PubMed] 
  8. Hampton MB, Orrenius S. Redox regulation of apoptotic cell death. Biofactors. 1998;8(1-2):1-5. [Crossref]  [PubMed] 
  9. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, et al. The receptor for the cytotoxic ligand TRAIL. Science. 1997;276 (5309):111-3. [Crossref]  [PubMed] 
  10. Jiang Y, Wen T, Yan R, Kim SR, Stowell SR, Wang W, et al. O-glycans on death receptors in cells modulate their sensitivity to TRAIL-induced apoptosis through affecting on their stability and oligomerization. FASEB J. 2020;34(9):11786-801. [Crossref]  [PubMed] 
  11. Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995;81(4):495-504. [Crossref]  [PubMed] 
  12. Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516. [Crossref]  [PubMed]  [PMC] 
  13. Li C, Zhang X, Kang X, Chen C, Guo F, Wang Q, et al. Upregulated TRAIL and reduced DcR2 mediate apoptosis of decidual PMN-MDSC in unexplained recurrent pregnancy loss. Front Immunol. 2020;11:1345. [Crossref]  [PubMed]  [PMC] 
  14. Isi H, Erdal ME, Akdeniz S, Oral D, İzci Ay Ö, Tekes S, et al. The Tumor Necrosis Factor-α- (TNF- α) gene-308 G/A polymorphism and The Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) gene polymorphisms in Behcet's Disease. Biotechnology & Biotechnological Equipment. 2010;24(3):2014-19. [Crossref] 
  15. Sandoughi M, Salimi S, Shahraki-Ghadimi H, Saravani M. The impact of TRAIL (C1595T and G1525A) and DR4 (rs20576) gene polymorphisms on systemic lupus erythematosus. Biochem Genet. 2020;58(4):649-59. [Crossref]  [PubMed] 
  16. Saravelos SH, Regan L. Unexplained recurrent pregnancy loss. Obstet Gynecol Clin North Am. 2014;41(1):157-66. [Crossref]  [PubMed] 
  17. Hogge WA, Byrnes AL, Lanasa MC, Surti U. The clinical use of karyotyping spontaneous abortions. Am J Obstet Gynecol. 2003;189(2): 397-400; discussion 400-2. [Crossref]  [PubMed] 
  18. Phillips TA, Ni J, Hunt JS. Death-inducing tumour necrosis factor (TNF) superfamily ligands and receptors are transcribed in human placentae, cytotrophoblasts, placental macro phages and placental cell lines. Placenta. 2001;22(8-9):663-72. [Crossref]  [PubMed] 
  19. Keogh RJ, Harris LK, Freeman A, Baker PN, Aplin JD, Whitley GS, et al. Fetal-derived trophoblast use the apoptotic cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand to induce smooth muscle cell death. Circ Res. 2007;100(6):834-41. [Crossref]  [PubMed] 
  20. Rai R, Sharma KL, Sharma S, Misra S, Kumar A, Mittal B. Death receptor (DR4) haplotypes are associated with increased susceptibility of gallbladder carcinoma in north Indian population. PLoS One. 2014;9(2):e90264. [Crossref]  [PubMed]  [PMC] 
  21. Alsalawy NF, Darwish RK, Kamal MM, ElTaweel AE, Shousha HI, Elbaz TM. Evaluation of trail receptor 1 (DR4) polymorphisms C626G and A683C as risk factors of hepatocellular carcinoma. J Med Virol. 2018;90(3): 490-6. [Crossref]  [PubMed] 
  22. Fisher MJ, Virmani AK, Wu L, Aplenc R, Harper JC, Powell SM, et al. Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer. Clin Cancer Res. 2001;7(6): 1688-97. [PubMed] 
  23. Horak P, Pils D, Roessler M, Tomek S, Elandt K, Zeillinger R, et al. Common death receptor 4 (DR4) polymorphisms do not predispose to ovarian cancer. Gynecol Oncol. 2005;97(2): 514-8. [Crossref]  [PubMed] 
  24. Frank B, Hemminki K, Shanmugam KS, Meindl A, Klaes R, Schmutzler RK, et al. Association of death receptor 4 haplotype 626C-683C with an increased breast cancer risk. Carcinogenesis. 2005;26(11):1975-7. [Crossref]  [PubMed] 
  25. Zahoor A, Mansoor Q, Farooqi AA, Fayyaz S, Naz G, Ismail M. Genetic variants in the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor (DR4) genes contribute to susceptibility to colorectal cancer in pakistani population. Cell Mol Biol (Noisy-le-grand). 2015;61(6):108-12. [PubMed] 
  26. Dechant MJ, Fellenberg J, Scheuerpflug CG, Ewerbeck V, Debatin KM. Mutation analysis of the apoptotic "death-receptors" and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines. Int J Cancer. 2004;109(5):661-7. [Crossref]  [PubMed] 
  27. Langsenlehner T, Langsenlehner U, Renner W, Kapp KS, Krippl P, Hofmann G, et al. The Glu228Ala polymorphism in the ligand binding domain of death receptor 4 is associated with increased risk for prostate cancer metastases. Prostate. 2008;68(3):264-8. [Crossref]  [PubMed] 
  28. Chen B, Liu S, Wang XL, Xu W, Li Y, Zhao WH, et al. TRAIL-R1 polymorphisms and cancer susceptibility: an evidence-based meta-analysis. Eur J Cancer. 2009;45(14): 2598-605. [Crossref]  [PubMed] 

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