تحلیل متا آنالیز بر پلی مورفیسم‌های ژن‌های WNT4 و CDKN2B-AS1 در ارتباط با بیماری اندومتریوز
محورهای موضوعی :
کلید واژه: اندومتریوز, متا آنالیز, ژن WNT4, ژن CDKN2B-AS1, مطالعات GWA, پلی مورفیسم, RNA غیرکد‌کننده.,
چکیده مقاله :
هدف: اندومتریوز بیماری پیچیده‌ای است که می‌تواند زمینه وراثتی داشته باشد و وقوع آن تحت بسیاری از عوامل ژنتیکی و محیطی است. مطالعات گستره ژنومی اثبات کرده‌اند که می‌توانند در شناسایی واریانت‌هایی که بر وقوع بیماری‌های پیچیده اثرگذار باشند، موفق عمل کنند. در مطالعه حاضر آنالیز و جمع‌بندی مطالعات گستره ژنومی در رابطه با واریانت‌های ژن WNT4 و CDKN2B-AS1، و همراهی آنها با وقوع این بیماری انجام شده است. مواد و روش‌ها: در متا آنالیز حاضر مطالعات درباره پلی مورفیسم‌های مرتبط با با ژن‌های WNT4 و CDKN2B-AS1 موجود در پایگاه داده GWAS بررسی شده‌اند. مطالعات مربوط به جمعیت‌هایی با اجداد اروپایی و آسیای شرقی بوده، و به منظور بررسی واریانتی با بیشترین سطح همراهی در لوکوس‌های ژنی فوق با وقوع بیماری اندومتریوز، از مدل آماری fixed-effect استفاده شده است. یافته‌ها: از میان واریانت‌های بررسی شده، لوکوس‌های rs3920498 (با معناداری p<1.1e-5 و نسبت احتمالی برابر با 1.19) و rs1537377 (با معناداری p<1.33e-10 و نسبت احتمالی برابر با 1.09) همراهی بیشتری با بیماری اندومتریوز دارند. نتیجه‌گیری: در مطالعه حاضر، مشخص شد که لوکوس‌های rs3920498 (در بالادست ژن WNT4) و rs1537377 (در پایین دست ژن CDKN2B-AS1) بیشترین همراهی را با بیماری اندومتریوز دارند.
Purpose: Endometriosis is a complex disease that can be hereditary and its occurrence is under many genetic and environmental factors. Genome-wide studies have proven that they can be successful in identifying variants that affect the occurrence of complex diseases. In the present study, the analysis and summation of genome-wide studies in relation to WNT4 and CDKN2B-AS1 gene variants, and their association with the occurrence of this disease, has been done. Materials and methods: In the present meta-analysis, studies on polymorphisms associated with WNT4 and CDKN2B-AS1 genes in the GWAS database have been reviewed. The studies were related to populations with European and East Asian ancestors, and in order to investigate the variant with the highest level of association in the above gene loci with the occurrence of endometriosis, the fixed-effect statistical model was used. Findings: Among the examined variants, loci rs3920498 (with significance p<1.1e-5 and probability ratio equal to 1.19) and rs1537377 (with significance p<1.33e-10 and probability ratio equal to 1.09) are more associated with endometriosis. Conclusion: In the present study, it was found that rs3920498 (upstream of WNT4 gene) and rs1537377 (downstream of CDKN2B-AS1 gene) loci are most associated with endometriosis disease.
1. Rahmioglu N, Nyholt DR, Morris AP, Missmer SA, Montgomery GW & Zondervan KT. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets. Human reproduction update. 2014; 20(5): 702-16.
2. Abramiuk M, Grywalska E, Małkowska P, Sierawska O, Hrynkiewicz R & Niedźwiedzka-Rystwej P. The role of the immune system in the development of endometriosis. Cells. 2022; 11(13): 2028.
3. Yuan Y, Li Y, Zhao W, Hu Y, Zhou C, Long T & Long L. WNT4 promotes macrophage polarization via granulosa cell M-CSF and reduces granulosa cell apoptosis in endometriosis. Cytokine. 2023; 172: 156400.
4. Matalliotakis M, Zervou MI, Matalliotaki C, Rahmioglu N, Koumantakis G, Kalogiannidis I & et al. The role of gene polymorphisms in endometriosis. Molecular Medicine Reports. 2017; 16(5): 5881-6.
5. Lamceva J, Uljanovs R & Strumfa I. The main theories on the pathogenesis of endometriosis. International journal of molecular sciences. 2023; 24(5): 4254.
6. Giacomini E, Minetto S, Li Piani L, Pagliardini L, Somigliana E & Viganò P. Genetics
and inflammation in endometriosis: Improving knowledge for development of new pharmacological strategies. International journal of molecular sciences. 2021; 22(16): 9033.
7. Malutan A, Drugan T, Georgescu C, Ciortea R, Bucuri C, Bobric A & et al. Vascular endothelial growth factor serum levels in women with advanced endometriosis. Acta Endocrinologica (Bucharest). 2016; 12(1): 7.
8. Chung MS & Han SJ. Endometriosis-associated angiogenesis and anti-angiogenic therapy for endometriosis. Frontiers in Global Women's Health. 2022; 3: 856316.
9. Wu Z, Yuan M, Li Y, Fu F, Ma W, Li H & et al. Analysis of WNT4 polymorphism in Chinese Han women with endometriosis. Reproductive BioMedicine Online. 2015; 30(4): 415-20.
10. Proestling K, Birner P, Gamperl S, Nirtl N, Marton E, Yerlikaya G & et al. Enhanced epithelial to mesenchymal transition (EMT) and upregulated MYC in ectopic lesions contribute independently to endometriosis. Reproductive Biology and Endocrinology. 2015; 13: 1-11.
11. Yang Y-M & Yang W-X. Epithelial-to-mesenchymal transition in the development of endometriosis. Oncotarget. 2017; 8(25): 41679.
12. Hudson QJ, Proestling K, Perricos A, Kuessel L, Husslein H, Wenzl R & Yotova I. The role of long non-coding RNAs in endometriosis. International Journal of Molecular Sciences. 2021; 22(21): 11425.
13. Yuan H, Lin Z, Liu Y, Jiang Y, Liu K, Tu M & et al. Intrahepatic cholangiocarcinoma induced M2-polarized tumor-associated macrophages facilitate tumor growth and invasiveness. Cancer cell international. 2020; 20(1): 1-14.
14. Wang S, Yi M, Zhang X, Zhang T, Jiang L, Cao L & et al. Effects of CDKN2B-AS1 on cellular proliferation, invasion and AKT3 expression are attenuated by miR-424-5p in a model of ovarian endometriosis. Reproductive biomedicine online. 2021; 42(6): 1057-66.
15. Zondervan K, Rahmioglu N, Morris A, Nyholt D, Montgomery G, Becker C & Missmer S. Beyond endometriosis GWAS: from genomics to phenomics to the patient Europe PMC Funders Group. Semin Reprod Med. 2016; 34: 242-54.
16. Lander ES. Initial sequencing and analysis of the human genome. Nature. 2001; 409(6822): 860-921.
17. Mafra F, Catto M, Bianco B, Barbosa CP & Christofolini D. Association of WNT4 polymorphisms with endometriosis in infertile patients. Journal of assisted reproduction and genetics. 2015; 32: 1359-64.
18. Uno S, Zembutsu H, Hirasawa A, Takahashi A, Kubo M, Akahane T & et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nature genetics. 2010; 42(8): 707-10.
19. Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N, De Vivo I & et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nature communications. 2017; 8(1): 15539.
20. Albertsen HM, Chettier R, Farrington P & Ward K. Genome-wide association study link novel loci to endometriosis. PloS one. 2013; 8(3): e58257.
21. Cousins FL, McKinnon BD, Mortlock S, Fitzgerald HC, Zhang C, Montgomery GW & Gargett CE. New concepts on the etiology of endometriosis. Journal of Obstetrics and Gynaecology Research. 2023; 49(4): 1090-105.
22. Powell JE, Fung JN, Shakhbazov K, Sapkota Y, Cloonan N, Hemani G & et al. Endometriosis risk alleles at 1p36. 12 act through inverse regulation of CDC42 and LINC00339. Human molecular genetics. 2016; 25(22): 5046-58.
23. Lee GH, Choi YM, Hong MA, Yoon SH, Kim JJ, Hwang K & Chae SJ. Association of CDKN2B-AS and WNT4 genetic polymorphisms in Korean patients with endometriosis. Fertility and Sterility. 2014; 102(5): 1393-7.
24. Uimari O, Rahmioglu N, Nyholt DR, Vincent K, Missmer SA, Becker C & et al. Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis. Human Reproduction. 2017; 32(4): 780-93.
25. Masuda T, Low S-K, Akiyama M, Hirata M & Ueda Y, Matsuda K & et al. GWAS of five gynecologic diseases and cross-trait analysis in Japanese. European Journal of Human Genetics. 2020; 28(1): 95-107.
26. Nyholt DR, Low S-K, Anderson CA, Painter JN, Uno S, Morris AP & et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nature genetics. 2012; 44(12): 1355-9.
27. Luong HT, Painter JN, Shakhbazov K, Chapman B, Henders AK, Powell JE & et al. Fine mapping of variants associated with endometriosis in the WNT4 region on chromosome 1p36. International Journal of Molecular Epidemiology and Genetics. 2013; 4(4): 193.
28. Zhao ZZ, Croft L, Nyholt DR, Chapman B, Treloar SA, Hull ML & Montgomery GW. Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis. MHR: Basic science of reproductive medicine. 2010; 17(2):
92-103.
29. Halvorsen M, Martin JS, Broadaway S & Laederach A. Disease-associated mutations that alter the RNA structural ensemble. PLoS genetics. 2010; 6(8): e1001074.
30. Herndon CN, Aghajanova L, Balayan S, Erikson D, Barragan F, Goldfien G & et al. Global transcriptome abnormalities of the eutopic endometrium from women with adenomyosis. Reproductive Sciences. 2016; 23(10): 1289-303.
31. Tsai E-M, Wang Y-S, Lin C-S, Lin W-Y, Hsi E, Wu M-T & Juo S-HH. A microRNA-520 mirSNP at the MMP2 gene influences susceptibility to endometriosis in Chinese women. Journal of human genetics. 2013; 58(4): 202-9.
32. Hawkins SM, Creighton CJ, Han DY, Zariff A, Anderson ML, Gunaratne PH & Matzuk MM. Functional microRNA involved in endometriosis. Molecular endocrinology. 2011; 25(5): 821-32.
33. Goumenou A, Arvanitis D, Matalliotakis I, Koumantakis E & Spandidos D. Loss of heterozygosity in adenomyosis on hMSH2, hMLH1, p16Ink4 and GALT loci. International journal of molecular medicine. 2000; 6(6): 667-738.