Protein‑protein interaction analysis to identify biomarker networks for endometriosis
- Authors:
- Published online on: September 22, 2017 https://doi.org/10.3892/etm.2017.5185
- Pages: 4647-4654
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Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Endometriosis is a benign gynecological disorder that occurs in 10% of women of reproductive age (1). The main symptoms include infertility and chronic pelvic pain (2). Although there are a number of studies on endometriosis, the majority of the mechanisms are not well understood (3–6). Identifying disease biomarkers and their interaction networks is important to improve the understanding of the causes of endometriosis, as well as to improve medical care.
Several databases have been developed that store associations between genes and diseases, such as the Online Mendelian Inheritance in Man (7), the Human Gene Mutation Database (8) and the Genetic Association Database (9). Due to the nature of the database curation process, the data are incomplete. Some gene-disease databases that combine gene-associated diseases from several expert, public and curated data sources also exist (10,11). With the rapid accumulation of gene-disease data, increasing research has been utilizing the gene-disease database as a start-point to mine disease biomarkers (12–14).
Protein-protein interaction (PPI) networks include information on the biological processes and molecular functions of cells and have been widely used to characterize the underlying mechanisms of genes associated with complex diseases (15,16). The majority of human diseases are caused by a group of correlated molecules or a network, rather than a single gene (17). Thus, identification and validation of biomarker networks is critical to disease diagnosis, prognosis and treatment.
In the present study, a disease network of endometriosis that integrated human PPIs and known disease-causing genes was constructed. Endometriosis-causing genes were identified from gene-disease databases. Subsequently, bioinformatics approaches, including PPI network construction, module analysis, functional enrichment analysis and text mining, were utilized in the research. The results of the present study may provide new targets for endometriosis therapy and identify the potential mechanisms of the disease.
Materials and methods
Seed gene selection
Endometriosis-related genes were obtained from Genotator (http://genotator.hms.harvard.edu/) (10) and DisGeNET (http://www.disgenet.org) (11). For each tool, gene lists were extracted using the query term, endometriosis. Genotator provides high quality gene-disease associations based upon data from 11 trustworthy resources. DisGeNET is a discovery platform that integrates information on gene-disease associations from several public data sources and literature (11). Thus, a list of genes that had been experimentally validated to be associated with endometriosis were obtained.
Disease-gene network construction
Endometriosis-associated genes were submitted to atBioNet (https://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm285284.htm) and PPIs were obtained. atBioNet is a network analysis tool that provides a systematic insight into gene interactions by examining significant functional modules (18). The default option is ‘Human Database’ that combines data from a variety of public PPI sources, including BioGRID (19), the Database of Interacting Proteins (20), the Human Protein Reference Database (21), IntAct (22), the Molecular INTeraction database (23), REACTOME (24) and the Signaling Pathways Integrated Knowledge Engine (25). The protein interaction network included 12,043 human proteins and 132,605 interactions. SCAN algorithm was used to identify functional modules and perform assessment of generated gene networks for biomarker discovery (26).
Pathway enrichment analysis
To identify potential roles of genes in endometriosis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) (27) pathway analysis component in atBioNet was used. Overrepresented KEGG pathways for each module were ranked according to the P-value obtained from Fisher's exact tests.
Literature mining
To identify the genes associated with endometriosis, mining from the PubMed database (https://www.ncbi.nlm.nih.gov/pubmed) with keywords ‘gene symbol’ and ‘endometriosis’ was conducted. Subsequently, the articles associated with endometriosis were screened manually. A high number of papers indicated that the relationship between potential biomarker genes and endometriosis is well studied and documented.
Results
Screening of seed genes related to endometriosis
A total of 271 and 229 genes were extracted from Genotator and DisGeNET, respectively. The common genes, of which there were 100, were used as seed genes to generate functional modules.
Construction of biomarker networks
Of 100 input genes, 96 were found in GenBank (https://www.ncbi.nlm.nih.gov/genbank/), and network clustering identified six major sub network modules from the original PPI network (Fig. 1). Hub genes in each module were identified (Table I).
KEGG pathway analysis
A total of 2,429 genes from the KEGG human database were added to the PPI network and genes in each module were selected for pathway enrichment analysis. The top 10 significantly enriched KEGG pathways for the six modules in endometriosis are demonstrated in Table II. Module A was a cancer cell proliferation module. The majority of the pathways in the first module were related to the proliferation of cancer cells and were associated with pathways in cancer, the cell cycle, oocyte meiosis, adherens junctions and the Wnt signaling pathway. The enriched pathways in module B were associated with the immune system and infectious diseases, including cytokine-cytokine receptor interaction, the mitogen-activated protein kinase signaling pathway, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, the intestinal immune network for immunoglobulin (Ig) A production and Toll-like receptor signaling pathways. Module C was associated with complement and coagulation cascades, extracellular matrix-receptor interaction, focal adhesion, and proteasome and hematopoietic cell lineages associated with immune and metastasis. The enriched pathways in module D were associated with inflammatory responses, including phagosome, cell adhesion molecules, antigen processing and presentation, natural killer cell mediated cytotoxicity, T cell receptor signaling pathways and the intestinal immune network for IgA production. The majority of the pathways in module E were related to processes of replication and repair, including DNA replication, base excision repair, nucleotide excision repair, mismatch repair and homologous recombination.
Endometriosis-associated genes identified in literature
A total of 15 genes, seven in the first module and eight in the second module, have previously been reported in literature to be candidate biomarkers for endometriosis (Fig. 2). For example, women with endometriosis had significantly higher SOX2 expression levels compared to controls (Fig. 2A) (28). Also, various genes identified in the second module (Fig. 2B), including CASP3, S100A13 and IL1R2, have been reported to be associated with endometriosis (29–31). Details for the 15 literature-confirmed potential endometriosis biomarkers are listed in Table III.
Table III.Details of the 15 potential endometriosis biomarkers in modules A and B demonstrated in literature. |
Discussion
The cause of endometriosis is not entirely understood. No single theory is able to explain all cases of endometriosis. The present study implemented PPI for endometriosis biomarker network analysis and identified biologically relevant functional modules. A number of genes and pathways identified in the modules have already been reported to participate in the pathogenesis of endometriosis (32–36).
Although endometriosis is a benign disorder, several common characteristics of this disease are shared with invasive cancer (37). Previous epidemiologic studies have demonstrated that women with endometriosis have an increased risk of ovarian and breast cancer (38,39). Coincidentally, the three chromosomal regions (9p, 11q and 22q) that have demonstrated loss of heterozygosity in ovarian endometriosis were the same that were observed in ovarian tumors (40). These studies have demonstrated that the inactivation of tumor suppressor genes has an important role in the development of endometriosis. The results of the present study demonstrated that expression of cancer-related pathways are significantly imbalanced in endometriosis in module A. The hub genes identified were AHR, AR, ARNT, ESR1, NRIP1, ESR2, TP53, NR5A1, NR3C1 and PGR.
The enriched pathways in module B were associated with the immune system and infectious diseases. The presence of proinflammatory cytokines in the peritoneal fluid of patients with endometriosis has been reported in previous studies (41–43). Cytokines may regulate the actions of leukocytes in the peritoneal fluid or may act directly on the ectopic endometrium (44). Dysregulation of the JAK-STAT pathway is associated with various immune disorders (45), which was also demonstrated in the results of the present study. IL10RA, IL15, IL10 and JAK3 from the Toll-like receptor signaling pathway and CASP1, IL18, IL1B and TRAF6 from the NOD-like receptor signaling pathway, which are important for generating mature proinflammatory cytokines, were also identified in this module and are confirmed by previous studies (35,46). Module B also included the osteoclastogenesis pathway, which is predominantly regulated by signaling pathways activated by immune receptors (47).
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that share a conserved domain structure. MMPs are capable of degrading various types of extracellular matrix (ECM) and serve an important function in tissue remodeling associated with various physiological and pathological processes (48). The expression of several MMPs is maximal during the menstrual phase in the human endometrium (49). MMPs also have a vital role in the pathogenesis of endometriosis and cancer, particularly in the processes of metastasis and invasion (33,50). MMP1, MMP7, MMP12, MMP13, IGF1, IGFBP1, PAPPA and TIMP2 were identified as the hub genes in module C. ECM-receptor interaction, focal adhesion and proteasomes were also identified in this module, as in previous studies (32,51,52).
The immune response is one of the major factors influencing pathogenesis of endometriosis. Numerous genes in the fourth module are involved in the function of the immune system. Hub genes in this module are members of the HLA gene family, including HLA-A, -B, -C, -DPB1, -DQA1, -DQB1 and -DRB1, which have key roles in the immune response, and it appears that endometriosis shares many similarities with autoimmune diseases (34,53). It has been demonstrated that patients with endometriosis display a significantly higher expression of HLA I and II molecules compared with individuals without endometriosis (54).
Oxidative stress has been proposed as a potential factor involved in the pathophysiology of endometriosis (55). Accumulation of reactive oxygen species may induce cellular injury, such as DNA damage. The present study demonstrated that the majority of the pathways in module E were related to replication and repair. APEX1, OGG1, XRCC1, ERCC2 and ERCC5 were the seed genes identified in this module. APEX1 and XRCC1 are key genes involved in the base excision repair pathway, which removes DNA adducts induced predominantly by oxidation and alkylation (56). APEX1 is an essential enzyme and has a central role in the DNA repair system; however, a study by Hsu et al (57) demonstrated that APEX1 Asp148Glu was not associated with endometriosis in patients in Taiwan. Future studies may confirm the association between APEX1 and the risk of endometriosis. XRCC1 has been demonstrated to physically interact with several enzymes known to be involved in the repair of single-strand breaks in DNA (58). A study by Hsieh et al (36) indicated that XRCC1 Arg399Gln polymorphism is correlated with a higher susceptibility to endometriosis.
In conclusion, the pathogenesis of endometriosis is likely multifactorial. The present study constructed a disease network of endometriosis that integrated human protein-protein interactions and known disease-causing genes. The present study has identified a number of biological mechanisms that may be associated with endometriosis. Further studies on the specific function and interactions of the genes in related modules are required to improve the understanding of endometriosis.
Acknowledgements
The present study was supported by grants from the National Natural Science Foundation of China (grant no. 81360336) and the Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University (grant no. 2015FB017).
References
Podgaec S, Abrao MS, Dias JA Jr, Rizzo LV, de Oliveira RM and Baracat EC: Endometriosis: An inflammatory disease with a Th2 immune response component. Hum Reprod. 22:1373–1379. 2007. View Article : Google Scholar : PubMed/NCBI | |
Braun DP and Dmowski WP: Endometriosis: Abnormal endometrium and dysfunctional immune response. Curr Opin Obstet Gynecol. 10:365–369. 1998. View Article : Google Scholar : PubMed/NCBI | |
Sha G, Wu D, Zhang L, Chen X, Lei M, Sun H, Lin S and Lang J: Differentially expressed genes in human endometrial endothelial cells derived from eutopic endometrium of patients with endometriosis compared with those from patients without endometriosis. Hum Reprod. 22:3159–3169. 2007. View Article : Google Scholar : PubMed/NCBI | |
Kato N, Sasou S and Motoyama T: Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary. Mod Pathol. 19:83–89. 2006. View Article : Google Scholar : PubMed/NCBI | |
Kvaskoff M, Mu F, Terry KL, Harris HR, Poole EM, Farland L and Missmer SA: Endometriosis: A high-risk population for major chronic diseases? Hum Reprod Update. 21:500–516. 2015. View Article : Google Scholar : PubMed/NCBI | |
Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R and Tayade C: Pathophysiology and immune dysfunction in endometriosis. Biomed Res Int. 2015:7959762015. View Article : Google Scholar : PubMed/NCBI | |
Hamosh A, Scott AF, Amberger JS, Bocchini CA and McKusick VA: Online mendelian inheritance in man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 33(Database issue): D514–D517. 2005. View Article : Google Scholar : PubMed/NCBI | |
Stenson PD, Mort M, Ball EV, Howells K, Phillips AD, Thomas NS and Cooper DN: The human gene mutation database: 2008 pdate. Genome Med. 1:132009. View Article : Google Scholar : PubMed/NCBI | |
Becker KG, Barnes KC, Bright TJ and Wang SA: The genetic association database. Nature Genet. 36:431–432. 2004. View Article : Google Scholar : PubMed/NCBI | |
Wall DP, Pivovarov R, Tong M, Jung JY, Fusaro VA, DeLuca TF and Tonellato PJ: Genotator: A disease-agnostic tool for genetic annotation of disease. BMC Med Genomics. 3:502010. View Article : Google Scholar : PubMed/NCBI | |
Bauer-Mehren A, Rautschka M, Sanz F and Furlong LI: DisGeNET: A Cytoscape plugin to visualize, integrate, search and analyze gene-disease networks. Bioinformatics. 26:2924–2926. 2010. View Article : Google Scholar : PubMed/NCBI | |
Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, et al: A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell. 125:801–814. 2006. View Article : Google Scholar : PubMed/NCBI | |
Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS, Rennert G, Moreno V, Kirchhoff T, Gold B, et al: Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet. 39:1338–1349. 2007. View Article : Google Scholar : PubMed/NCBI | |
Jia P, Kao CF, Kuo PH and Zhao Z: A comprehensive network and pathway analysis of candidate genes in major depressive disorder. BMC Syst Biol. 5 Suppl 3:S122011. View Article : Google Scholar : PubMed/NCBI | |
Vidal M, Cusick ME and Barabási AL: Interactome networks and human disease. Cell. 144:986–998. 2011. View Article : Google Scholar : PubMed/NCBI | |
Wu G, Feng X and Stein L: A human functional protein interaction network and its application to cancer data analysis. Genome Biol. 11:R532010. View Article : Google Scholar : PubMed/NCBI | |
Schadt EE: Molecular networks as sensors and drivers of common human diseases. Nature. 461:218–223. 2009. View Article : Google Scholar : PubMed/NCBI | |
Ding Y, Chen M, Liu Z, Ding D, Ye Y, Zhang M, Kelly R, Guo L, Su Z, Harris SC, et al: atBioNet-an integrated network analysis tool for genomics and biomarker discovery. BMC Genomics. 13:3252012. View Article : Google Scholar : PubMed/NCBI | |
Stark C, Breitkreutz BJ, Chatr-Aryamontri A and Tyers M: The BioGRID Interaction Database: 2011 pdate. Nucleic Acids Res. 39(Database issue): D698–D704. 2010.PubMed/NCBI | |
Xenarios I, Rice DW, Salwinski L, Baron MK, Marcotte EM and Eisenberg D: DIP: The database of interacting proteins. Nucleic Acids Res. 28:289–291. 2000. View Article : Google Scholar : PubMed/NCBI | |
Prasad TS Keshava, Goel R, Kandasamy K, Keerthikumar S, Kumar S, Mathivanan S, Telikicherla D, Raju R, Shafreen B, Venugopal A, et al: Human protein reference database-2009 update. Nucleic Acids Res. 37(Database issue): D767–D772. 2009. View Article : Google Scholar : PubMed/NCBI | |
Aranda B, Achuthan P, Alam-Faruque Y, Armean I, Bridge A, Derow C, Feuermann M, Ghanbarian AT, Kerrien S, Khadake J, et al: The IntAct molecular interaction database in 2010. Nucleic Acids Res. 38(Database issue): D525–D531. 2010. View Article : Google Scholar : PubMed/NCBI | |
Licata L, Briganti L, Peluso D, Perfetto L, Iannuccelli M, Galeota E, Sacco F, Palma A, Nardozza AP, Santonico E, et al: MINT, the molecular interaction database: 2012 pdate. Nucleic Acids Res. 40(Database issue): D857–D861. 2012. View Article : Google Scholar : PubMed/NCBI | |
Matthews L, Gopinath G, Gillespie M, Caudy M, Croft D, de Bono B, Garapati P, Hemish J, Hermjakob H, Jassal B, et al: Reactome knowledgebase of human biological pathways and processes. Nucleic Acids Res. 37(Database issue): D619–D622. 2009. View Article : Google Scholar : PubMed/NCBI | |
Elkon R, Vesterman R, Amit N, Ulitsky I, Zohar I, Weisz M, Mass G, Orlev N, Sternberg G, Blekhman R, et al: SPIKE-a database, visualization and analysis tool of cellular signaling pathways. BMC bioinformatics. 9:1102008. View Article : Google Scholar : PubMed/NCBI | |
Xu X, Yuruk N, Feng Z and Schweiger T: SCAN: A structural clustering algorithm for networks. Proceedings of the 13th ACM SIGKDD international conference on Knowledge Discovery and Data Mining. ACM. San Jose, CA. pp. 824–833. 2007; | |
Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI | |
Hwang JH, Oh JJ, Wang T, Jin YC, Lee JS, Choi JR, Lee KS, Joo JK and Lee HG: Identification of biomarkers for endometriosis in eutopic endometrial cells from patients with endometriosis using a proteomics approach. Mol Med Rep. 8:183–188. 2013. View Article : Google Scholar : PubMed/NCBI | |
Wei WD, Ruan F, Tu FX, Zhou CY and Lin J: Expression of suppressor of cytokine signaling-3 and caspase-3 in endometriosis and their correlation. Zhonghua Bing Li Xue Za Zhi. 42:515–518. 2013.(In Chinese). PubMed/NCBI | |
Hayrabedyan S, Kyurkchiev S and Kehayov I: Endoglin (cd105) and S100A13 as markers of active angiogenesis in endometriosis. Reprod Biol. 5:51–67. 2005.PubMed/NCBI | |
Hou Z, Zhou J, Ma X, Fan L, Liao L and Liu J: Role of interleukin-1 receptor type II in the pathogenesis of endometriosis. Fertil Steril. 89:42–51. 2008. View Article : Google Scholar : PubMed/NCBI | |
Selam B, Kayisli UA, Garcia-Velasco JA and Arici A: Extracellular matrix-dependent regulation of Fas ligand expression in human endometrial stromal cells. Biol Reprod. 66:1–5. 2002. View Article : Google Scholar : PubMed/NCBI | |
Osteen KG, Yeaman GR and Bruner-Tran KL: Matrix metalloproteinases and endometriosis. Semin Reprod Med. 21:155–164. 2003. View Article : Google Scholar : PubMed/NCBI | |
de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, Ke X, Monsuur AJ, Whittaker P, Delgado M, et al: A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 38:1166–1172. 2006. View Article : Google Scholar : PubMed/NCBI | |
Kumar H, Kawai T and Akira S: Toll-like receptors and innate immunity. Biochem Biophys Res Commun. 388:621–625. 2009. View Article : Google Scholar : PubMed/NCBI | |
Hsieh YY, Chang CC, Chen SY, Chen CP, Lin WH and Tsai FJ: XRCC1 399 Arg-related genotype and allele, but not XRCC1 His107Arg, XRCC1 Trp194Arg, KCNQ2, AT1R and hOGG1 polymorphisms, are associated with higher susceptibility of endometriosis. Gynecol Endocrinol. 28:305–309. 2012. View Article : Google Scholar : PubMed/NCBI | |
Jiang QY and Wu RJ: Growth mechanisms of endometriotic cells in implanted places: A review. Gynecol Endocrinol. 28:562–567. 2012. View Article : Google Scholar : PubMed/NCBI | |
Vlahos NF, Economopoulos KP and Fotiou S: Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer. Best Pract Res Clin Obstet Gynaecol. 24:39–50. 2010. View Article : Google Scholar : PubMed/NCBI | |
Pollacco J, Sacco K, Portelli M, Schembri-Wismayer P and Calleja-Agius J: Molecular links between endometriosis and cancer. Gynecol Endocrinol. 28:577–581. 2012. View Article : Google Scholar : PubMed/NCBI | |
Jiang X, Hitchcock A, Bryan EJ, Watson RH, Englefield P, Thomas EJ and Campbell IG: Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumor suppressor gene loci. Cancer Res. 56:3534–3539. 1996.PubMed/NCBI | |
Hsieh YY, Chang CC, Tsai FJ, Hsu CM, Lin CC and Tsai CH: Interleukin-2 receptor beta (IL-2R beta)-627*C homozygote but not IL-12R beta 1 codon 378 or IL-18 105 polymorphism is associated with higher susceptibility to endometriosis. Fertil Steril. 84:510–512. 2005. View Article : Google Scholar : PubMed/NCBI | |
Ayaz L, Celik SK, Cayan F, Aras-Ates N and Tamer L: Functional association of interleukin-18 gene −607 C/A promoter polymorphisms with endometriosis. Fertil Steril. 95:298–300. 2011. View Article : Google Scholar : PubMed/NCBI | |
Monsanto SP, Edwards AK, Zhou J, Nagarkatti P, Nagarkatti M, Young SL, Lessey BA and Tayade C: Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients. Fertil Steril. 105:968–977. 2016. View Article : Google Scholar : PubMed/NCBI | |
Harada T, Iwabe T and Terakawa N: Role of cytokines in endometriosis. Fertil Steril. 76:1–10. 2001. View Article : Google Scholar : PubMed/NCBI | |
Shuai K and Liu B: Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 3:900–911. 2003. View Article : Google Scholar : PubMed/NCBI | |
Petrilli V, Dostert C, Muruve DA and Tschopp J: The inflammasome: A danger sensing complex triggering innate immunity. Curr Opin Immunol. 19:615–622. 2007. View Article : Google Scholar : PubMed/NCBI | |
Harada M, Osuga Y, Hirata T, Hirota Y, Koga K, Yoshino O, Morimoto C, Fujiwara T, Momoeda M, Yano T, et al: Concentration of osteoprotegerin (OPG) in peritoneal fluid is increased in women with endometriosis. Hum Reprod. 19:2188–2191. 2004. View Article : Google Scholar : PubMed/NCBI | |
Nissinen L and Kähäri VM: Matrix metalloproteinases in inflammation. Biochim Biophys Acta. 1840:2571–2580. 2014. View Article : Google Scholar : PubMed/NCBI | |
Cominelli A, Chevronnay HP Gaide, Lemoine P, Courtoy PJ, Marbaix E and Henriet P: Matrix metalloproteinase-27 is expressed in CD163+/CD206+ M2 macrophages in the cycling human endometrium and in superficial endometriotic lesions. Mol Hum Reprod. 20:767–775. 2014. View Article : Google Scholar : PubMed/NCBI | |
Nagase H, Visse R and Murphy G: Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 69:562–573. 2006. View Article : Google Scholar : PubMed/NCBI | |
Mu L, Zheng W, Wang L, Chen XJ, Zhang X and Yang JH: Alteration of focal adhesion kinase expression in eutopic endometrium of women with endometriosis. Fertil Steril. 89:529–537. 2008. View Article : Google Scholar : PubMed/NCBI | |
Celik O, Hascalik S, Elter K, Tagluk ME, Gurates B and Aydin NE: Combating endometriosis by blocking proteasome and nuclear factor-kappaB pathways. Hum Reprod. 23:2458–2465. 2008. View Article : Google Scholar : PubMed/NCBI | |
Nothnick WB: Treating endometriosis as an autoimmune disease. Fertil Steril. 76:223–231. 2001. View Article : Google Scholar : PubMed/NCBI | |
Kitawaki J, Obayashi H, Kado N, Ishihara H, Koshiba H, Maruya E, Saji H, Ohta M, Hasegawa G, Nakamura N, et al: Association of HLA class I and class II alleles with susceptibility to endometriosis. Hum Immunol. 63:D1033–D1038. 2002. View Article : Google Scholar | |
Zhang X, Sharma RK, Agarwal A and Falcone T: Effect of pentoxifylline in reducing oxidative stress-induced embryotoxicity. J Assist Reprod Genet. 22:415–417. 2005. View Article : Google Scholar : PubMed/NCBI | |
Wood RD, Mitchell M, Sgouros J and Lindahl T: Human DNA repair genes. Science. 291:1284–1289. 2001. View Article : Google Scholar : PubMed/NCBI | |
Hsu CM, Chang WS, Hwang JJ, Wang JY, Hsiao YL, Tsai CW, Liu JC, Ying TH and Bau DT: The role of apurinic/apyrimidinic endonuclease DNA repair gene in endometriosis. Cancer Genomics Proteomics. 11:295–301. 2014.PubMed/NCBI | |
Brem R and Hall J: XRCC1 is required for DNA single-strand break repair in human cells. Nucleic Acids Res. 33:2512–2520. 2005. View Article : Google Scholar : PubMed/NCBI |