Top

Published in:

01-12-2021 | Polycystic Ovary Syndrome | Research

Identification of key pathways and genes in polycystic ovary syndrome via integrated bioinformatics analysis and prediction of small therapeutic molecules

Authors: Praveenkumar Devarbhavi, Lata Telang, Basavaraj Vastrad, Anandkumar Tengli, Chanabasayya Vastrad, Iranna Kotturshetti

Published in: Reproductive Biology and Endocrinology | Issue 1/2021

Abstract

To enhance understanding of polycystic ovary syndrome (PCOS) at the molecular level; this investigation intends to examine the genes and pathways associated with PCOS by using an integrated bioinformatics analysis. Based on the expression profiling by high throughput sequencing data GSE84958 derived from the Gene Expression Omnibus (GEO) database, the differentially expressed genes (DEGs) between PCOS samples and normal controls were identified. We performed a functional enrichment analysis. A protein-protein interaction (PPI) network, miRNA- target genes and TF - target gene networks, were constructed and visualized, with which the hub gene nodes were identified. Validation of hub genes was performed by using receiver operating characteristic (ROC) and RT-PCR. Small drug molecules were predicted by using molecular docking. A total of 739 DEGs were identified, of which 360 genes were up regulated and 379 genes were down regulated. GO enrichment analysis revealed that up regulated genes were mainly involved in peptide metabolic process, organelle envelope and RNA binding and the down regulated genes were significantly enriched in plasma membrane bounded cell projection organization, neuron projection and DNA-binding transcription factor activity, RNA polymerase II-specific. REACTOME pathway enrichment analysis revealed that the up regulated genes were mainly enriched in translation and respiratory electron transport and the down regulated genes were mainly enriched in generic transcription pathway and transmembrane transport of small molecules. The top 10 hub genes (SAA1, ADCY6, POLR2K, RPS15, RPS15A, CTNND1, ESR1, NEDD4L, KNTC1 and NGFR) were identified from PPI network, miRNA - target gene network and TF - target gene network. The modules analysis showed that genes in modules were mainly associated with the transport of respiratory electrons and signaling NGF, respectively. We find a series of crucial genes along with the pathways that were most closely related with PCOS initiation and advancement. Our investigations provide a more detailed molecular mechanism for the progression of PCOS, detail information on the potential biomarkers and therapeutic targets.

Meier RK. Polycystic Ovary Syndrome. Nurs Clin North Am. 2018;53(3):407–20. https://doi.org/10.1016/j.cnur.2018.04.008.CrossRefPubMed

Belenkaia LV, Lazareva LM, Walker W, Lizneva DV, Suturina LV. Criteria, phenotypes and prevalence of polycystic ovary syndrome. Minerva Ginecol 2019;71(3):211-223. doi:10.23736/S0026-4784.19.04404-6

Escobar-Morreale HF, Roldán-Martín MB. Type 1 Diabetes and Polycystic Ovary Syndrome: Systematic Review and Meta-analysis. Diabetes Care. 2016;39(4):639–48. https://doi.org/10.2337/dc15-2577.CrossRefPubMed

Oliver-Williams C, Vassard D, Pinborg A, Schmidt L. Risk of cardiovascular disease for women with polycystic ovary syndrome: results from a national Danish registry cohort study. Eur J Prev Cardiol. 2020:2047487320939674. https://doi.org/10.1177/2047487320939674.

Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes Rev. 2013;14(2):95–109. https://doi.org/10.1111/j.1467-789X.2012.01053.x.CrossRefPubMed

Wu J, Yao XY, Shi RX, Liu SF, Wang XY. A potential link between polycystic ovary syndrome and non-alcoholic fatty liver disease: an update meta-analysis. Reprod Health. 2018;15(1):77. https://doi.org/10.1186/s12978-018-0519-2.CrossRefPubMedPubMedCentral

Joham AE, Boyle JA, Zoungas S, Teede HJ. Hypertension in Reproductive-Aged Women With Polycystic Ovary Syndrome and Association With Obesity. Am J Hypertens. 2015;28(7):847–51. https://doi.org/10.1093/ajh/hpu251.CrossRefPubMed

Forlenza GP, Calhoun A, Beckman KB, Halvorsen T, Hamdoun E, Zierhut H, Sarafoglou K, Polgreen LE, Miller BS, Nathan B, et al. Next generation sequencing in endocrine practice. Mol Genet Metab. 2015;115(2-3):61–71. https://doi.org/10.1016/j.ymgme.2015.05.002.CrossRefPubMedPubMedCentral

Wang LP, Peng XY, Lv XQ, Liu L, Li XL, He X, Lv F, Pan Y, Wang L, Liu KF, et al. High throughput circRNAs sequencing profile of follicle fluid exosomes of polycystic ovary syndrome patients. J Cell Physiol 2019. doi:10.1002/jcp.28201

10.

Clough E, Barrett T. The Gene Expression Omnibus Database. Methods Mol Biol. 2016;1418:93–110. https://doi.org/10.1007/978-1-4939-3578-9_5.CrossRefPubMedPubMedCentral

11.

Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015;43(7):e47. doi:10.1093/nar/gkv007

12.

Ferreira JA. The Benjamini-Hochberg method in the case of discrete test statistics. Int J Biostat 2007;3(1):. doi:10.2202/1557-4679.1065

13.

Thomas PD. The Gene Ontology and the Meaning of Biological Function. Methods Mol Biol. 2017;1446:15–24. https://doi.org/10.1007/978-1-4939-3743-1_2.CrossRefPubMedPubMedCentral

14.

Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res 2009;37(Web Server issue):W305-W311. doi:10.1093/nar/gkp427

15.

Fabregat A, Jupe S, Matthews L, Sidiropoulos K, Gillespie M, Garapati P, Haw R, Jassal B, Korninger F, May B, et al. The Reactome Pathway Knowledgebase. Nucleic Acids Res. 2018;46(D1):D649–55. https://doi.org/10.1093/nar/gkx1132.CrossRefPubMed

16.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447–52. https://doi.org/10.1093/nar/gku1003.CrossRefPubMed

17.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B. Ideker T Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504. https://doi.org/10.1101/gr.1239303.CrossRefPubMedPubMedCentral

18.

Przulj N, Wigle DA, Jurisica I. Functional topology in a network of protein interactions. Bioinformatics. 2004;20(3):340–8. https://doi.org/10.1093/bioinformatics/btg415.CrossRefPubMed

19.

Nguyen TP, Liu WC, Jordán F. Inferring pleiotropy by network analysis: linked diseases in the human PPI network. BMC Syst Biol 2011;5:179. Published 2011 Oct 31. doi:10.1186/1752-0509-5-179

20.

Shi Z, Zhang B. Fast network centrality analysis using GPUs. BMC Bioinformatics. 2011;12:149. https://doi.org/10.1186/1471-2105-12-149.CrossRefPubMedPubMedCentral

21.

Fadhal E, Gamieldien J, Mwambene EC. Protein interaction networks as metric spaces: a novel perspective on distribution of hubs. BMC Syst Biol. 2014;8:6. https://doi.org/10.1186/1752-0509-8-6.CrossRefPubMedPubMedCentral

22.

Zaki N, Efimov D, Berengueres J. Protein complex detection using interaction reliability assessment and weighted clustering coefficient. BMC Bioinformatics. 2013;14:163. https://doi.org/10.1186/1471-2105-14.CrossRefPubMedPubMedCentral

23.

Fan Y, Xia J. miRNet-Functional Analysis and Visual Exploration of miRNA-Target Interactions in a Network Context. Methods Mol Biol. 2018;1819:215–33. https://doi.org/10.1007/978-1-4939-8618-7_10.CrossRefPubMed

24.

Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Müller M. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011;12:77. https://doi.org/10.1186/1471-2105-12-77.CrossRefPubMedPubMedCentral

25.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. https://doi.org/10.1006/meth.2001.1262.CrossRefPubMed

26.

Shah KN, Patel SS. Phosphatidylinositide 3-kinase inhibition: A new potential target for the treatment of polycystic ovarian syndrome. Pharm Biol. 2016;54(6):975–83. https://doi.org/10.3109/13880209.2015.1091482.CrossRefPubMed

27.

Wang Y, Fu X, Xu J, Wang Q, Kuang H. Systems pharmacology to investigate the interaction of berberine and other drugs in treating polycystic ovary syndrome. Sci Rep 2016;6:28089. Published 2016 Jun 16. doi:10.1038/srep28089

28.

Wu XK, Zhou SY, Liu JX, Pöllänen P, Sallinen K, Mäkinen M, Erkkola R. Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome. Fertil Steril. 2003;80(4):954–65. https://doi.org/10.1016/s0015-0282(03)01007-0.CrossRefPubMed

29.

Polak K, Czyzyk A, Simoncini T, Meczekalski B. New markers of insulin resistance in polycystic ovary syndrome. J Endocrinol Invest. 2017;40(1):1–8. https://doi.org/10.1007/s40618-016-0523-8.CrossRefPubMed

30.

Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270–84. https://doi.org/10.1038/nrendo.2018.24.CrossRefPubMed

31.

Carvalho LML, Ferreira CN, Sóter MO, Sales MF, Rodrigues KF, Martins SR, Candido AL, Reis FM, Silva IFO, Campos FMF, et al. Microparticles: Inflammatory and haemostatic biomarkers in Polycystic Ovary Syndrome. Mol Cell Endocrinol. 2017;443:155–62. https://doi.org/10.1016/j.mce.2017.01.017.CrossRefPubMed

32.

Delfín DA, DeAguero JL, McKown EN. The Extracellular Matrix Protein ABI3BP in Cardiovascular Health and Disease. Front Cardiovasc Med. 2019;6:23. https://doi.org/10.3389/fcvm.2019.00023.CrossRefPubMedPubMedCentral

33.

Romo-Yáñez J, Domínguez-Castro M, Flores-Reyes JS, Estrada-Juárez H, Mancilla-Herrera I, Hernández-Pineda J, Bazan-Tejeda ML, Aguinaga-Ríos M, Reyes-Muñoz E. Hyperglycemia differentially affects proliferation, apoptosis, and BNIP3 and p53 mRNA expression of human umbilical cord Wharton's jelly cells from non-diabetic and diabetic pregnancies. Biochem Biophys Res Commun. 2019;508(4):1149–54. https://doi.org/10.1016/j.bbrc.2018.12.037.CrossRefPubMed

34.

Schweighofer N, Lerchbaum E, Trummer O, Schwetz V, Pilz S, Pieber TR, Obermayer-Pietsch B. Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome. Gene. 2012;504(1):133–9. https://doi.org/10.1016/j.gene.2012.04.050.CrossRefPubMed

35.

Nakamura N, Hatano E, Iguchi K, Sato M, Kawaguchi H, Ohtsu I, Sakurai T, Aizawa N, Iijima H, Nishiguchi S, et al. Elevated levels of circulating ITIH4 are associated with hepatocellular carcinoma with nonalcoholic fatty liver disease: from pig model to human study. BMC Cancer. 2019;19(1):621. https://doi.org/10.1186/s12885-019-5825-8.CrossRefPubMedPubMedCentral

36.

Da Li, Cao T, Sun X, Jin S, Di Xie, Huang X, Yang X, Carmichael GG, Taylor HS, Diano S, et al. Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform. Nat Commun 2020;11(1):342. doi:10.1038/s41467-019-14185-z

37.

Zhang X, Hu C, Zhang N, Wei WY, Li LL, Wu HM, Ma ZG, Tang QZ. Matrine attenuates pathological cardiac fibrosis via RPS5/p38 in mice. Acta Pharmacol Sin 2020. doi:10.1038/s41401-020-0473-8

38.

Rosenthal LM, Leithner C, Tong G, Streitberger KJ, Krech J, Storm C, Schmitt KRL. RBM3 and CIRP expressions in targeted temperature management treated cardiac arrest patients-A prospective single center study. PLoS One. 2019;14(12):e0226005. https://doi.org/10.1371/journal.pone.0226005.CrossRefPubMedPubMedCentral

39.

Hatchwell E. BAK1 gene variation and abdominal aortic aneurysms-variants are likely due to sequencing of a processed gene on chromosome 20. Hum Mutat. 2010;31(1):108–11. https://doi.org/10.1002/humu.21147.CrossRefPubMed

40.

Raffa S, Chin XLD, Stanzione R, Forte M, Bianchi F, Cotugno M, Marchitti S, Micaloni A, Gallo G, Schirone L, et al. The reduction of NDUFC2 expression is associated with mitochondrial impairment in circulating mononuclear cells of patients with acute coronary syndrome. Int J Cardiol. 2019;286:127–33. https://doi.org/10.1016/j.ijcard.2019.02.027.CrossRefPubMed

41.

Zhang H, Gong G, Wang P, Zhang Z, Kolwicz SC, Rabinovitch PS, Tian R, Wang W. Heart specific knockout of Ndufs4 ameliorates ischemia reperfusion injury. J Mol Cell Cardiol. 2018;123:38–45. https://doi.org/10.1016/j.yjmcc.2018.08.022.CrossRefPubMedPubMedCentral

42.

Iwahana T, Okada S, Kanda M, Oshima M, Iwama A, Matsumiya G, Kobayashi Y. Novel myocardial markers GADD45G and NDUFS5 identified by RNA-sequencing predicts left ventricular reverse remodeling in advanced non-ischemic heart failure: a retrospective cohort study. BMC Cardiovasc Disord. 2020;20(1):116. https://doi.org/10.1186/s12872-020-01396-2.CrossRefPubMedPubMedCentral

43.

Gusic M, Schottmann G, Feichtinger RG, Du C, Scholz C, Wagner M, Mayr JA, Lee CY, Yépez VA, Lorenz N, et al. Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis. Am J Hum Genet. 2020;106(1):102–11. https://doi.org/10.1016/j.ajhg.2019.12.005.CrossRefPubMed

44.

Abdulhag UN, Soiferman D, Schueler-Furman O, Miller C, Shaag A, Elpeleg O, Edvardson S, Saada A. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy. Eur J Hum Genet. 2015;23(2):159–64. https://doi.org/10.1038/ejhg.2014.85.CrossRefPubMed

45.

Hu H, Nan J, Sun Y, Zhu D, Xiao C, Wang Y, Zhu L, Wu Y, Zhao J, Wu R, et al. Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3. Proc Natl Acad Sci U S A. 2017;114(45):11908–13. https://doi.org/10.1073/pnas.1704723114.CrossRefPubMedPubMedCentral

46.

Pyun JH, Kim HJ, Jeong MH, Ahn BY, Vuong TA, Lee DI, Choi S, Koo SH, Cho H, Kang JS. Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation. Nat Commun. 2018;9(1):5107. https://doi.org/10.1038/s41467-018-07606-y.CrossRefPubMedPubMedCentral

47.

Cetinkaya A, Berge B, Sen-Hild B, Troidl K, Gajawada P, Kubin N, Valeske K, Schranz D, Akintürk H, Schönburg M, et al. Radixin Relocalization and Nonmuscle α-Actinin Expression Are Features of Remodeling Cardiomyocytes in Adult Patients with Dilated Cardiomyopathy. Dis Markers. 2020;2020:9356738. https://doi.org/10.1155/2020/9356738.CrossRefPubMedPubMedCentral

48.

Yang D, Jin C, Ma H, Huang M, Shi GP, Wang J, Xiang M. EphrinB2/EphB4 pathway in postnatal angiogenesis: a potential therapeutic target for ischemic cardiovascular disease. Angiogenesis. 2016;19(3):297–309. https://doi.org/10.1007/s10456-016-9514-9.CrossRefPubMed

49.

Chen S, Wang C, Wang X, Xu C, Wu M, Wang P, Tu X, Wang QK. Significant Association Between CAV1 Variant rs3807989 on 7p31 and Atrial Fibrillation in a Chinese Han Population. J Am Heart Assoc. 2015;4(5):e001980. https://doi.org/10.1161/JAHA.115.001980.CrossRefPubMedPubMedCentral

50.

Nöthe-Menchen T, Wallmeier J, Pennekamp P, Höben IM, Olbrich H, Loges NT, Raidt J, Dougherty GW, Hjeij R, Dworniczak B, et al. Randomization of left-right Asymmetry and Congenital Heart defects: the role of DNAH5 in humans and mice. Circ Genom Precis Med 2019;doi:10.1161/CIRCGEN.119.002686

51.

Dahlberg J, Sjögren M, Hedblad B, Engström G, Melander O. Genetic variation in NEDD4L, an epithelial sodium channel regulator, is associated with cardiovascular disease and cardiovascular death. J Hypertens. 2014;32(2):294–9. https://doi.org/10.1097/HJH.0000000000000044.CrossRefPubMed

52.

Karam S, Margaria JP, Bourcier A, Mika D, Varin A, Bedioune I, Lindner M, Bouadjel K, Dessillons M, Gaudin F, et al. Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure. Circulation. 2020;142(2):161–74. https://doi.org/10.1161/CIRCULATIONAHA.119.042573.CrossRefPubMed

53.

Alharatani R, Ververi A, Beleza-Meireles A, Ji W, Mis E, Patterson QT, Griffin JN, Bhujel N, Chang CA, Dixit A, et al. Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome. Hum Mol Genet. 2020;29(11):1900–21. https://doi.org/10.1093/hmg/ddaa050.CrossRefPubMedPubMedCentral

54.

Ostergaard E, Weraarpachai W, Ravn K, Born AP, Jønson L, Duno M, Wibrand F, Shoubridge EA, Vissing J. Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature. J Med Genet. 2015;52(3):203–7. https://doi.org/10.1136/jmedgenet-2014-102914.CrossRefPubMed

55.

Zi Xu YX, Ande SR, Mishra S. Prohibitin: A new player in immunometabolism and in linking obesity and inflammation with cancer. Cancer Lett. 2018;415:208–16. https://doi.org/10.1016/j.canlet.2017.12.001.CrossRefPubMed

56.

Kunej T, Wang Z, Michal JJ, Daniels TF, Magnuson NS, Jiang Z. Functional UQCRC1 polymorphisms affect promoter activity and body lipid accumulation. Obesity. 2007;15(12):2896–901. https://doi.org/10.1038/oby.2007.344.CrossRefPubMed

57.

Van der Schueren B, Vangoitsenhoven R, Geeraert B, De Keyzer D, Hulsmans M, Lannoo M, Huber HJ, Mathieu C, Holvoet P. Low cytochrome oxidase 4I1 links mitochondrial dysfunction to obesity and type 2 diabetes in humans and mice. Int J Obes. 2015;39(8):1254–63. https://doi.org/10.1038/ijo.2015.58.CrossRef

58.

Jin W, Jin W, Pan D. Ifi27 is indispensable for mitochondrial function and browning in adipocytes. Biochem Biophys Res Commun. 2018;501(1):273–9. https://doi.org/10.1016/j.bbrc.2018.04.234.CrossRefPubMed

59.

Emdad L, Das SK, Hu B, Kegelman T, Kang DC, Lee SG, Sarkar D, Fisher PB. AEG-1/MTDH/LYRIC: A Promiscuous Protein Partner Critical in Cancer, Obesity, and CNS Diseases. Adv Cancer Res. 2016;131:97–132. https://doi.org/10.1016/bs.acr.2016.05.002.CrossRefPubMed

60.

Liu Y, Zhang R, Xin J, Sun Y, Li J, Wei D, Zhao AZ. Identification of S100A16 as a novel adipogenesis promoting factor in 3T3-L1 cells. Endocrinology. 2011;152(3):903–11. https://doi.org/10.1210/en.2010-1059.CrossRefPubMed

61.

Scherag A, Kleber M, Boes T, Kolbe AL, Ruth A, Grallert H, Illig T, Heid IM, Toschke AM, Grau K, et al. SDCCAG8 obesity alleles and reduced weight loss after a lifestyle intervention in overweight children and adolescents. Obesity. 2012;20(2):466–70. https://doi.org/10.1038/oby.2011.339.CrossRefPubMed

62.

Shi Y, Long F. Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice. Elife. 2017;6:e31649. https://doi.org/10.7554/eLife.31649.CrossRefPubMedPubMedCentral

63.

Sharma M, Schlegel M, Brown EJ, Sansbury BE, Weinstock A, Afonso MS, Corr EM, van Solingen C, Shanley LC, Peled D, et al. Netrin-1 Alters Adipose Tissue Macrophage Fate and Function in Obesity. Immunometabolism 2019;1(2):e190010. doi:10.20900/immunometab20190010

64.

Parente DJ, Garriga C, Baskin B, Douglas G, Cho MT, Araujo GC, Shinawi M. Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity. Am J Med Genet A. 2017;173(1):213–6. https://doi.org/10.1002/ajmg.a.37977.CrossRefPubMed

65.

Saint-Laurent C, Garcia S, Sarrazy V, Dumas K, Authier F, Sore S, Tran A, Gual P, Gennero I, Salles JP, et al. Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia. PLoS One. 2018;13(4):e0195876. https://doi.org/10.1371/journal.pone.0195876.CrossRefPubMedPubMedCentral

66.

Lee S. The association of genetically controlled CpG methylation (cg158269415) of protein tyrosine phosphatase, receptor type N2 (PTPRN2) with childhood obesity. Sci Rep. 2019;9(1):4855. https://doi.org/10.1038/s41598-019-40486-w.CrossRefPubMedPubMedCentral

67.

Alsters SI, Goldstone AP, Buxton JL, Zekavati A, Sosinsky A, Yiorkas AM, Holder S, Klaber RE, Bridges N, van Haelst MM, et al. Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism. PLoS One. 2015;10(6):e0131417. https://doi.org/10.1371/journal.pone.0131417.CrossRefPubMedPubMedCentral

68.

Lee J, Harris AN, Holley CL, Mahadevan J, Pyles KD, Lavagnino Z, Scherrer DE, Fujiwara H, Sidhu R, Zhang J, et al. Rpl13a small nucleolar RNAs regulate systemic glucose metabolism. J Clin Invest. 2016;126(12):4616–25. https://doi.org/10.1172/JCI88069.CrossRefPubMedPubMedCentral

69.

Shiffman D, Pare G, Oberbauer R, Louie JZ, Rowland CM, Devlin JJ, Mann JF, McQueen MJ. A gene variant in CERS2 is associated with rate of increase in albuminuria in patients with diabetes from ONTARGET and TRANSCEND. PLoS One. 2014;9(9):e106631. https://doi.org/10.1371/journal.pone.0106631.CrossRefPubMedPubMedCentral

70.

Yaghootkar H, Stancáková A, Freathy RM, Vangipurapu J, Weedon MN, Xie W, Wood AR, Ferrannini E, Mari A, Ring SM, et al. Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion. Diabetes. 2015;64(6):2279–85. https://doi.org/10.2337/db14-1456.CrossRefPubMed

71.

Rotroff DM, Yee SW, Zhou K, Marvel SW, Shah HS, Jack JR, Havener TM, Hedderson MM, Kubo M, Herman MA, et al. Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes. Diabetes. 2018;67(7):1428–40. https://doi.org/10.2337/db17-1164.CrossRefPubMedPubMedCentral

72.

Cheng Y, Liu J, Luan Y, Liu Z, Lai H, Zhong W, Yang Y, Yu H, Feng N, Wang H, et al. Sarm1 Gene Deficiency Attenuates Diabetic Peripheral Neuropathy in Mice. Diabetes. 2019;68(11):2120–30. https://doi.org/10.2337/db18-1233.CrossRefPubMedPubMedCentral

73.

Baig MH, Kausar MA, Husain FM, Shakil S, Ahmad I, Yadav BS, Saeed M. Interfering PLD1-PED/PEA15 interaction using self-inhibitory peptides: An in silico study to discover novel therapeutic candidates against type 2 diabetes. Saudi J Biol Sci. 2019;26(1):160–4. https://doi.org/10.1016/j.sjbs.2018.08.020.CrossRefPubMed

74.

Zhang Z, Tremblay J, Raelson J, Sofer T, Du L, Fang Q, Argos M, Marois-Blanchet FC, Wang Y, Yan L, et al. EPHA4 regulates vascular smooth muscle cell contractility and is a sex-specific hypertension risk gene in individuals with type 2 diabetes. J Hypertens. 2019;37(4):775–89. https://doi.org/10.1097/HJH.0000000000001948.CrossRefPubMed

75.

Lebailly B, He C, Rogner UC. Linking the circadian rhythm gene Arntl2 to interleukin 21 expression in type 1 diabetes. Diabetes. 2014;63(6):2148–57. https://doi.org/10.2337/db13-1702.CrossRefPubMed

76.

Ferris ST, Carrero JA, Mohan JF, Calderon B, Murphy KM, Unanue ER. A minor subset of Batf3-dependent antigen-presenting cells in islets of Langerhans is essential for the development of autoimmune diabetes. Immunity. 2014;41(4):657–69. https://doi.org/10.1016/j.immuni.2014.09.012.CrossRefPubMedPubMedCentral

77.

Lempainen J, Härkönen T, Laine A, Knip M. Ilonen J; Finnish Pediatric Diabetes Register. Associations of polymorphisms in non-HLA loci with autoantibodies at the diagnosis of type 1 diabetes: INS and IKZF4 associate with insulin autoantibodies. Pediatr Diabetes. 2013;14(7):490–6. https://doi.org/10.1111/pedi.12046.CrossRefPubMed

78.

McCallum RW, Parameswaran V, Burgess JR. Multiple endocrine neoplasia type 1 (MEN 1) is associated with an increased prevalence of diabetes mellitus and impaired fasting glucose. Clin Endocrinol. 2006;65(2):163–8. https://doi.org/10.1111/j.1365-2265.2006.02563.x.CrossRef

79.

Wang Y, Bao MH, Zhang QS, Li JM, Tang L. Association of ATP6AP2 Gene Polymorphisms with Essential Hypertension in a South Chinese Han Population. Asian Pac J Cancer Prev. 2015;16(17):8017–8. https://doi.org/10.7314/apjcp.2015.16.17.8017.CrossRefPubMed

80.

Tian L, Neuber-Hess M, Mewburn J, Dasgupta A, Dunham-Snary K, Wu D, Chen KH, Hong Z, Sharp WW, Kutty S, et al. Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension. J Mol Med. 2017;95(4):381–93. https://doi.org/10.1007/s00109-017-1522-8.CrossRefPubMed

81.

Zhang Y, Wang S, Huang H, Zeng A, Han Y, Zeng C, Zheng S, Ren H, Wang Y, Huang Y, et al. GRK4-mediated adiponectin receptor-1 phosphorylative desensitization as a novel mechanism of reduced renal sodium excretion in hypertension. Clin Sci. 2020;134(18):2453–67. https://doi.org/10.1042/CS20200671.CrossRef

82.

Carr G, Barrese V, Stott JB, Povstyan OV, Jepps TA, Figueiredo HB, Zheng D, Jamshidi Y, Greenwood IA. MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension. Cardiovasc Res. 2016;112(2):581–9. https://doi.org/10.1093/cvr/cvw177.CrossRefPubMedPubMedCentral

83.

Atiomo W, Shafiee MN, Chapman C, Metzler VM, Abouzeid J, Latif A, Chadwick A, Kitson S, Sivalingam VN, Stratford IJ, et al. Corrigendum: Expression of NAD(P) H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome. Clin Endocrinol. 2017;87(6):886. https://doi.org/10.1111/cen.13515.CrossRef

84.

Lara HE, Dissen GA, Leyton V, Paredes A, Fuenzalida H, Fiedler JL, Ojeda SR. An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat. Endocrinology. 2000;141(3):1059–72. https://doi.org/10.1210/endo.141.3.7395.CrossRefPubMed

85.

Douma Z, Dallel M, Bahia W, Ben Salem A, Hachani B, Ali F, Almawi WY, Lautier C, Haydar S, Grigorescu F, Mahjoub T. Association of estrogen receptor gene variants (ESR1 and ESR2) with polycystic ovary syndrome in Tunisia. Gene 2020;741:144560. doi:10.1016/j.gene.2020.144560

86.

Jin SS, Lin XF, Zheng JZ, Wang Q, Guan HQ. lncRNA NEAT1 regulates fibrosis and inflammatory response induced by nonalcoholic fatty liver by regulating miR-506/GLI3. Eur Cytokine Netw. 2019;30(3):98–106. https://doi.org/10.1684/ecn.2019.0432.CrossRefPubMed

87.

Zhang X, Tang QZ, Wan AY, Zhang HJ, Wei L. SAA1 gene variants and childhood obesity in China. Lipids Health Dis. 2013;12:161. https://doi.org/10.1186/1476-511X-12-161.CrossRefPubMedPubMedCentral

88.

Deng Y, Wang J, Xie G, Zeng X, Li H. Circ-HIPK3 Strengthens the Effects of Adrenaline in Heart Failure by MiR-17-3p - ADCY6 Axis. Int J Biol Sci. 2019;15(11):2484–96. https://doi.org/10.7150/ijbs.36149.CrossRefPubMedPubMedCentral

89.

Miao R, Wang Y, Wan J, Leng D, Gong J, Li J, Zhang Y, Pang W, Zhai Z, Yang Y, Miao R, Wang Y, Wan J, et al. Microarray Analysis and Detection of MicroRNAs Associated with Chronic Thromboembolic Pulmonary Hypertension. Biomed Res Int. 2017;2017:8529796. https://doi.org/10.1155/2017/8529796.CrossRefPubMedPubMedCentral

90.

Karthikeyan R, Marimuthu G, Sooriyakumar M, BaHammam AS, Spence DW, Pandi-Perumal SR, Brown GM, Cardinali DP. Per3 length polymorphism in patients with type 2 diabetes mellitus. Horm Mol Biol Clin Investig. 2014;18(3):145–9. https://doi.org/10.1515/hmbci-2013-0049.CrossRefPubMed

91.

Lu Y, Habtetsion TG, Li Y, Zhang H, Qiao Y, Yu M, Tang Y, Zhen Q, Cheng Y, Liu Y. Association of NCOA2 gene polymorphisms with obesity and dyslipidemia in the Chinese Han population. Int J Clin Exp Pathol. 2015;8(6):7341–9.PubMedPubMedCentral

92.

Zhu Q, Chang A, Xu A, Luo K. The regulatory protein SnoN antagonizes activin/Smad2 protein signaling and thereby promotes adipocyte differentiation and obesity in mice. J Biol Chem. 2018;293(36):14100–11. https://doi.org/10.1074/jbc.RA118.003678.CrossRefPubMedPubMedCentral

93.

Ying Y, Luo Y, Peng H. EBF1 gene polymorphism and its interaction with smoking and drinking on the risk of coronary artery disease for Chinese patients. Biosci Rep. 2018;38(3):BSR20180324. https://doi.org/10.1042/BSR20180324.CrossRefPubMedPubMedCentral

94.

Zhang S, Deng W, Liu Q, Wang P, Yang W, Ni W. Altered m6 A modification is involved in up-regulated expression of FOXO3 in luteinized granulosa cells of non-obese polycystic ovary syndrome patients. J Cell Mol Med. 2020;24(20):11874–82. https://doi.org/10.1111/jcmm.15807.CrossRefPubMedPubMedCentral

Title: Identification of key pathways and genes in polycystic ovary syndrome via integrated bioinformatics analysis and prediction of small therapeutic molecules
Authors: Praveenkumar Devarbhavi
Lata Telang
Basavaraj Vastrad
Anandkumar Tengli
Chanabasayya Vastrad
Iranna Kotturshetti
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Polycystic Ovary Syndrome
Polycystic Ovary Syndrome
Biomarkers
Published in: Reproductive Biology and Endocrinology / Issue 1/2021
Electronic ISSN: 1477-7827
DOI: https://doi.org/10.1186/s12958-021-00706-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Identification of key pathways and genes in polycystic ovary syndrome via integrated bioinformatics analysis and prediction of small therapeutic molecules

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

HSF1 promotes endometriosis development and glycolysis by up-regulating PFKFB3 expression

Comparative effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG HP) in assisted reproductive technology (ART) treatments: a non-interventional study in Germany

No significant long-term complications from inadvertent exposure to gonadotropin-releasing hormone agonist during early pregnancy in mothers and offspring: a retrospective analysis

Prevalence and associated factors of erectile dysfunction, psychological disorders, and sexual performance in primary vs. secondary infertility men

Maternal and infant outcomes during the COVID-19 pandemic: a retrospective study in Guangzhou, China

The effects of statins on hyperandrogenism in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials