{"paper_id":"b848f686-e393-42cc-9d92-07ce5776c8e7","body_text":"Abstract\nBackground\nEndometriosis is a multifactorial estrogen dependent gynecological disease characterized by implantation of functional endometrial tissue at ectopic positions. Though this disease is benign, it is associated with an increased risk of malignant transformation. Epigenetic disruptions like aberrant DNA methylation, resulting changes in gene expression capacity, are important in tumor progression and malignant cellular transformation. Therefore, variation in genes involved in DNA methylation might lead to disease susceptibility.\nPurpose\nTo investigate the association between DNA methyl transferases (DNMT1 and DNMT3B) single nucleotide polymorphisms (SNPs) and the risk of endometriosis in South Indian women.\nMethods\nIn the present study, we examined the genotypic and allele distribution of DNMT1 (rs10423341C/A, rs2228611G/Aandrs4804490C/A) and DNMT3B (rs1569686G/T) among the endometriosis patients (n = 150) and controls (n = 150). The genotypes were analyzed by polymerase chain reaction (PCR) and sequencing methods. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (Dʹ) for pairwise linkage disequilibrium (LD) were surveyed by Haploview Software.\nResult\nSignificant increase in the frequencies of DNMT1 rs10423341 (P = 0.04601), rs2228611 (P = 0.00175) and DNMT3B rs1569686 (P = 0.033) genotypes and alleles was observed in patients compared to controls. In addition, the frequency of A/A/C (P = 0.0065) haplotype was significantly high in patients. But the DNMT1 (rs4804490) SNP did not show significant association with the disease.\nConclusion\nThe DNMT1 and DNMT3B polymorphism may constitute an inheritable risk factor for endometriosis in South Indian women. To the best of our knowledge there is no reported study on the association of polymorphisms in DNMT1 and DNMT3B with endometriosis risk.\nSimilar content being viewed by others\nAbbreviations\n- CI:\n-\nConfidence interval\n- χ2 :\n-\nChi square\n- D′:\n-\nDisequilibrium coefficient\n- LD:\n-\nLinkage disequilibrium\n- HWE:\n-\nHardy–Weinberg equilibrium\n- OR:\n-\nOdds ratio\n- DNMT1:\n-\nDNA methyl transferase 2\n- DNMT3B:\n-\nDNA methyl transferase 3B\n- PR:\n-\nProgesterone receptor\n- APC:\n-\nAdenomatous polyposis coli\n- PTEN:\n-\nPhosphatase and tensin homologue\n- PCR:\n-\nPolymerase chain reaction\n- SNPs:\n-\nSingle nucleotide polymorphisms\n- TSGs:\n-\nTumor suppressor genes,\n- SF-1:\n-\nSteroidogenic factor-1\n- ESR2:\n-\nEstrogen receptor 2\nReferences\nZondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Viganò P (2018) Endometriosis Nat Rev Dis Primers 4(1):9\nParasar P, Ozcan P, Terry KL (2017) Endometriosis: Epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep 6(1):34–41\nSachedina A, Todd N (2020) Dysmenorrhea, endometriosis and chronic pelvic pain in adolescents. J Clin Res Pediatr Endocrinol 12(Suppl 1):7–17\nSampson JA (1927) Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 14(4):422–469\nBhanoori M, Deenadayal M, Kennedy S, Shivaji S (2007) The G2964A 3’-untranslated region polymorphism of the signal transducer and activator of transcription 6 gene is associated with endometriosis in South Indian women. Hum Reprod 22(4):1026–1030\nBhanoori M, Kameshwari DB, Zondervan KT, Deenadayal M, Kennedy S, Shivaji S (2008) The endothelial nitric oxide synthase Glu298Asp polymorphism is not a risk factor for endometriosis in south Indian women. Eur J Obstet Gynecol Reprod Biol 139(1):53–58\nGovatati S, Tangudu NK, Deenadayal M, Chakravarty B, Shivaji S, Bhanoori M (2012) Association of E-cadherin single nucleotide polymorphisms with the increased risk of endometriosis in Indian women. Mol Hum Reprod 18(5):280–287\nGovatati S, Chakravarty B, Deenadayal M, Kodati VL, Manolla ML, Sisinthy S, Bhanoori M (2012) p53 and risk of endometriosis in Indian women. Genet Test Mol Biomark 16(8):865–873\nGovatati S, Kodati VL, Deenadayal M, Chakravarty B, Shivaji S, Bhanoori M (2014) Mutations in the PTEN tumor gene and risk of endometriosis: a case-control study. Hum Reprod 29(2):324–336\nGovatati S, Challa K, Reddy SB, Pramod K, Deenadayal M, Chakravarty B, Shivaji S, Bhanoori M (2015) BRCA1 alterations are associated with endometriosis, but BRCA2 alterations show no detectable endometriosis risk: a study in Indian population. J Assist Reprod Genet 32(2):277–285\nTempfer CB, Simoni M, Destenaves B, Fauser BC (2009) Functional genetic polymorphisms and female reproductive disorders: part II–endometriosis. Hum Reprod Update 15(1):97–118\nGuo SW (2009) Epigenetics of endometriosis. Mol Hum Reprod 15(10):587–607\nSchuebel K, Gitik M, Domschke K, Goldman D (2016) Making sense of epigenetics. Int J Neuropsychopharmacol 19(11):058\nRajendran G, Shanmuganandam K, Bendre A, Muzumdar D, Goel A, Shiras A (2011) Epigenetic regulation of DNA methyltransferases: DNMT1 and DNMT3B in gliomas. J Neurooncol 104(2):483–494\nMoore LD, Le T, Fan G (2013) DNA methylation and its basic function. Neuropsychopharmacology 38(1):23–38\nZhang W, Xu J (2017) DNA methyltransferases and their roles in tumorigenesis. Biomark Res 5:1. https://doi.org/10.1186/s40364-017-0081-z\nHoushdaran S, Nezhat CR, Vo KC, Zelenko Z, Irwin JC, Giudice LC (2016) Aberrant endometrial DNA methylome and associated gene expression in women with endometriosis. Biol Reprod 95(5):93\nWu Y, Strawn E, Basir Z, Halverson G, Guo SW (2007) Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis. Fertil Steril 87(1):24–32\nDeng N, Zhou H, Fan H, Yuan Y (2017) Single nucleotide polymorphisms and cancer susceptibility. Oncotarget 8(66):110635–110649\nCheng P, Chen H, Zhang RP, Liu SR, Zhou-Cun A (2014) Polymorphism in DNMT1 may modify the susceptibility to oligospermia. Reprod Biomed Online 28:644–649\nHaggarty P, Hoad G, Horgan GW, Campbell DM (2013) DNA methyltransferase candidate polymorphisms, imprinting methylation, and birth outcome. PLoS ONE 8:e68896\nJaiswal SK, Sukla KK, Kumari N, Lakhotia AR, Kumar A, Rai AK (2015) Maternal risk for down syndrome and polymorphisms in the promoter region of the DNMT3B gene: a case-control study. Birth Defects Res A Clin Mol Teratol 103:299–305\nCoppedè F, Bosco P, Tannorella P, Romano C, Antonucci I, Stuppia L, Romano C, Migliore L (2013) DNMT3B promoter polymorphisms and maternal risk of birth of a child with Down syndrome. Hum Reprod 28(2):545–550\nZondervan KT, Cardon LR, Kennedy SH (2002) What makes a good case-control study? Design issues for complex traits such as endometriosis. Hum Reprod 17(6):1415–1423\nBarrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265\nDyson MT, Roqueiro D, Monsivais D, Ercan CM, Pavone ME, Brooks DC, Kakinuma T, Ono M, Jafari N, Dai Y, Bulun SE (2014) Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet 10(3):e1004158\nLi Y, An D, Guan YX, Kang S (2017) Aberrant methylation of the E-cadherin gene promoter region in endometrium and ovarian endometriotic cysts of patients with ovarian endometriosis. Gynecol Obstet Investig 82(1):78–85\nNoble LS, Simpson ER, Johns A, Bulun SE (1996) Aromatase expression in endometriosis. J Clin Endocrinol Metab 81(1):174–179\nNishida M, Nasu K, Ueda T, Fukuda J, Takai N, Miyakawa I (2005) Endometriotic cells are resistant to interferon-gamma-induced cell growth inhibition and apoptosis: a possible mechanism involved in the pathogenesis of endometriosis. Mol Hum Reprod 11(1):29–34\nZeitoun K, Takayama K, Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE (1998) Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J Clin Endocrinol Metab 83(12):4474–4480\nNishida M, Nasu K, Fukuda J, Kawano Y, Narahara H, Miyakawa I (2004) Down-regulation of interleukin-1 receptor type 1 expression causes the dysregulated expression of CXC chemokines in endometriotic stromal cells: a possible mechanism for the altered immunological functions in endometriosis. J Clin Endocrinol Metab 89(10):5094–5100\nXue Q, Lin Z, Cheng YH, Huang CC, Marsh E, Yin P, Milad MP, Confino E, Reierstad S, Innes J, Bulun SE (2007) Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod 77(4):681–687\nXue Q, Lin Z, Yin P, Milad MP, Cheng YH, Confino E, Reierstad S, Bulun SE (2007) Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5’ CpG island in endometriosis. J Clin Endocrinol Metab 92(8):3261–3267\nWu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo SW (2005) Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol 193(2):371–380\nWu Y, Strawn E, Basir Z, Halverson G, Guo SW (2006) Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics 1(2):106–111\nLiu ZJ, Zhang XB, Zhang Y, Yang X (2004) Progesterone receptor gene inactivation and CpG island hypermethylation in human leukemia cancer cells. FEBS Lett 567(2–3):327–332\nSerrano-Gomez SJ, Maziveyi M, Alahari SK (2016) Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer 15:18\nMostowska A, Sajdak S, Pawlik P, Lianeri M, Jagodzinski PP (2013) DNMT1, DNMT3A and DNMT3B gene variants in relation to ovarian cancer risk in the Polish population. Mol Biol Rep 40(8):4893–4899\nLi H, Liu JW, Sun LP, Yuan Y (2017) A meta-analysis of the association between DNMT1 polymorphisms and cancer risk. Biomed Res Int 2017:3971259\nChen CL, Liu SS, Ip SM, Wong LC, Ng TY, Ngan HY (2003) E-cadherin expression is silenced by DNA methylation in cervical cancer cell lines and tumours. Eur J Cancer 39(4):517–523\nWang X, Li B (2017) DNMT1 regulates human endometrial carcinoma cell proliferation. Onco Targets Ther 10:1865–1873\nVázquez-Arreguín K, Tantin D (2016) The Oct1 transcription factor and epithelial malignancies: old protein learns new tricks. Biochim Biophys Acta 1859(6):792–804\nTakai N, Miyazaki T, Nishida M, Nasu K, Miyakawa I (2003) The significance of Elf-1 expression in epithelial ovarian carcinoma. Int J Mol Med 12(3):349–354\nSaradalekshmi KR et al (2014) DNA methyl transferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia. PLoS ONE 9(5):e98182\nLuo Y, Yu L, Yu T, Jiang F, Cai X, Zhao Y, Pan S, Luo C (2015) The association of DNA methyltransferase 1 gene polymorphisms with susceptibility to childhood acute lymphoblastic leukemia. Biomed Pharmacother 73:35–39\nYang XX, He XQ, Li FX, Wu YS, Gao Y, Li M (2012) Risk-association of DNA methyltransferases polymorphisms with gastric cancer in the Southern Chinese population. Int J Mol Sci 13(7):8364–8378\nLee SJ, Jeon HS, Jang JS, Park SH, Lee GY, Lee BH, Kim CH, Kang YM, Lee WK, Kam S, Park RW, Kim IS, Cho YL, Jung TH, Park JY (2005) DNMT3B polymorphisms and risk of primary lung cancer. Carcinogenesis 26(2):403–409\nBarišić A, Kolak M, Peterlin A, Tul N, Gašparović Krpina M, Ostojić S, Peterlin B, Pereza N (2020) DNMT3B rs1569686 and rs2424913 gene polymorphisms are associated with positive family history of preterm birth and smoking status. Croat Med J 61(1):8–17\nZhang Y, Xu H, Shen Y, Gong Z, Xiao T (2015) Association of DNMT3B -283 T > C and -579 G > T polymorphisms with decreased cancer risk: evidence from a meta-analysis. Int J Clin Exp Med 8(8):13028–13038\nAcknowledgements\nWe are most grateful to all of the patients who participated in the present study and also sincerely thank Dr. Suresh Govatati for sample collection and DNA isolation.\nFunding\nThis work was supported in part by grants from the SERB (DST), India (Lr. No: SR/FT/LS-188/2009) and OU-DST PURSE Programme-II (DST Sanction No. SR/PURSE Phase 2/32 (G)), Department of Science and Technology (DST), India to Dr. Manjula Bhanoori.\nAuthor information\nAuthors and Affiliations\nContributions\nKVV: execution of experiments, analysis and interpretation of data, statistical analysis and drafting of manuscript. SS: data analysis. MD: acquisition of data. SS: analysis and interpretation of data, drafting of manuscript. MB: conception and design of study, analysis and interpretation of data, statistical analysis, drafting of manuscript. All authors will have seen and agreed to the ‘Author Contribution’ statement.\nCorresponding author\nEthics declarations\nConflict of interest\nThe authors declare that there is no conflict of interest.\nEthical approval\nThe study was approved by the ethical committee and review board of Centre of Cellular and Molecular biology (CCMB), Hyderabad. In the study all the participants were of South Indian origin (Dravidian linguistic group).\nInformed consent\nInformed written consent form was obtained from all subjects prior to participation in this study.\nAdditional information\nPublisher's Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nSupplementary Information\nBelow is the link to the electronic supplementary material.\nRights and permissions\nAbout this article\nCite this article\nVeena, K.V., Siddamalla, S., Deenadayal, M. et al. DNMT1 and DNMT3B gene variants and their association with endometriosis in South Indian women. Mol Biol Rep 49, 321–329 (2022). https://doi.org/10.1007/s11033-021-06877-x\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s11033-021-06877-x","source_license":"CC0","license_restricted":false}