Association between single nucleotide polymorphism of the CYP19A1 and ESR2 genes and endometriosis

Purpose Endometriosis is a frequent gynaecological condition, both in Poland and in the world. The development of this disease is supported by hormonal, immunological and environmental factors. During the recent years, a particular attention has been focused on the genetic polymorphisms which may be of particular significance for the increased incidence rates of endometriosis. According to literature data, Oestrogen Receptor 2 (ESR2) and Cytochrome P450 Family 19 Subfamily A Member 1 (CYP19A1) genes may be accounted to the potential risk factors of infertility associated with endometriosis. The reported research was aimed to evaluate the association between single nucleotide polymorphisms (SNPs) rs17179740 of ESR2 and rs2899470 of CYP19A1 genes and the incidence of endometriosis.

The study material included blood specimens, collected from patients (n = 200) with endometriosis. Blood samples from age-matched, endometriosis-free women (n = 200) served as control. The High-Resolution Melter (HRM) technique was applied for polymorphism analysis.

Regarding rs2899470 polymorphism TT homozygotes was significantly more prevalent among the patients with endometriosis than in the controls (OR 2.19; p = 0.04). In case of rs17179740, GG homozygotes, as well as AG-AA genotypes, were significantly more prevalent among the endometriosis patients (OR 2.48, p = 0.04 and OR 2.36, p = 0.04, respectively).

Summing up, the investigated polymorphisms of ESR2 and CYP19A1 gene are associated with the observed incidence of endometriosis. Similar content being viewed by others Availability of data and material All data generated and/or analyzed during this study are included in this published article. Code availability Data will not be shared, because they are part of a clinical database. Abbreviations - CI: - Confidence intervals - CYP19A1 : - Cytochrome P450 Family 19 Subfamily A Member 1 - ESR2 : - Estrogen receptor 2 - HRM: - High-resolution melter - OR: - Odds ratios - rASRM: - The Revised American Society for Reproductive Medicine - SNP: - Single nucleotide polymorphism

Defrère S, Lousse JC, González-Ramos R, Colette S, Donnez J, Van Langendonckt A (2008) Potential involvement of iron in the pathogenesis of peritoneal endometriosis. Mol Hum Reprod 14:377–385 May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM (2010) Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update 16:651–674 Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Kado N, Tsukamoto K, Hasegawa G, Nakamura N, Honjo H (2001) Oestrogen recepto-34. r-alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata. Hum Reprod 16:51–55 Wieser F, Schneeberger C, Tong D, Tempfer C, Huber JC, Wenzl R (2002) PROGINS receptor gene polymorphism is associated with endometriosis. Fertil Steril 77:309–312 Baranova H, Canis M, Ivaschenko T, Albuisson E, Bothorishvilli R, Baranov V, Malet P, Bruhat MA (1999) Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 genes in the development of endometriosis. Mol Hum Reprod 5:636–641 Hadfield RM, Manek S, Weeks DE, Mardon HJ, Barlow DH, Kennedy SH (2001) OXEGENE Collaborative Group. Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes gSTM1, gSTT1 and Cyp1a1. Mol Hum Reprod 7:1073–1078 Nakago S, Hadfield RM, Zondervan KT, Mardon H, Manek S, Weeks DE, Barlow D, Kennedy S (2001) Association between endometriosis and N-acetyl transferase 2 polymorphisms in a UK population. Mol Hum Reprod 7:1079–1083 Arvanitis DA, Koumantakis GE, Goumenou AG, Matalliotakis IM, Koumantakis EE, Spandidos DA (2003) Cyp1a1, Cyp19, and gSTM1 polymorphisms increase the risk of endometriosis. Fertil Steril 79:702–709 Means GD, Mahendroo MS, Corbin CJ, Mathis JM, Powell FE, Mendelson CR, Simpson ER (1989) Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. J Biol Chem 264:19385–19391 Tworoger SS, Chubak J, Aiello EJ, Ulrich CM, Atkinson C, Potter JD, Yasui Y, Stapleton PL, Lampe JW, Farin FM, Stanczyk FZ, McTiernan A (2004) Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women. Cancer Epidemiol Biomarkers Prev 13:94–101 Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E, Novik KL, Kelemen L, Ogata S, Pharoah PD, Easton DF, Day NE, Ponder BA (2005) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 97:153–154 Petry CJ, Ong KK, Michelmore KF, Artigas S, Wingate DL, Balen AH, de Zegher F, Ibáñez L, Dunger DB (2005) Association of aromatase (CYP19) gene variation with features of hyperan-drogenism in two populations of young woman. Hum Reprod 20:1837–1843 Vietri MT, Cioffi M, Sessa M, Simeone S, Bontempo P, Trabucco E, Ardovino M, Colacurci N, Molinari AM, Cobellis L (2009) CYP17 and CYP19 gene polymorphisms in women affected with endometriosis. Fertil Steril 92:1532–1535 Cardoso JV, Machado DE, Ferrari R, Silva MCD, Berardo PT, Perini JA (2017) Combined effect of the PGR +331C > T, CYP17A1 -34A > G and CYP19A1 1531G > a polymorphisms on the risk of developing endometriosis. Rev Bras Ginecol Obstet 39:273–281 Tuo Y, Yang J, Chen XJ, Liu F (2019) Correlation between polymorphism of CYP19A1, GSTM1, GSTT1 and GSTP1 gene and endometriosis. Zhonghua Yi Xue Za Zhi 99:515–519 Lee H, Lee IS, Choue R (2013) Obesity, inflammation and diet. Pediatr Gastroenterol Hepatol Nutr 16:143–152 Lee L, Asada H, Kizuka F, Tamura I, Maekawa R, Taketani T, Sato S, Yamagata Y, Tamura H, Sugino N (2013) Changes in histone modification and DNA methylation of the StAR and Cyp19a1 promoter regions in granulosa cells undergoing luteinization during ovulation in rats. Endocrinology 154:458–470 Bowers LW, Maximo IX, Brenner AJ, Beeram M, Hursting SD, Price RS, Tekmal RR, Jolly ChA, de Graffenried LA (2014) NSAID use reduces breast cancer recurrence in overweight and obese women: role of prostaglandin-aromatase interactions. Cancer Res 74:4446–4457 Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjold M, Gustafsson JA (1997) Human estrogen receptor beta-gene structure, chromosomal localization, and expressionpattern. J Clin Endocrinol Metab 82:4258–4265 Tsukamoto K, Inoue S, Hosoi T, Orimo H, Emi M (1998) Isolation and radiation hybrid mapping of dinucleotide repeat polymorphism at the human estrogen receptor beta locus. J Hum Genet 43:73–74 Khattri A, Pandey RK, Gupta NJ, Chakravarty B, Deenadayal M, Singh L, Thangaraj K (2009) Estrogen receptor beta gene mutations in Indian infertile men. Mol Hum Reprod 15:513–520 Wang W, Li Y, Maitituoheti M, Yang R, Wu Z, Wang T, Ma D, Wang S (2013) Association of an oestrogen receptor gene polymorphism in Chinese Han women with endometriosis and endometriosis-related infertility. Reprod Biomed Online 26:93–98 Szaflik T, Smolarz B, Romanowicz H, Bryś M, Forma E, Szyłło K (2020) Polymorphisms in the 3’UTR Region of ESR2 and CYP19A1 Genes in Women With Endometriosis. Eur J Obstet Gynecol Reprod Biol 250:241–245 Mafra FA, Bianco B, Christofolini DM, Souza AM, Zulli K, Barbosa CP (2010) Luteinizing hormone beta-subunit gene (LHbeta) polymorphism in infertility and endometriosis-associated infertility. Eur J Obstet Gynecol Reprod Biol 151:66 Zulli K, Bianco B, Mafra FA, Teles JS, Christofolini DM, Barbosa CP (2010) Polymorphism of the estrogen receptor β gene is related to infertility and infertility-associated endometriosis. Arq Bras Endocrinol Metabol 54:567 Ruiz LA, Dutil J, Ruiz A, Fourquet J, Abac S, Laboy J, Flores I (2011) Single nucleotide polymorphisms in the lysyl oxidase-like protein 4 and complement component 3 genes are associated with increased risk for endometriosis and endometriosis-associated infertility. Fertil Steril 96:512 Zhang H, Zhang Z, Li G, Wang S, Zhang S, Xie B (2015) Association of FCRL3 genetic polymorphisms with endometriosis-related infertility risk: an independent study in Han Chinese. Medicine (Baltimore) 94:e1168 Chang CY, Chen Y, Lin WC, Chen CM, Chen CP, Lee SC, Jinn-Chyuan Sheu J, Tsai FJ (2012) MUC2 polymorphisms are associated with endometriosis development and infertility: a case-control study. BMC Med Genet 13:15 Peluso C, Christofolini DM, Goldman CS, Mafra FA, Cavalcanti V, Barbosa CP, Bianco B (2013) TYK2 rs34536443 polymorphism is associated with a decreased susceptibility to endometriosis-related infertility. Hum Immunol 74:93 Kang S, Li Y, Li B, Wang N, Zhou RM, Zhao XW (2014) Genetic variation of the E-cadherin gene is associated with primary infertility in patients with ovarian endometriosis. Fertil Steril 102:1149 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Misztal M, Jagodziński PP (2015) Polymorphic variants in vitamin D signaling pathway genes and the risk of endometriosis-associated infertility. Mol Med Rep 12:7109 Yang CW, Chang CY, Lai MT, Chang HW, Lu CC, Chen Y, Chen ChM, Lee SCh, Tsai PW, Yang SH, Lin ChH, Chyuan Sheu JJ, Tsai FJ (2015) Genetic variations of MUC17 are associated with endometriosis development and related infertility. BMC Med Genet 16:60 Cavalcanti V, Ponce TG, Mafra FA, André GM, Christofolini DM, Barbosa CP, Bianco B (2016) Evaluation of the frequency of G-765C polymorphism in the promoter region of the COX-2 gene and its correlation with the expression of this gene in the endometrium of women with endometriosis. Arch Gynecol Obstet 293:109 Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87:905–931 Mansur Ade P, Nogueira CC, Strunz CM, Aldrighi JM, Ramires JA (2005) Genetic polymorphisms of estrogen receptors in patients with premature coronary artery disease. Arch Med Res 36:511–517 Nott SL, Huang Y, Fluharty BR, Sokolov AM, Huang M, Cox C, Muyan M (2008) Do estrogen receptor beta polymorphisms play a role in the pharmacogenetics of estrogen signaling? Curr Pharmacogenomics Person Med 6:239–259 Wang Z, Yoshida S, Negoro K, Kennedy S, Barlow D, Maruo T (2004) Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha gene affect the risk of developing endometriosis in a japanese population. Fertil Steril 81:1650–1656 Bulun SE, Zeitoun KM, Kilic G (2000) Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues. Am J Obstet Gynecol 182:767–775 Ahsan H, Whittemore AS, Chen Y, Senie RT, Hamilton SP, Wang Q, Gurvich I, Santella RM (2005) Variants in estrogen-biosynthesis genes CYP17 and CYP19 and breast cancer risk: a family-based genetic association study. Breast Cancer Res 7:R71-81 Berstein LM, Imyanitov EN, Kovalevskij AJ, Maximov SJ, Vasilyev DA, Buslov KG, Sokolenko AP, Iyevleva AG, Chekmariova EV, Thijssen JH (2004) CYP17 and CYP19 genetic polymorphisms in endometrial cancer: association with intratumoral aromatase activity. Cancer Lett 207:191–196 Kado N, Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Tsukamoto K, Hasegawa G, Nakamura N, Yoshikawa T, Honjo H (2002) Association of the CYP17 gene and CYP19 gene polymorphisms with risk of endometriosis in Japanese women. Hum Reprod 17:897–902 Tuo Y, He JY, Yan WJ, Yang J (2016) Association between CYP19A1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and the development of endometriosis in a Chinese population. Genet Mol Res 19:15

Authors acknowledge the financial support provided by the Institute of Polish Mother’s Memorial Hospital, Lodz, Poland, to conduct the study. Thank Bożena Góralczyk M.D. Ph.D. and Tomasz Szaflik M.D. Ph.D. for help in collecting research material. Funding This work was supported by the Institute of Polish Mother’s Memorial Hospital, Lodz, Poland from the Statutory Development Fund. Author information Authors and Affiliations Contributions Conceived and designed the experiments: BS. Performed the experiments – case group: BS. Case group design and collect: HR. Performed the experiments – control group: BS. Analysed data: BS. Contributed reagents/materials/analysis tools BS. Contributed to the writing of manuscript: BS. All authors approved the final manuscript. Corresponding author Ethics declarations Conflict of interests Authors declare no conflict of interest. Author Beata Smolarz declares that she has no conflict of interest. Author Hanna Romanowicz declares that she has no conflict of interest. Ethics approval and consent to participate This work was supported by the Institute of Polish Mother’s Memorial Hospital, Lodz, Poland from the Statutory Development Fund. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent to participate Informed consent was obtained from all individual participants included in the study. A formal consent was also issued by the Bioethical Committee of the Institute of the Polish Mother’s Memorial Hospital in Lodz (Approval number, 8/2016). The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Consent for publication Informed consent was obtained from all individual participants included in the study. A formal consent was also issued by the Bioethical Committee of the Institute of the Polish Mother’s Memorial Hospital in Lodz (Approval number, 8/2016). Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions About this article Cite this article Smolarz, B., Romanowicz, H. Association between single nucleotide polymorphism of the CYP19A1 and ESR2 genes and endometriosis. Arch Gynecol Obstet 304, 439–445 (2021). https://doi.org/10.1007/s00404-021-06051-5 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s00404-021-06051-5