Causal relationship between selectins and endometriosis: a Mendelian randomization study

Causal relationship between selectins and endometriosis: a Mendelian randomization study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Causal relationship between selectins and endometriosis: a Mendelian randomization study Juan Chen, Jie Zhou, LinJie Su, Hongbo Hu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4160567/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective : Previous observational research has indicated an association between plasma selectin family members and endometriosis, and our objective was to investigate the causal association between selectins and endometriosis. Methods : Using pooled statistics from genome-wide association studies of predominantly European ancestry and utilizing Mendelian randomization (MR), we analyzed the causal effect of the selectins E/P/L on endometriosis and the causal association of selectins with endometriosis at different sites. Results : This study revealed a causal relationship between E-selectin and endometriosis (ratio of 0.92, 95% CI (0.86, 0.98) p = 0.01). And the causal relationship between selectins and endometriosis at different sites. Conclusion : Our genetic predictions suggest that higher levels of selectins may provide protection against endogamy and may serve as therapeutic targets in the future. Introduction Endometriosis is a common chronic disease affecting multiple systemic organs throughout the body in women of reproductive age and potentially leads to infertility, dysmenorrhea, pelvic adhesions, gastrointestinal issues such as diarrhea and constipation, heightened anxiety, fatigue, severe depression, and other associated complications(Anon, 2012; Brawn et al., 2014; Chen et al., 2016; Ramin-Wright et al., 2018). Moreover, it poses a risk of malignancy(Giannella et al., 2021), imposes a significant economic burden and is recognized as a substantial public health concern(Chen et al., 2020; Simoens et al., 2012; Wang et al., 2022). The prevailing theory attributes its development to the retrograde flow of menstrual blood, wherein endometrial cells adhere to the peritoneal surface, proliferate, and invade surrounding tissues. Additionally, altered immune and inflammatory responses are implicated(Du et al., 2017; Harris et al., 2016), although further research is warranted to fully elucidate the pathophysiology. Selectins are Ca^2+-dependent lectins that constitute a trio of carbohydrate-binding proteins found on endothelial cells, leukocytes, and platelets. These selectins, namely, E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L), are members of the C-type lectin family(Tedder et al., 1995). They play critical roles in intercellular and cell-to-matrix adhesion processes. Selectins facilitate initial adhesion and are pivotal amidst the shift from rapid to slow rolling of leukocytes preceding their firm adhesion to endothelial cells. Their interactions with ligands modulate various physiological and pathological processes(Crockett-Torabi & Fantone, 1995; Ivetic et al., 2019; Purdy et al., 2022), including cell migration, adhesion, and signaling. Previous investigations have delineated the dual role of selectins. They participate in recognizing inflammatory factors, thus facilitating the recruitment of immune cells to sites of inflammation and thereby restraining pathological inflammation(Pethaperumal et al., 2022; Spertini et al., 1991). Conversely, selectins have been implicated in promoting cancer metastasis. Studies have revealed a strong correlation between the expression of ligands of selectins in cancer cells and the incidence of metastasis, as well as poor prognosis, among cancer patients(Läubli & Borsig, 2010). However, the association between selectins and endometriosis remains uncertain. While L. Kusel et al. proposed intercellular adhesion molecules as potential biomarkers for diagnosing endometriosis, another study revealed no significant differences in serum selectin levels between women who have endometriosis and those who do not(Kuessel et al., 2017).Additional investigations are warranted to clarify the connection between selectins and endometriosis(Proestling et al., 2020). Recently, two-sample Mendelian randomization (MR) analysis has emerged as a reliable method for revealing causality and exploring the influence of factors related to exposure on a range of diseases. Mendelian randomization leverages genetic variation as an instrumental variable (IV) to assess causality between exposure factors and disease, effectively controlling for genetic and environmental confounders. Through this method, which entails gathering data on exposure and results from distinct samples to estimate causal effects, we can enhance our comprehension of the complex associations between selectins and endometriosis. Materials and methods Study Design MR analyses hinge upon three primary assumptions: ( 1 ) instrumental variables (IVs) must demonstrate a strong correlation with factors related to exposure, and ( 2 ) IVs must remain unaffected by confounding factors. ( 3 ) IVs should solely impact outcomes through exposure pathways(Davies et al., 2018). Initially, we identified three selectins derived from publicly accessible GWAS data and subsequently selected instrumental variables for each selectin utilizing pooled statistics from GWAS. Subsequently, MR analyses were conducted using pooled genome-wide association study (GWAS) data from two distinct cohorts—the European Molecular Biology Laboratory (EMBL-EBI) and FinnGen—to assess the causal influence of selectins on endometriosis. Furthermore, MR analyses were conducted to evaluate the cause-and-effect associations between selectins and the probability of various endometriosis sub phenotypes, including pelvic peritoneal endometriosis, endometriosis associated with infertility, tubal endometriosis, intestinal endometriosis, unspecified/other sites of endometriosis, ovarian endometriosis, rectovaginal diaphragm involvement, vaginal endometriosis, and uterine endometriosis, among others. GWAS summary data for exposure To explore the causative link between selectins and the risk of endometriosis, we will collect data on genetic variation in selectins and endometriosis from GWASs for use as a dataset. Datasets typically contain a large number of individual samples, genotype data, and sizes of effects related to the disease. We examined the IEU Open GWAS ( https://gwas.mrcieu.ac.uk/ ), compiling a large number of overviewing statistics from numerous GWASs. We systematically analyzed endometriosis samples collected from two large cohorts, the EMBL-EBI cohort and the FinnGen cohort. Summary statistics from Genome-Wide Association Studies (GWAS) for endometriosis in European individuals from EMBL-EBI were obtained from using the GWAS ID " ebi-a-GCST90018839 ", e.g., the IEU OpenGWAS database, and in the FinnGen cohort can be found in the R package TwoSampleMR (v0.5.6)(Hemani et al., 2018),accessed using the GWAS ID "finn-b-N14_ENDOMETRIOSIS", e.g., the IEU OpenGWAS database ( https://gwas.mrcieu.ac.uk/ ). In EMBL-EBI, the diagnosis of endometriosis is defined according to N80 in the International Classification of Diseases, 10th edition (ICD-10).Endometriosis GWAS in EMBL-EBI included 4511 cases and 227,260 female controls. In FinnGen, endometriosis is defined as N80 in the ICD-10, 617 in the ICD-9, and 6253 in the ICD-8. The pooled statistics of FinnGen's endometriosis GWAS included 8288 cases and 68,969 controls. We also curated data on endometriosis from different sites within the FinnGen cohort in the GWAS database, including endometriosis (2,372 cases, 68,969 controls), ovarian endometriosis (3,231 cases, 68,969 controls), tubal endometriosis (116 cases, 68,969 controls), and pelvic peritoneal endometriosis (2951 cases, 2959 controls) data. endometriosis (2,953 patients, 68,969 controls), rectovaginal septum and vaginal endometriosis (1,360 patients, 68,969 controls), intestinal endometriosis (177 patients, 68,969 controls), unspecified/other endometriosis (1,435 patients, 68,969 controls), and endometriosis combined with infertility (1, 593 patients, 70,651 controls). Instrumental Variable Selection In our two-sample Mendelian randomization study, we employed genetic variants associated with selectins as instrumental variables (IVs) to generate summary statistics, applying a genome-wide threshold of 5.00E-06. Initially, we identified 18, 79, and 27 SNPs associated with endometriosis at P < 1 × 10 − 5 for E-selectin, P-selectin, and L-selectin, respectively. These 124 SNPs were chosen as IVs for the three selectins, and 119 SNPs associated with endometriosis at P < 5 × 10 − 8 were identified. 119 SNPs associated with endometriosis. SNPs with linkage disequilibrium (LD) were excluded from the analysis. The LD of the selected SNPs strongly associated with endometriosis should satisfy r2 < 0.001 with a window size of 10,000 kb(Myers et al., 2020). A significant step in the MR analysis was to ensure that the effect of the SNP on exposure corresponded to the effect of the identical allele on the outcome. Following the alignment of outcomes, IVs located within palindromic sequences were excluded. We extracted pertinent details, including chromosome, effect allele (EA), alternate allele (OA), effect allele frequency (EAF), effect size (β), standard error (SE), and p-value. Subsequently, we computed the explained variance (R^2) and F-statistic to assess the strength of association between the identified instrumental variables (IVs) and the exposure. Generally, SNPs with F-statistic parameters < 10 were regarded as weak instruments(Burgess et al., 2017). The formula used for computing the F statistic was F = R^2 × n-k-1/k × (1-R^2), where n represents the sample size, k represents the number of IVs used, and R^2 signifies the proportion of exposure variance explained by the IVs. Mendelian analysis Preliminary analysis To estimate the causal effect of selectins on endometriosis, we performed MR analyses on two separate samples. The inverse variance weighted (IVW) method is the basic analytical method, and the Wald ratio test includes only the characteristics of one IV(Burgess et al., 2013). MR results are expressed as the dominance ratio (OR) and the corresponding 95% confidence interval (CI). The results were statistically significant when the p-value for IVW was less than 0.05 and when the IVW and MR-Egger were in the same direction. Bidirectional causal analysis To assess the bidirectional causality of endometriosis and selectin, we used endometriosis as the "exposure" and selectin as the "outcome". We selected SNPs substantially associated with endometriosis (P < 5*10 − 8) as IVs. Sensitivity analysis In this study, we used multiple methods to evaluate heterogeneity and horizontal pleiotropy among SNPs. We applied Cochran's Q-statistic, funnel plots, MR‒Egger intercepts, and MR-PRESSO to detect and resolve outliers, as well as a random-effects model to assess the stability of the results(Burgess & Thompson, 2017; Cohen et al., 2015; Verbanck et al., 2018). In addition, a single analysis was conducted to validate the effect of each SNP on the overall causal estimate. Together, these methods helped to ensure the confidence and robustness of the MR analyses. All the statistical analyses were performed using R (version 4.2.3) combined with the TwoSampleMR and MR-PRESSO software packages(Ong & MacGregor, 2019). Results Effect of selectins on endometriosis MR analysis revealed that among the three selectins in the FinnGen database, the genetic prediction of E-selectin (OR = 0.92, 95% CI (0.86, 0.98), p = 0.015) was associated with a reduced risk of endometriosis, whereas the same conclusion was reached with the EMBL-EBI databaseTable 2, where the genetic prediction of E-selectin was correlated. However, P-selectin (OR = 1.01, 95% CI (0.90, 1.13), p = 0.871) and L-selectin (OR = 1.04, 95% CI (0.94, 1.15), p = 0.493) were not significantly differentTable 1. Table 1 MR analysis of causal effects of selectin on endometriosis exposure outcom No.of SNP OR(95%CI) P-value E-selectin Endometriosis 2 0.92(0.86,0.98) 0.015 L-selectin Endometriosis 3 1.01(0.90,1.13) 0.871 P-selectin Endometriosis 5 1.04(0.94,1.15) 0.493 Causal effect of E-selectin on endometriosis at different sites MR analysis indicated that genetic prediction of E-selectin was associated with pelvic peritoneal endometriosis (OR = 0.86, 95% CI (0.80, 0.92), p = 0.001), endometriosis combined with infertility (OR = 0.84, 95% CI (0.76, 0.92), p = 0.003), intestinal surface endometriosis (OR = 0.70 95% CI (0.51, 0.96), p = 0.046), unspecified/other endometriosis (OR = 0.85, 95% CI (0.75, 0.96), p = 0.023), ovarian endometriosis (OR = 0. 92 (95% CI (0.86, 0.99), p = 0.037), rectovaginal diaphragm and vaginal uterine endometriosis (OR = 0.88, 95% CI (0.79, 0.97), p = 0.036) were associated with a reduced risk, while the associations with uterine endometriosis (OR = 0.97, 95% CI (0.90, 1.05), p = 0.499) and tubal endometriosis (OR = 0.24, 95% CI (0.04, 1.30), p = 0.131) were not statistically significantTable 3. Table 2 MR analysis of the causal effects of E-selectin on endometriosis outcome MR method No.of SNP OR (95%CI) P-value finn-b-N14_ENDOMETRIOSIS MR Egger 14 0.92(0.88,0.96) 0.004 Weighted median 14 0.92(0.89,0.95) 0.000 Inverse variance weighted 14 0.92(0.89,0.95) 0.000 ebi-a-GCST90018839 MR Egger 16 0.94(0.90,0.99) 0.035 Weighted median 16 0.94(0.90,0.97) 0.001 Inverse variance weighted 16 0.94(0.91,0.97) 0.000 finn-b-N14_ENDOMETRIOSIS:E-selectin from the FinnGen cohort;ebi-a-GCST90018839:E-selectin from the EMBL-EBI cohort. Table 3: MR analysis of the causal effects of E-selectin on different typesendometriosis Discussion In this study, using pooled statistics from two large European GWASs, the European Molecular Biology Laboratory and FinnGen, we investigated the causal effect of three selectins on the risk of endometriosis using a harmonized MR framework to analyze GWAS data. Our results suggest a causal relationship between E-selectin and endometriosis, revealing that E-selectin reduces the risk of endometriosis. In addition, MR analysis revealed a causal relationship between different subphenotypes of endometriosis categorized by the location of the ectopic site, and our study suggested that E-selectin reduces the risk of pelvic peritoneal endometriosis, endometriosis combined with infertility, intestinal surface endometriosis, unspecified/other endometriosis, ovarian endometriosis, rectovaginal diaphragm, and vaginal endometriosis. These findings have considerable implications for the advancement of endometriosis management. Although endometriosis is histologically benign, it is characterized by malignant tumors such as rapid proliferation, infiltration, metastasis, and easy recurrence and is known as "immortal cancer". Although various factors contributing to the onset of endometriosis have been elucidated, the exact etiology, pathogenesis and treatment of endometriosis are still unclear and contentious(Saunders & Horne, 2021; Wang et al., 2020). The development of effective preventive and therapeutic strategies for endometriosis requires an in-depth understanding of this disease. Sampson introduced the retrograde menstruation theory, positing that menstrual blood carrying endometrial cells refluxes through the fallopian tubes into the pelvic cavity rather than being discharged from the body, resulting in the development of ectopic endometriotic lesions. Although Sampson's theory enjoys widespread acceptance, various alternative hypotheses have been advanced, including hypotheses regarding stem cell derivation and immune system modifications(Maruyama, 2022; Shigesi et al., 2019). Endometriosis is believed to arise from a multifaceted interplay of genetic, anatomical, environmental, and immunological elements(Burney, 2013; Vercellini et al., 2014; Wang et al., 2020). Although the origins of endometriosis remain debated, there is broad consensus that this condition entails a localized inflammatory reaction, with vascularization at the site of endometriotic invasion pivotal to lesion formation(Koninckx et al., 2021). Remarkably, selectins have emerged as significant players in regulating the inflammatory cascade(Guo et al., 2015; Tvaroška et al., 2020). Currently, the role of selectins in the pathogenesis of endometriosis is unclear. It has been suggested that selectins are cell adhesion molecules that, like other molecules, are responsible for initiating leukocyte extravasation during the inflammatory response. Upregulation of these cell adhesion molecules leads to increased endometrial cell invasiveness, which not only causes endothelial cell adhesion but also increases angiogenesis, leading to macrophage extravasation. Abdominal pain during menstruation is also a result of the inflammatory nature of the pain caused by the disease(Schmidt et al., 2000). The study also revealed that only a few E-selectins are expressed in endometriosis tissues, that this expression is overall very weak, and that overexpression induces an inflammatory response, thereby exacerbating endometriosis. Whereas circulating levels of soluble E-selectin or E-selectin expressed on the endothelial surface usually correlate with the duration and/or severity of inflammatory disease, suggesting a role for E-selectin in the etiology or progression of the disease(Barthel et al., 2007), this finding contradicts the conclusions that we reached in our study. However, other studies have shown that the inflammatory response can lead to the upregulation of the expression of E-selectin, which recruits leukocytes, promotes inflammatory cell infiltration of the vessel wall, and promotes differentiation into macrophages, which produce proteases that promote the breakdown of ectopic endothelial tissues(Tabas & Bornfeldt, 2016). Liu ZJ et al. demonstrated that signaling molecules mediating vascular E-selectin downregulation also inhibit circulating endothelial cell homing, tumor angiogenesis, and tumor growth. Therefore, the intrapelvic environment and angiogenesis of ectopic lesions reduce endometriosis development. In addition, E-selectin enhances leukocyte resistance to shear adhesion(Liu et al., 2011), thereby reducing the implantation of endometriotic foci(Kang et al., 2016). The expression or aberrant expression of selectins can have a tremendous impact on various aspects of cell adhesion, migration, inflammatory response, signaling, immune homeostasis, and tissue repair, which in turn affects the onset and progression of endometriosis; thus, selectins can be important regulators of the development of endometriosis. An in-depth understanding of the causal relationship between selectins and endometriosis can help to unravel the pathophysiologic process of this disease and provide new targets and strategies for its treatment. Although it is still in the early stages, several studies have explored the possibility of utilizing selectin modulation for the treatment of endometriosis. We can reduce the symptoms of endometriosis patients by inhibiting the selectin signaling pathway and affecting the ability of selectins to bind to their ligands, reduce adhesion and migration between leukocytes and endothelial cells, and participate in the inflammatory response and tissue repair process. Second, by regulating the inflammatory response, selectins are involved in regulating the inflammatory response, and their aberrant expression may lead to the onset and exacerbation of pelvic inflammation, which in turn affects the development of endometriosis. Modulation of the inflammatory response may become another strategy for the treatment of endometriosis. In addition, blocking angiogenesis and thus reducing nutritional support to endometriotic lesions may also help to slow the progression of endometriosis. Exploring the mechanisms of targeted selectin-selectin ligand interactions could also have a great impact on the management of endometriosis. Future studies should also design additional experiments and methods to further elucidate the relationship between selectins and endometriosis and provide more effective strategies and approaches for the treatment and management of endometriosis. To sum up, the causal role of E-selectin in endometriosis was confirmed in our study. Despite the use of two-sample data, further independent validation of these causal relationships is warranted. Moreover, considering the underlying pathophysiology of endometriosis, additional experimental validation is imperative to obtain a more thorough understanding of the molecular mechanisms and functions of these selectins in the development of endometriosis. This study has several strengths. First, by capitalizing on the random assignment of genetic variation during the formation of gametes and fertilization, the findings of the Mendelian randomization analysis are less vulnerable to confounding influences and causality reversal. Second, we employed distinct datasets for exposure (selectin) and outcome (endometriosis) measurements, ensuring two-sample MR analyses and thus minimizing biases that may inflate the significance of weak instrumental variables. Third, the consistent estimates of the cause-and-effect relationship of E-selectin on endometriosis across the two primary cohorts, namely, the UK Molecular Biology Laboratory and FinnGen, mitigate concerns regarding false-positive findings. Finally, we conducted various complementary analyses, including assessments of heterogeneity, multiplicity, and leave-one-out sensitivity, to test the plausibility of hypotheses pertaining to instrumental variables. However, it is our necessity to recognize specific limitations. First, within the setting of endometriosis, a condition predominantly affecting females, existing genome-wide association studies (GWASs) investigating various E-selectins have been conducted with an inherent bias toward sex combinations. Given that two-sample Mendelian randomization (MR) requires coherence in the underlying populations of both sets of samples, potential disparities in genetic estimations of E-selectin between females and males must be considered. Such differences may introduce bias into the results of our MR study. Second, since this study exclusively involved individuals of European descent, its findings may not be readily generalizable to other demographic groups. Further investigations into the causal among coagulation factors and endometriosis within diverse populations are warranted. Conclusion To the best of our knowledge, this study represents inaugural investigation utilizing Mendelian randomization to study the causal connection between selectins and the risk of endometriosis within a European population. Our results substantiate a causal link between E-selectin and susceptibility to endometriosis and its various subtypes. These findings hold considerable significance for the formulation of strategies targeting both the prevention and treatment of endometriosis. Declarations Acknowledgements The authors express their gratitude to the participants and investigators of the FinnGen Study and EMBL-EBI Study. The authors also appreciate the ieu open gwsa project for providing the selectins and endometriosis GWAS summary statistics. Authors’ contributions Hongbo Hu,Jie Zhou,JuanChen contributed to the concept and design of the study. Juan Chen,Jie Zhou was responsible for statistical analysis and writing of the manuscript. Hongbo Hu,Jie Zhou,Juan Chen, LinJie Su assisted with the statistical analysis. All authors have read and approved the final manuscript. Funding This study was no funded. Data availability The datasets analyzed during the current study are available in the ieu gwas project (https://gwas.mrcieu.ac.uk/) . Declarations Ethics approval and consent to participate. Our analysis used publicly available genome-wide association study (GWAS) summary statistics. No new data were collected, and no new ethical approval was required. Consent for publication. Not applicable. Competing interests The authors declare no competing interests. References Anon. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98(3):591–8. https://doi.org/10.1016/j.fertnstert.2012.05.031 . Barthel SR, Gavino JD, Descheny L, Dimitroff CJ. Targeting selectins and selectin ligands in inflammation and cancer. Expert Opin Ther Targets. 2007;11(11):1473–91. https://doi.org/10.1517/14728222.11.11.1473 . Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update. 2014;20(5):737–47. https://doi.org/10.1093/humupd/dmu025 . Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658–65. https://doi.org/10.1002/gepi.21758 . Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017;26(5):2333–55. https://doi.org/10.1177/0962280215597579 . Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377–89. https://doi.org/10.1007/s10654-017-0255-x . Burney RO. The genetics and biochemistry of endometriosis. Curr Opin Obstet Gynecol. 2013;25(4):280–6. https://doi.org/10.1097/GCO.0b013e3283630d56 . Chen I, Thavorn K, Yong PJ, Choudhry AJ, Allaire C. Hospital-Associated Cost of Endometriosis in Canada: A Population-Based Study. J Minim Invasive Gynecol. 2020;27(5):1178–87. https://doi.org/10.1016/j.jmig.2019.09.771 . Chen LC, Hsu JW, Huang KL, Bai YM, Su TP, Li CT, Chen MH. Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal follow-up study. J Affect Disord. 2016;190:282–5. https://doi.org/10.1016/j.jad.2015.10.030 . Cohen JF, Chalumeau M, Cohen R, Korevaar DA, Khoshnood B, Bossuyt PM. Cochran's Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy. J Clin Epidemiol. 2015;68(3):299–306. https://doi.org/10.1016/j.jclinepi.2014.09.005 . Crockett-Torabi E, Fantone JC. The selectins: insights into selectin-induced intracellular signaling in leukocytes. Immunol Res. 1995;14(4):237–51. https://doi.org/10.1007/bf02935622 . Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. https://doi.org/10.1136/bmj.k601 . Du Y, Liu X, Guo SW. Platelets impair natural killer cell reactivity and function in endometriosis through multiple mechanisms. Hum Reprod. 2017;32(4):794–810. https://doi.org/10.1093/humrep/dex014 . Giannella L, Marconi C, Di Giuseppe J, Delli Carpini G, Fichera M, Grelloni C, Ciavattini A. Malignant Transformation of Postmenopausal Endometriosis: A Systematic Review of the Literature. Cancers (Basel). 2021;13(16). https://doi.org/10.3390/cancers13164026 . Guo SW, Ding D, Geng JG, Wang L, Liu X. P-selectin as a potential therapeutic target for endometriosis. Fertil Steril. 2015;103(4):990–e10001008. https://doi.org/10.1016/j.fertnstert.2015.01.001 . Harris HR, Costenbader KH, Mu F, Kvaskoff M, Malspeis S, Karlson EW, Missmer SA. Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses' Health Study II. Ann Rheum Dis. 2016;75(7):1279–84. https://doi.org/10.1136/annrheumdis-2015-207704 . Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, Haycock PC. The MR-Base platform supports systematic causal inference across the human phenome. Elife 7. 2018. https://doi.org/10.7554/eLife.34408 . Ivetic A, Green H, H. L., Hart SJ. L-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling. Front Immunol. 2019;10:1068. https://doi.org/10.3389/fimmu.2019.01068 . Kang SA, Blache CA, Bajana S, Hasan N, Kamal M, Morita Y, Tanaka T. The effect of soluble E-selectin on tumor progression and metastasis. BMC Cancer. 2016;16:331. https://doi.org/10.1186/s12885-016-2366-2 . Koninckx PR, Fernandes R, Ussia A, Schindler L, Wattiez A, Al-Suwaidi S, Tahlak M. Pathogenesis Based Diagnosis and Treatment of Endometriosis. Front Endocrinol (Lausanne). 2021;12:745548. https://doi.org/10.3389/fendo.2021.745548 . Kuessel L, Wenzl R, Proestling K, Balendran S, Pateisky P, Yotova H. (2017). Soluble VCAM-1/soluble ICAM-1 ratio is a promising biomarker for diagnosing endometriosis. Hum Reprod , 32 (4), 770–779. https://doi.org/10.1093/humrep/dex028 . Liu ZJ, Tian R, Li Y, An W, Zhuge Y, Livingstone AS, Velazquez OC. (2011). Inhibition of tumor angiogenesis and melanoma growth by targeting vascular E-selectin. Ann Surg , 254 (3), 450–456; discussion 456–457. https://doi.org/10.1097/SLA.0b013e31822a72dc . Läubli H, Borsig L. Selectins promote tumor metastasis. Semin Cancer Biol. 2010;20(3):169–77. https://doi.org/10.1016/j.semcancer.2010.04.005 . Maruyama T. A Revised Stem Cell Theory for the Pathogenesis of Endometriosis. J Pers Med. 2022;12(2). https://doi.org/10.3390/jpm12020216 . Myers TA, Chanock SJ, Machiela MJ. LDlinkR: An R Package for Rapidly Calculating Linkage Disequilibrium Statistics in Diverse Populations. Front Genet. 2020;11:157. https://doi.org/10.3389/fgene.2020.00157 . Ong JS, MacGregor S. Implementing MR-PRESSO and GCTA-GSMR for pleiotropy assessment in Mendelian randomization studies from a practitioner's perspective. Genet Epidemiol. 2019;43(6):609–16. https://doi.org/10.1002/gepi.22207 . Pethaperumal S, Hung SC, Lien TS, Sun DS, Chang HH. P-Selectin is a Critical Factor for Platelet-Mediated Protection on Restraint Stress-Induced Gastrointestinal Injury in Mice. Int J Mol Sci. 2022;23(19). https://doi.org/10.3390/ijms231911909 . Proestling K, Wenzl R, Yotova I, Hauser C, Husslein H, Kuessel L. Investigating selected adhesion molecules as urinary biomarkers for diagnosing endometriosis. Reprod Biomed Online. 2020;40(4):555–8. https://doi.org/10.1016/j.rbmo.2020.01.014 . Purdy M, Obi A, Myers D, Wakefield T. P- and E- selectin in venous thrombosis and non-venous pathologies. J Thromb Haemost. 2022;20(5):1056–66. https://doi.org/10.1111/jth.15689 . Ramin-Wright A, Schwartz ASK, Geraedts K, Rauchfuss M, Wölfler MM, Haeberlin F, Leeners B. Fatigue - a symptom in endometriosis. Hum Reprod. 2018;33(8):1459–65. https://doi.org/10.1093/humrep/dey115 . Saunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 2021;184(11):2807–24. https://doi.org/10.1016/j.cell.2021.04.041 . Schmidt M, Regidor PA, Engel K, Regidor M, Winterhager E, Scotti S, Schindler AE. E- and P-selectin expression in endometriotic tissues and the corresponding endometria. Gynecol Endocrinol. 2000;14(2):111–7. https://doi.org/10.3109/09513590009167669 . Shigesi N, Kvaskoff M, Kirtley S, Feng Q, Fang H, Knight JC, Becker CM. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum Reprod Update. 2019;25(4):486–503. https://doi.org/10.1093/humupd/dmz014 . Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, D'Hooghe T. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012;27(5):1292–9. https://doi.org/10.1093/humrep/des073 . Spertini O, Kansas GS, Munro JM, Griffin JD, Tedder TF. Regulation of leukocyte migration by activation of the leukocyte adhesion molecule-1 (LAM-1) selectin. Nature. 1991;349(6311):691–4. https://doi.org/10.1038/349691a0 . Tabas I, Bornfeldt KE. Macrophage Phenotype and Function in Different Stages of Atherosclerosis. Circ Res. 2016;118(4):653–67. https://doi.org/10.1161/circresaha.115.306256 . Tedder TF, Steeber DA, Chen A, Engel P. The selectins: vascular adhesion molecules. Faseb j. 1995;9(10):866–73. Tvaroška I, Selvaraj C, Koča J. Selectins-The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules-A Review. Molecules. 2020;25(12). https://doi.org/10.3390/molecules25122835 . Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8. https://doi.org/10.1038/s41588-018-0099-7 . Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75. https://doi.org/10.1038/nrendo.2013.255 . Wang Y, Nicholes K, Shih IM. The Origin and Pathogenesis of Endometriosis. Annu Rev Pathol. 2020;15:71–95. https://doi.org/10.1146/annurev-pathmechdis-012419-032654 . Wang Y, Wang X, Liao K, Luo B, Luo J. The burden of endometriosis in China from 1990 to 2019. Front Endocrinol (Lausanne). 2022;13:935931. https://doi.org/10.3389/fendo.2022.935931 . Additional Declarations No competing interests reported. Supplementary Files Eselectinendometriosis.zip Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4160567","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":284052772,"identity":"9348ac2a-d432-411e-a5e6-9f6c5da851fc","order_by":0,"name":"Juan Chen","email":"","orcid":"","institution":"Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Chen","suffix":""},{"id":284052775,"identity":"c2da3516-3df7-417c-aa2f-53598f2927c0","order_by":1,"name":"Jie Zhou","email":"","orcid":"","institution":"Yuebei People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Zhou","suffix":""},{"id":284052777,"identity":"0f1ce56d-86c7-4764-a656-e79947caeb77","order_by":2,"name":"LinJie Su","email":"","orcid":"","institution":"Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"LinJie","middleName":"","lastName":"Su","suffix":""},{"id":284052779,"identity":"ec509b1c-0883-47ea-8f50-67c400f30908","order_by":3,"name":"Hongbo Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYBACg8M8BgckDCTk2NibDxCnxbC9x/CBRYWFMR/PsQTitBjzHEs2qDhTkThPIkeBOC1mEsnHJG62SaS3MeQwMPyo2EZYi41EYpvkzDaJ3DaGswcYe87cJk6LtCRIC2NfAjNjGxFazOQftkn/BTqMjZnHgDgtxhKJzQYSZyQS2NiI1WI4I7HxgUSFhGEbD1vCQaL8YnAjsQEYlXXy8vMfH3zwo4IILSjgAInqR8EoGAWjYBTgAgDBYjuThrEAkAAAAABJRU5ErkJggg==","orcid":"","institution":"Yuebei People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hongbo","middleName":"","lastName":"Hu","suffix":""}],"badges":[],"createdAt":"2024-03-25 04:02:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4160567/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4160567/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76988787,"identity":"5568d547-668a-45cd-b2ca-e6e87173b4c0","added_by":"auto","created_at":"2025-02-24 04:32:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":675389,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4160567/v1/195e8f5d-4753-436b-a1f9-0d1bb9472832.pdf"},{"id":53702527,"identity":"d3bdc0e8-042d-4993-bd82-559e234442ec","added_by":"auto","created_at":"2024-03-29 05:51:41","extension":"zip","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":623885,"visible":true,"origin":"","legend":"","description":"","filename":"Eselectinendometriosis.zip","url":"https://assets-eu.researchsquare.com/files/rs-4160567/v1/42d64d613ea31608afd6c84c.zip"}],"financialInterests":"No competing interests reported.","formattedTitle":"Causal relationship between selectins and endometriosis: a Mendelian randomization study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a common chronic disease affecting multiple systemic organs throughout the body in women of reproductive age and potentially leads to infertility, dysmenorrhea, pelvic adhesions, gastrointestinal issues such as diarrhea and constipation, heightened anxiety, fatigue, severe depression, and other associated complications(Anon, 2012; Brawn et al., 2014; Chen et al., 2016; Ramin-Wright et al., 2018). Moreover, it poses a risk of malignancy(Giannella et al., 2021), imposes a significant economic burden and is recognized as a substantial public health concern(Chen et al., 2020; Simoens et al., 2012; Wang et al., 2022). The prevailing theory attributes its development to the retrograde flow of menstrual blood, wherein endometrial cells adhere to the peritoneal surface, proliferate, and invade surrounding tissues. Additionally, altered immune and inflammatory responses are implicated(Du et al., 2017; Harris et al., 2016), although further research is warranted to fully elucidate the pathophysiology.\u003c/p\u003e \u003cp\u003eSelectins are Ca^2+-dependent lectins that constitute a trio of carbohydrate-binding proteins found on endothelial cells, leukocytes, and platelets. These selectins, namely, E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L), are members of the C-type lectin family(Tedder et al., 1995). They play critical roles in intercellular and cell-to-matrix adhesion processes. Selectins facilitate initial adhesion and are pivotal amidst the shift from rapid to slow rolling of leukocytes preceding their firm adhesion to endothelial cells. Their interactions with ligands modulate various physiological and pathological processes(Crockett-Torabi \u0026amp; Fantone, 1995; Ivetic et al., 2019; Purdy et al., 2022), including cell migration, adhesion, and signaling. Previous investigations have delineated the dual role of selectins. They participate in recognizing inflammatory factors, thus facilitating the recruitment of immune cells to sites of inflammation and thereby restraining pathological inflammation(Pethaperumal et al., 2022; Spertini et al., 1991). Conversely, selectins have been implicated in promoting cancer metastasis. Studies have revealed a strong correlation between the expression of ligands of selectins in cancer cells and the incidence of metastasis, as well as poor prognosis, among cancer patients(L\u0026auml;ubli \u0026amp; Borsig, 2010). However, the association between selectins and endometriosis remains uncertain. While L. Kusel et al. proposed intercellular adhesion molecules as potential biomarkers for diagnosing endometriosis, another study revealed no significant differences in serum selectin levels between women who have endometriosis and those who do not(Kuessel et al., 2017).Additional investigations are warranted to clarify the connection between selectins and endometriosis(Proestling et al., 2020).\u003c/p\u003e \u003cp\u003eRecently, two-sample Mendelian randomization (MR) analysis has emerged as a reliable method for revealing causality and exploring the influence of factors related to exposure on a range of diseases. Mendelian randomization leverages genetic variation as an instrumental variable (IV) to assess causality between exposure factors and disease, effectively controlling for genetic and environmental confounders. Through this method, which entails gathering data on exposure and results from distinct samples to estimate causal effects, we can enhance our comprehension of the complex associations between selectins and endometriosis.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eMR analyses hinge upon three primary assumptions: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) instrumental variables (IVs) must demonstrate a strong correlation with factors related to exposure, and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) IVs must remain unaffected by confounding factors. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) IVs should solely impact outcomes through exposure pathways(Davies et al., 2018). Initially, we identified three selectins derived from publicly accessible GWAS data and subsequently selected instrumental variables for each selectin utilizing pooled statistics from GWAS. Subsequently, MR analyses were conducted using pooled genome-wide association study (GWAS) data from two distinct cohorts\u0026mdash;the European Molecular Biology Laboratory (EMBL-EBI) and FinnGen\u0026mdash;to assess the causal influence of selectins on endometriosis. Furthermore, MR analyses were conducted to evaluate the cause-and-effect associations between selectins and the probability of various endometriosis sub phenotypes, including pelvic peritoneal endometriosis, endometriosis associated with infertility, tubal endometriosis, intestinal endometriosis, unspecified/other sites of endometriosis, ovarian endometriosis, rectovaginal diaphragm involvement, vaginal endometriosis, and uterine endometriosis, among others.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eGWAS summary data for exposure\u003c/h2\u003e \u003cp\u003eTo explore the causative link between selectins and the risk of endometriosis, we will collect data on genetic variation in selectins and endometriosis from GWASs for use as a dataset. Datasets typically contain a large number of individual samples, genotype data, and sizes of effects related to the disease. We examined the IEU Open GWAS (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), compiling a large number of overviewing statistics from numerous GWASs. We systematically analyzed endometriosis samples collected from two large cohorts, the EMBL-EBI cohort and the FinnGen cohort. Summary statistics from Genome-Wide Association Studies (GWAS) for endometriosis in European individuals from EMBL-EBI were obtained from using the GWAS ID \" ebi-a-GCST90018839 \", e.g., the IEU OpenGWAS database, and in the FinnGen cohort can be found in the R package TwoSampleMR (v0.5.6)(Hemani et al., 2018),accessed using the GWAS ID \"finn-b-N14_ENDOMETRIOSIS\", e.g., the IEU OpenGWAS database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). In EMBL-EBI, the diagnosis of endometriosis is defined according to N80 in the International Classification of Diseases, 10th edition (ICD-10).Endometriosis GWAS in EMBL-EBI included 4511 cases and 227,260 female controls. In FinnGen, endometriosis is defined as N80 in the ICD-10, 617 in the ICD-9, and 6253 in the ICD-8. The pooled statistics of FinnGen's endometriosis GWAS included 8288 cases and 68,969 controls. We also curated data on endometriosis from different sites within the FinnGen cohort in the GWAS database, including endometriosis (2,372 cases, 68,969 controls), ovarian endometriosis (3,231 cases, 68,969 controls), tubal endometriosis (116 cases, 68,969 controls), and pelvic peritoneal endometriosis (2951 cases, 2959 controls) data. endometriosis (2,953 patients, 68,969 controls), rectovaginal septum and vaginal endometriosis (1,360 patients, 68,969 controls), intestinal endometriosis (177 patients, 68,969 controls), unspecified/other endometriosis (1,435 patients, 68,969 controls), and endometriosis combined with infertility (1, 593 patients, 70,651 controls).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInstrumental Variable Selection\u003c/h2\u003e \u003cp\u003eIn our two-sample Mendelian randomization study, we employed genetic variants associated with selectins as instrumental variables (IVs) to generate summary statistics, applying a genome-wide threshold of 5.00E-06. Initially, we identified 18, 79, and 27 SNPs associated with endometriosis at P\u0026thinsp;\u0026lt;\u0026thinsp;1 \u0026times; 10\u0026thinsp;\u0026minus;\u0026thinsp;5 for E-selectin, P-selectin, and L-selectin, respectively. These 124 SNPs were chosen as IVs for the three selectins, and 119 SNPs associated with endometriosis at P\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times; 10\u0026thinsp;\u0026minus;\u0026thinsp;8 were identified. 119 SNPs associated with endometriosis. SNPs with linkage disequilibrium (LD) were excluded from the analysis. The LD of the selected SNPs strongly associated with endometriosis should satisfy r2\u0026thinsp;\u0026lt;\u0026thinsp;0.001 with a window size of 10,000 kb(Myers et al., 2020). A significant step in the MR analysis was to ensure that the effect of the SNP on exposure corresponded to the effect of the identical allele on the outcome. Following the alignment of outcomes, IVs located within palindromic sequences were excluded. We extracted pertinent details, including chromosome, effect allele (EA), alternate allele (OA), effect allele frequency (EAF), effect size (β), standard error (SE), and p-value. Subsequently, we computed the explained variance (R^2) and F-statistic to assess the strength of association between the identified instrumental variables (IVs) and the exposure. Generally, SNPs with F-statistic parameters\u0026thinsp;\u0026lt;\u0026thinsp;10 were regarded as weak instruments(Burgess et al., 2017). The formula used for computing the F statistic was F\u0026thinsp;=\u0026thinsp;R^2 \u0026times; n-k-1/k \u0026times; (1-R^2), where n represents the sample size, k represents the number of IVs used, and R^2 signifies the proportion of exposure variance explained by the IVs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eMendelian analysis\u003c/h2\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003ePreliminary analysis\u003c/h2\u003e \u003cp\u003eTo estimate the causal effect of selectins on endometriosis, we performed MR analyses on two separate samples. The inverse variance weighted (IVW) method is the basic analytical method, and the Wald ratio test includes only the characteristics of one IV(Burgess et al., 2013). MR results are expressed as the dominance ratio (OR) and the corresponding 95% confidence interval (CI). The results were statistically significant when the p-value for IVW was less than 0.05 and when the IVW and MR-Egger were in the same direction.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBidirectional causal analysis\u003c/h2\u003e \u003cp\u003eTo assess the bidirectional causality of endometriosis and selectin, we used endometriosis as the \"exposure\" and selectin as the \"outcome\". We selected SNPs substantially associated with endometriosis (P\u0026thinsp;\u0026lt;\u0026thinsp;5*10\u0026thinsp;\u0026minus;\u0026thinsp;8) as IVs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eIn this study, we used multiple methods to evaluate heterogeneity and horizontal pleiotropy among SNPs. We applied Cochran's Q-statistic, funnel plots, MR‒Egger intercepts, and MR-PRESSO to detect and resolve outliers, as well as a random-effects model to assess the stability of the results(Burgess \u0026amp; Thompson, 2017; Cohen et al., 2015; Verbanck et al., 2018). In addition, a single analysis was conducted to validate the effect of each SNP on the overall causal estimate. Together, these methods helped to ensure the confidence and robustness of the MR analyses. All the statistical analyses were performed using R (version 4.2.3) combined with the TwoSampleMR and MR-PRESSO software packages(Ong \u0026amp; MacGregor, 2019).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eEffect of selectins on endometriosis\u003c/h2\u003e\n \u003cp\u003eMR analysis revealed that among the three selectins in the FinnGen database, the genetic prediction of E-selectin (OR\u0026thinsp;=\u0026thinsp;0.92, 95% CI (0.86, 0.98), p\u0026thinsp;=\u0026thinsp;0.015) was associated with a reduced risk of endometriosis, whereas the same conclusion was reached with the EMBL-EBI databaseTable 2, where the genetic prediction of E-selectin was correlated. However, P-selectin (OR\u0026thinsp;=\u0026thinsp;1.01, 95% CI (0.90, 1.13), p\u0026thinsp;=\u0026thinsp;0.871) and L-selectin (OR\u0026thinsp;=\u0026thinsp;1.04, 95% CI (0.94, 1.15), p\u0026thinsp;=\u0026thinsp;0.493) were not significantly differentTable 1.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMR analysis of causal effects of selectin on endometriosis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eexposure\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eoutcom\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo.of SNP\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR(95%CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eE-selectin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndometriosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.92(0.86,0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL-selectin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndometriosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.01(0.90,1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.871\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP-selectin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndometriosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.04(0.94,1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.493\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eCausal effect of E-selectin on endometriosis at different sites\u003c/h2\u003e\n \u003cp\u003eMR analysis indicated that genetic prediction of E-selectin was associated with pelvic peritoneal endometriosis (OR\u0026thinsp;=\u0026thinsp;0.86, 95% CI (0.80, 0.92), p\u0026thinsp;=\u0026thinsp;0.001), endometriosis combined with infertility (OR\u0026thinsp;=\u0026thinsp;0.84, 95% CI (0.76, 0.92), p\u0026thinsp;=\u0026thinsp;0.003), intestinal surface endometriosis (OR\u0026thinsp;=\u0026thinsp;0.70 95% CI (0.51, 0.96), p\u0026thinsp;=\u0026thinsp;0.046), unspecified/other endometriosis (OR\u0026thinsp;=\u0026thinsp;0.85, 95% CI (0.75, 0.96), p\u0026thinsp;=\u0026thinsp;0.023), ovarian endometriosis (OR\u0026thinsp;=\u0026thinsp;0. 92 (95% CI (0.86, 0.99), p\u0026thinsp;=\u0026thinsp;0.037), rectovaginal diaphragm and vaginal uterine endometriosis (OR\u0026thinsp;=\u0026thinsp;0.88, 95% CI (0.79, 0.97), p\u0026thinsp;=\u0026thinsp;0.036) were associated with a reduced risk, while the associations with uterine endometriosis (OR\u0026thinsp;=\u0026thinsp;0.97, 95% CI (0.90, 1.05), p\u0026thinsp;=\u0026thinsp;0.499) and tubal endometriosis (OR\u0026thinsp;=\u0026thinsp;0.24, 95% CI (0.04, 1.30), p\u0026thinsp;=\u0026thinsp;0.131) were not statistically significantTable 3.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMR analysis of the causal effects of E-selectin on endometriosis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eoutcome\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMR method\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo.of SNP\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR (95%CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003efinn-b-N14_ENDOMETRIOSIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.92(0.88,0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeighted median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.92(0.89,0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.92(0.89,0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eebi-a-GCST90018839\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.94(0.90,0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeighted median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.94(0.90,0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.94(0.91,0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003efinn-b-N14_ENDOMETRIOSIS:E-selectin from the FinnGen cohort;ebi-a-GCST90018839:E-selectin from the EMBL-EBI cohort.\u003c/p\u003e\n \u003cp\u003eTable\u0026nbsp;3: MR analysis of the causal effects of E-selectin on different typesendometriosis\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, using pooled statistics from two large European GWASs, the European Molecular Biology Laboratory and FinnGen, we investigated the causal effect of three selectins on the risk of endometriosis using a harmonized MR framework to analyze GWAS data. Our results suggest a causal relationship between E-selectin and endometriosis, revealing that E-selectin reduces the risk of endometriosis. In addition, MR analysis revealed a causal relationship between different subphenotypes of endometriosis categorized by the location of the ectopic site, and our study suggested that E-selectin reduces the risk of pelvic peritoneal endometriosis, endometriosis combined with infertility, intestinal surface endometriosis, unspecified/other endometriosis, ovarian endometriosis, rectovaginal diaphragm, and vaginal endometriosis. These findings have considerable implications for the advancement of endometriosis management.\u003c/p\u003e \u003cp\u003eAlthough endometriosis is histologically benign, it is characterized by malignant tumors such as rapid proliferation, infiltration, metastasis, and easy recurrence and is known as \"immortal cancer\". Although various factors contributing to the onset of endometriosis have been elucidated, the exact etiology, pathogenesis and treatment of endometriosis are still unclear and contentious(Saunders \u0026amp; Horne, 2021; Wang et al., 2020). The development of effective preventive and therapeutic strategies for endometriosis requires an in-depth understanding of this disease. Sampson introduced the retrograde menstruation theory, positing that menstrual blood carrying endometrial cells refluxes through the fallopian tubes into the pelvic cavity rather than being discharged from the body, resulting in the development of ectopic endometriotic lesions. Although Sampson's theory enjoys widespread acceptance, various alternative hypotheses have been advanced, including hypotheses regarding stem cell derivation and immune system modifications(Maruyama, 2022; Shigesi et al., 2019). Endometriosis is believed to arise from a multifaceted interplay of genetic, anatomical, environmental, and immunological elements(Burney, 2013; Vercellini et al., 2014; Wang et al., 2020). Although the origins of endometriosis remain debated, there is broad consensus that this condition entails a localized inflammatory reaction, with vascularization at the site of endometriotic invasion pivotal to lesion formation(Koninckx et al., 2021). Remarkably, selectins have emerged as significant players in regulating the inflammatory cascade(Guo et al., 2015; Tvaroška et al., 2020).\u003c/p\u003e \u003cp\u003eCurrently, the role of selectins in the pathogenesis of endometriosis is unclear. It has been suggested that selectins are cell adhesion molecules that, like other molecules, are responsible for initiating leukocyte extravasation during the inflammatory response. Upregulation of these cell adhesion molecules leads to increased endometrial cell invasiveness, which not only causes endothelial cell adhesion but also increases angiogenesis, leading to macrophage extravasation. Abdominal pain during menstruation is also a result of the inflammatory nature of the pain caused by the disease(Schmidt et al., 2000). The study also revealed that only a few E-selectins are expressed in endometriosis tissues, that this expression is overall very weak, and that overexpression induces an inflammatory response, thereby exacerbating endometriosis. Whereas circulating levels of soluble E-selectin or E-selectin expressed on the endothelial surface usually correlate with the duration and/or severity of inflammatory disease, suggesting a role for E-selectin in the etiology or progression of the disease(Barthel et al., 2007), this finding contradicts the conclusions that we reached in our study. However, other studies have shown that the inflammatory response can lead to the upregulation of the expression of E-selectin, which recruits leukocytes, promotes inflammatory cell infiltration of the vessel wall, and promotes differentiation into macrophages, which produce proteases that promote the breakdown of ectopic endothelial tissues(Tabas \u0026amp; Bornfeldt, 2016). Liu ZJ et al. demonstrated that signaling molecules mediating vascular E-selectin downregulation also inhibit circulating endothelial cell homing, tumor angiogenesis, and tumor growth. Therefore, the intrapelvic environment and angiogenesis of ectopic lesions reduce endometriosis development. In addition, E-selectin enhances leukocyte resistance to shear adhesion(Liu et al., 2011), thereby reducing the implantation of endometriotic foci(Kang et al., 2016).\u003c/p\u003e \u003cp\u003eThe expression or aberrant expression of selectins can have a tremendous impact on various aspects of cell adhesion, migration, inflammatory response, signaling, immune homeostasis, and tissue repair, which in turn affects the onset and progression of endometriosis; thus, selectins can be important regulators of the development of endometriosis. An in-depth understanding of the causal relationship between selectins and endometriosis can help to unravel the pathophysiologic process of this disease and provide new targets and strategies for its treatment. Although it is still in the early stages, several studies have explored the possibility of utilizing selectin modulation for the treatment of endometriosis. We can reduce the symptoms of endometriosis patients by inhibiting the selectin signaling pathway and affecting the ability of selectins to bind to their ligands, reduce adhesion and migration between leukocytes and endothelial cells, and participate in the inflammatory response and tissue repair process. Second, by regulating the inflammatory response, selectins are involved in regulating the inflammatory response, and their aberrant expression may lead to the onset and exacerbation of pelvic inflammation, which in turn affects the development of endometriosis. Modulation of the inflammatory response may become another strategy for the treatment of endometriosis. In addition, blocking angiogenesis and thus reducing nutritional support to endometriotic lesions may also help to slow the progression of endometriosis. Exploring the mechanisms of targeted selectin-selectin ligand interactions could also have a great impact on the management of endometriosis. Future studies should also design additional experiments and methods to further elucidate the relationship between selectins and endometriosis and provide more effective strategies and approaches for the treatment and management of endometriosis.\u003c/p\u003e \u003cp\u003eTo sum up, the causal role of E-selectin in endometriosis was confirmed in our study. Despite the use of two-sample data, further independent validation of these causal relationships is warranted. Moreover, considering the underlying pathophysiology of endometriosis, additional experimental validation is imperative to obtain a more thorough understanding of the molecular mechanisms and functions of these selectins in the development of endometriosis.\u003c/p\u003e \u003cp\u003eThis study has several strengths. First, by capitalizing on the random assignment of genetic variation during the formation of gametes and fertilization, the findings of the Mendelian randomization analysis are less vulnerable to confounding influences and causality reversal. Second, we employed distinct datasets for exposure (selectin) and outcome (endometriosis) measurements, ensuring two-sample MR analyses and thus minimizing biases that may inflate the significance of weak instrumental variables. Third, the consistent estimates of the cause-and-effect relationship of E-selectin on endometriosis across the two primary cohorts, namely, the UK Molecular Biology Laboratory and FinnGen, mitigate concerns regarding false-positive findings. Finally, we conducted various complementary analyses, including assessments of heterogeneity, multiplicity, and leave-one-out sensitivity, to test the plausibility of hypotheses pertaining to instrumental variables.\u003c/p\u003e \u003cp\u003eHowever, it is our necessity to recognize specific limitations. First, within the setting of endometriosis, a condition predominantly affecting females, existing genome-wide association studies (GWASs) investigating various E-selectins have been conducted with an inherent bias toward sex combinations. Given that two-sample Mendelian randomization (MR) requires coherence in the underlying populations of both sets of samples, potential disparities in genetic estimations of E-selectin between females and males must be considered. Such differences may introduce bias into the results of our MR study. Second, since this study exclusively involved individuals of European descent, its findings may not be readily generalizable to other demographic groups. Further investigations into the causal among coagulation factors and endometriosis within diverse populations are warranted.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo the best of our knowledge, this study represents inaugural investigation utilizing Mendelian randomization to study the causal connection between selectins and the risk of endometriosis within a European population. Our results substantiate a causal link between E-selectin and susceptibility to endometriosis and its various subtypes. These findings hold considerable significance for the formulation of strategies targeting both the prevention and treatment of endometriosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors express their gratitude to the participants and investigators of the FinnGen Study and\u0026nbsp;EMBL-EBI Study. The authors also appreciate the ieu open gwsa project for providing the selectins and endometriosis GWAS summary statistics.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHongbo Hu,Jie Zhou,JuanChen contributed to the concept and design of the study. Juan Chen,Jie Zhou was responsible for statistical analysis and writing of the manuscript. Hongbo Hu,Jie Zhou,Juan Chen, LinJie Su assisted with the statistical analysis. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was no funded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during the current study are available in the ieu gwas project\u003ca href=\"https://d.docs.live.net/7387fad4da68b7c7/Documents/(https:/gwas.mrcieu.ac.uk/)\"\u003e(https://gwas.mrcieu.ac.uk/)\u003c/a\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur analysis used publicly available genome-wide association study (GWAS) summary statistics. No new data were collected, and no new ethical approval was required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAnon. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98(3):591\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.fertnstert.2012.05.031\u003c/span\u003e\u003cspan address=\"10.1016/j.fertnstert.2012.05.031\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarthel SR, Gavino JD, Descheny L, Dimitroff CJ. Targeting selectins and selectin ligands in inflammation and cancer. Expert Opin Ther Targets. 2007;11(11):1473\u0026ndash;91. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1517/14728222.11.11.1473\u003c/span\u003e\u003cspan address=\"10.1517/14728222.11.11.1473\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update. 2014;20(5):737\u0026ndash;47. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/humupd/dmu025\u003c/span\u003e\u003cspan address=\"10.1093/humupd/dmu025\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658\u0026ndash;65. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/gepi.21758\u003c/span\u003e\u003cspan address=\"10.1002/gepi.21758\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017;26(5):2333\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/0962280215597579\u003c/span\u003e\u003cspan address=\"10.1177/0962280215597579\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377\u0026ndash;89. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10654-017-0255-x\u003c/span\u003e\u003cspan address=\"10.1007/s10654-017-0255-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurney RO. The genetics and biochemistry of endometriosis. Curr Opin Obstet Gynecol. 2013;25(4):280\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/GCO.0b013e3283630d56\u003c/span\u003e\u003cspan address=\"10.1097/GCO.0b013e3283630d56\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen I, Thavorn K, Yong PJ, Choudhry AJ, Allaire C. Hospital-Associated Cost of Endometriosis in Canada: A Population-Based Study. J Minim Invasive Gynecol. 2020;27(5):1178\u0026ndash;87. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jmig.2019.09.771\u003c/span\u003e\u003cspan address=\"10.1016/j.jmig.2019.09.771\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen LC, Hsu JW, Huang KL, Bai YM, Su TP, Li CT, Chen MH. Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal follow-up study. J Affect Disord. 2016;190:282\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jad.2015.10.030\u003c/span\u003e\u003cspan address=\"10.1016/j.jad.2015.10.030\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen JF, Chalumeau M, Cohen R, Korevaar DA, Khoshnood B, Bossuyt PM. Cochran's Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy. J Clin Epidemiol. 2015;68(3):299\u0026ndash;306. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jclinepi.2014.09.005\u003c/span\u003e\u003cspan address=\"10.1016/j.jclinepi.2014.09.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrockett-Torabi E, Fantone JC. The selectins: insights into selectin-induced intracellular signaling in leukocytes. Immunol Res. 1995;14(4):237\u0026ndash;51. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/bf02935622\u003c/span\u003e\u003cspan address=\"10.1007/bf02935622\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/bmj.k601\u003c/span\u003e\u003cspan address=\"10.1136/bmj.k601\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDu Y, Liu X, Guo SW. Platelets impair natural killer cell reactivity and function in endometriosis through multiple mechanisms. Hum Reprod. 2017;32(4):794\u0026ndash;810. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/humrep/dex014\u003c/span\u003e\u003cspan address=\"10.1093/humrep/dex014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiannella L, Marconi C, Di Giuseppe J, Delli Carpini G, Fichera M, Grelloni C, Ciavattini A. Malignant Transformation of Postmenopausal Endometriosis: A Systematic Review of the Literature. Cancers (Basel). 2021;13(16). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/cancers13164026\u003c/span\u003e\u003cspan address=\"10.3390/cancers13164026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo SW, Ding D, Geng JG, Wang L, Liu X. P-selectin as a potential therapeutic target for endometriosis. Fertil Steril. 2015;103(4):990\u0026ndash;e10001008. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.fertnstert.2015.01.001\u003c/span\u003e\u003cspan address=\"10.1016/j.fertnstert.2015.01.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris HR, Costenbader KH, Mu F, Kvaskoff M, Malspeis S, Karlson EW, Missmer SA. Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses' Health Study II. Ann Rheum Dis. 2016;75(7):1279\u0026ndash;84. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/annrheumdis-2015-207704\u003c/span\u003e\u003cspan address=\"10.1136/annrheumdis-2015-207704\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, Haycock PC. The MR-Base platform supports systematic causal inference across the human phenome. Elife 7. 2018. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7554/eLife.34408\u003c/span\u003e\u003cspan address=\"10.7554/eLife.34408\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIvetic A, Green H, H. L., Hart SJ. L-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling. Front Immunol. 2019;10:1068. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fimmu.2019.01068\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2019.01068\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang SA, Blache CA, Bajana S, Hasan N, Kamal M, Morita Y, Tanaka T. The effect of soluble E-selectin on tumor progression and metastasis. BMC Cancer. 2016;16:331. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12885-016-2366-2\u003c/span\u003e\u003cspan address=\"10.1186/s12885-016-2366-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoninckx PR, Fernandes R, Ussia A, Schindler L, Wattiez A, Al-Suwaidi S, Tahlak M. Pathogenesis Based Diagnosis and Treatment of Endometriosis. Front Endocrinol (Lausanne). 2021;12:745548. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fendo.2021.745548\u003c/span\u003e\u003cspan address=\"10.3389/fendo.2021.745548\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuessel L, Wenzl R, Proestling K, Balendran S, Pateisky P, Yotova H. (2017). Soluble VCAM-1/soluble ICAM-1 ratio is a promising biomarker for diagnosing endometriosis. \u003cem\u003eHum Reprod\u003c/em\u003e, \u003cem\u003e32\u003c/em\u003e(4), 770\u0026ndash;779. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/humrep/dex028\u003c/span\u003e\u003cspan address=\"10.1093/humrep/dex028\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu ZJ, Tian R, Li Y, An W, Zhuge Y, Livingstone AS, Velazquez OC. (2011). Inhibition of tumor angiogenesis and melanoma growth by targeting vascular E-selectin. \u003cem\u003eAnn Surg\u003c/em\u003e, \u003cem\u003e254\u003c/em\u003e(3), 450\u0026ndash;456; discussion 456\u0026ndash;457. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/SLA.0b013e31822a72dc\u003c/span\u003e\u003cspan address=\"10.1097/SLA.0b013e31822a72dc\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eL\u0026auml;ubli H, Borsig L. Selectins promote tumor metastasis. Semin Cancer Biol. 2010;20(3):169\u0026ndash;77. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.semcancer.2010.04.005\u003c/span\u003e\u003cspan address=\"10.1016/j.semcancer.2010.04.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaruyama T. A Revised Stem Cell Theory for the Pathogenesis of Endometriosis. J Pers Med. 2022;12(2). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/jpm12020216\u003c/span\u003e\u003cspan address=\"10.3390/jpm12020216\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMyers TA, Chanock SJ, Machiela MJ. LDlinkR: An R Package for Rapidly Calculating Linkage Disequilibrium Statistics in Diverse Populations. Front Genet. 2020;11:157. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fgene.2020.00157\u003c/span\u003e\u003cspan address=\"10.3389/fgene.2020.00157\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOng JS, MacGregor S. Implementing MR-PRESSO and GCTA-GSMR for pleiotropy assessment in Mendelian randomization studies from a practitioner's perspective. Genet Epidemiol. 2019;43(6):609\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/gepi.22207\u003c/span\u003e\u003cspan address=\"10.1002/gepi.22207\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePethaperumal S, Hung SC, Lien TS, Sun DS, Chang HH. P-Selectin is a Critical Factor for Platelet-Mediated Protection on Restraint Stress-Induced Gastrointestinal Injury in Mice. Int J Mol Sci. 2022;23(19). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/ijms231911909\u003c/span\u003e\u003cspan address=\"10.3390/ijms231911909\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProestling K, Wenzl R, Yotova I, Hauser C, Husslein H, Kuessel L. Investigating selected adhesion molecules as urinary biomarkers for diagnosing endometriosis. Reprod Biomed Online. 2020;40(4):555\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.rbmo.2020.01.014\u003c/span\u003e\u003cspan address=\"10.1016/j.rbmo.2020.01.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePurdy M, Obi A, Myers D, Wakefield T. P- and E- selectin in venous thrombosis and non-venous pathologies. J Thromb Haemost. 2022;20(5):1056\u0026ndash;66. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/jth.15689\u003c/span\u003e\u003cspan address=\"10.1111/jth.15689\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamin-Wright A, Schwartz ASK, Geraedts K, Rauchfuss M, W\u0026ouml;lfler MM, Haeberlin F, Leeners B. Fatigue - a symptom in endometriosis. Hum Reprod. 2018;33(8):1459\u0026ndash;65. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/humrep/dey115\u003c/span\u003e\u003cspan address=\"10.1093/humrep/dey115\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 2021;184(11):2807\u0026ndash;24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.cell.2021.04.041\u003c/span\u003e\u003cspan address=\"10.1016/j.cell.2021.04.041\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmidt M, Regidor PA, Engel K, Regidor M, Winterhager E, Scotti S, Schindler AE. E- and P-selectin expression in endometriotic tissues and the corresponding endometria. Gynecol Endocrinol. 2000;14(2):111\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3109/09513590009167669\u003c/span\u003e\u003cspan address=\"10.3109/09513590009167669\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShigesi N, Kvaskoff M, Kirtley S, Feng Q, Fang H, Knight JC, Becker CM. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum Reprod Update. 2019;25(4):486\u0026ndash;503. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/humupd/dmz014\u003c/span\u003e\u003cspan address=\"10.1093/humupd/dmz014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, D'Hooghe T. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012;27(5):1292\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/humrep/des073\u003c/span\u003e\u003cspan address=\"10.1093/humrep/des073\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpertini O, Kansas GS, Munro JM, Griffin JD, Tedder TF. Regulation of leukocyte migration by activation of the leukocyte adhesion molecule-1 (LAM-1) selectin. Nature. 1991;349(6311):691\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/349691a0\u003c/span\u003e\u003cspan address=\"10.1038/349691a0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTabas I, Bornfeldt KE. Macrophage Phenotype and Function in Different Stages of Atherosclerosis. Circ Res. 2016;118(4):653\u0026ndash;67. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/circresaha.115.306256\u003c/span\u003e\u003cspan address=\"10.1161/circresaha.115.306256\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTedder TF, Steeber DA, Chen A, Engel P. The selectins: vascular adhesion molecules. Faseb j. 1995;9(10):866\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTvaroška I, Selvaraj C, Koča J. Selectins-The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules-A Review. Molecules. 2020;25(12). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/molecules25122835\u003c/span\u003e\u003cspan address=\"10.3390/molecules25122835\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41588-018-0099-7\u003c/span\u003e\u003cspan address=\"10.1038/s41588-018-0099-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVercellini P, Vigan\u0026ograve; P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261\u0026ndash;75. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/nrendo.2013.255\u003c/span\u003e\u003cspan address=\"10.1038/nrendo.2013.255\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Nicholes K, Shih IM. The Origin and Pathogenesis of Endometriosis. Annu Rev Pathol. 2020;15:71\u0026ndash;95. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1146/annurev-pathmechdis-012419-032654\u003c/span\u003e\u003cspan address=\"10.1146/annurev-pathmechdis-012419-032654\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Wang X, Liao K, Luo B, Luo J. The burden of endometriosis in China from 1990 to 2019. Front Endocrinol (Lausanne). 2022;13:935931. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fendo.2022.935931\u003c/span\u003e\u003cspan address=\"10.3389/fendo.2022.935931\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4160567/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4160567/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: Previous observational research has indicated an association between plasma selectin family members and endometriosis, and our objective was to investigate the causal association between selectins and endometriosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Using pooled statistics from genome-wide association studies of predominantly European ancestry and utilizing Mendelian randomization (MR), we analyzed the causal effect of the selectins E/P/L on endometriosis and the causal association of selectins with endometriosis at different sites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: This study revealed a causal relationship between E-selectin and endometriosis (ratio of 0.92, 95% CI (0.86, 0.98) p = 0.01). And the causal relationship between selectins and endometriosis at different sites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Our genetic predictions suggest that higher levels of selectins may provide protection against endogamy and may serve as therapeutic targets in the future.\u003c/p\u003e","manuscriptTitle":"Causal relationship between selectins and endometriosis: a Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-29 05:51:36","doi":"10.21203/rs.3.rs-4160567/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0cb15992-938e-4bf3-b260-53f3614dc77b","owner":[],"postedDate":"March 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-24T04:23:53+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-29 05:51:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4160567","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4160567","identity":"rs-4160567","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}