Causal Relationship Between Inflammatory Cytokines and Polycystic Ovary Syndrome: A Bidirectional Mendelian Randomization Study

Causal Relationship Between Inflammatory Cytokines and Polycystic Ovary Syndrome: A Bidirectional 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 Inflammatory Cytokines and Polycystic Ovary Syndrome: A Bidirectional Mendelian Randomization Study Danling Tian, Jinfeng Chen, Liang Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4882537/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Nov, 2024 Read the published version in Journal of Ovarian Research → Version 1 posted 7 You are reading this latest preprint version Abstract Polycystic ovary syndrome (PCOS) is defined as a chronic low-grade inflammatory reproductive endocrine disorder. PCOS can induce various metabolic disorders, which are associated with a state of mild and slow-acting inflammation. Nevertheless,it‘s uncertain that the causation about PCOS and inflammatory factors. The causality between inflammatory cytokines and PCOS was analyzed by bidirectional Mendelian randomization (MR) in this current probe. We performed an interactive MR study to assess the causal relationships between 91 inflammatory cytokines and PCOS using Genome Wide Association Study (GWAS) data. We underwent dual-sample MR analysis with inverse variance weights (IVW) as the predominant MR methodology with multiple validity and heterogeneity analyses. MR-Egger, weighted median, simple mode, weighted mode and MR-PRESSO were analyzed as multiple likelihood sensitivity analyses to enhance the final results.The results came out interleukin-1-alpha (IL-1A) levels (odds ratio [OR] = 1.051, 95% fiducial interval [95% CI] = 1.009–1.095, P = 0.02) and oncostatin-M (OSM) levels ( [OR] = 1.041, [95% CI] = 1.001–1.082, P = 0.04) were positively associated with the development of PCOS. Moreover, interleukin-7 (IL-7) levels ([OR] = 0.935, [95% CI] = 0.884–0.989, P = 0.02); interleukin-15 receptor subunit alpha (IL15RA) levels ([OR] = 0.959, [95% CI] = 0.929–0.99, P = 0.01); and C-X-C motif chemokine 11 (CXCL11) levels ([OR] = 0.959, [95% CI] = 0.922–0.996. P = 0.03) were strongly negatively associated with PCOS. However, we did not find any strong positive results in the reverse analysis, suggesting that although inflammatory factors contribute to the pathogenesis of PCOS, PCOS itself does not trigger inflammatory factor production.Our study provides genetic evidence for the connection between systemic inflammatory regulators and PCOS. Treatments targeting specific inflammatory factors may help to mitigate the risk of PCOS. The levels of five of the 91 inflammatory factors included in this study, namely, IL1A and OSM, were associated with PCOS. IL1A and OSM contribute to the progression of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively correlated with the development of PCOS. inflammatory cytokines mendelian randomization polycystic ovary syndrome relationship reverse Figures Figure 1 Figure 2 1 Introduction Polycystic ovary syndrome (PCOS) become a usual suspect,whose morbidity fall in between 5 to 15 percent among women of childbearing age. ( 1 ). The etiology of PCOS is complex; clinical manifestations include menstrual irregularities, hyperandrogenemia, and polycystic ovarian morphology. Study finds that mild phlegmonosis taking an significant effect on nosogenesis of polycystic ovary syndrome. ( 2 ). A previous study demonstrated that the dysregulation of glucose metabolism and lipid metabolism caused by PCOS triggers low-grade inflammation in the endothelium, which also affects the ovarian tissue. Moreover, the presence of chronic inflammation may contribute to the development of insulin resistance (IR), which in turn is intensified by the release of androgens and proinflammatory cytokines from adipose tissue ( 3 ). Study finds that mild phlegmonosis taking an significant effect on nosogenesis of polycystic ovary syndrome. Furthermore, hirsutism, androgenetic alopecia, and acne are including( 4 ). Ovarian cysts are caused by an inappropriate of female gender steroids, which can lead to the formation of cysts in the precocious ovarian follicles.Normally, the egg is inside the cyst and is expelled every month for fertilization.If the egg is transformed directly into a cyst, it can prevent ovulation and cause menstrual disorders ( 5 ).It is also a direct cause of infertility. PCOS should be viewed as a high-risk condition during pregnancy, necessitating the diagnosis and monitoring of affected women. It is also important to acknowledge the elevated risk of endometrial cancer in premenopausal women with PCOS, despite the overall low absolute risks ( 6 ). Metabolic disorders and related complications include IR and diabetes, hyperlipidemia, hypertension, fatty liver, metabolic syndrome, and sleep apnea. Reproductive complications include menstrual irregularities/amenorrhea, low fertility, endometrial hyperplasia, and cancer. Associated psychosocial problems include depression and eating disorders. In addition, cosmetic conditions include hirsutism, androgenetic alopecia, and acne ( 7 ). Moreover, PCOS is a life-long condition . According to new diagnostic criteria, women with normal menstrual cycles can now also be diagnosed with PCOS. Nonetheless, the involvement for polycystic ovary syndrome with inflammatory factors still appears to be unknown. Further exploration of the underlying mechanism of PCOS is warranted for the development of novel and effective clinical interventions. 2 Materials and Methods 2.1 Study Design and Data Sources First of all,we obtained the data about 91 inflammatory cytokines in publications in genome-wide association study (GWAS),that was proven genetic variation.Nest,we probed into the etiopathogenesis in polycystic ovary syndrome about cytokine.Bidirectional Mendelian randomization (MR) can be used to determine whether common genetic variants are causally linked to an outcome of interest ( 8 ). MR provides a new approach to causal inference based on observational epidemiologic studies by using genetic variants that are strongly correlated with underlying traits as instrumental variables (IVs) to infer causal relationships between these traits and the outcome of interest. Since gametes are formed according to the Mendelian inheritance law of "random assignment of parental alleles to offspring", genetic differences are unaffected by the customary mix of environmental exposure, socioeconomic status, and behavioral factors; the fact that genetic variation is inherited from the parents and remains invariant after birth, and that its correlations with consequences are time-plausible.Therefore, MR can overcome the problems of confounding and reverse causation in traditional observational epidemiologic studies. Genetic variation can be used as a tool to link risk factors and outcomes, estimating such effects with less confounding and bias than traditional epidemiologic methods ( 9 ). I. Additionally, MR is an efficient and cost-effective methodology owing to the wide availability of published data, which enables the screening of suitable genetic variables ( 10 ). MR is based on three main hypotheses: (i) genetic variation in the selected IVs is strongly associated with the underlying trait; (ii) Independence of heritable variations are not affected by confounding factors; and (iii) genetic variation affects the outcome only through the underlying trait, not through alternative pathways ( 11 ). The latest STROBE-MR guidelines were followed for the MR analyses, which were conducted under three basic assumptions: (i) IVs are strongly associated with inflammatory factors; (ii) genetic factors and IVs that were selected for this study were independent of any potential confounders; and (iii) IVs affecting susceptibility to PCOS can only be altered by inflammatory factors and not by any other alternative pathways ( 12 ). The following assumptions are met in this two-sample bidirectional MR (Fig. 1 ): In this MR analysis, the two datasets used are from the public GWAS dataset. The data of 34,388 PCOS patients and 195,922 controls of European origin were obtained from the R10 version of the Finnish database. PCOS patients were diagnosed according to the inclusion criteria. The levels of 91 inflammatory cytokines, which were identified from a genome-wide pQTL analysis, were measured in 11 cohorts of 14,824 participants of European ancestry using the Olink Target 96 inflammation panel ( 13 ). 2.2 Tool Variable Selection Rigorous data harmonization was performed to ensure that single nucleotide polymorphism (SNP) effects on the underlying traits and outcomes corresponded to the same alleles. It was ensured that the same alleles were present in both datasets. We removed palindromic SNPs to avoid the ambiguity of having the same alleles for both the underlying traits and outcomes. We set p < 1e-5 as genome-wide significance threshold for selecting SNPs closely associated with polycystic ovary syndrome and inflammatory cytokines.SNPs tightly associated with inflammatory cytokines.In order to avoid obscure outcome, we group SNPs according to linkage disequilibrium coefficients (kb = 10,000, r2 = 0.001). We used R2 and F tests to determine instrument strength to prevent weak instrument bias.Complete details on all SNPs included in this survey can be consulted in Supplemental materials .(Table 1 of Supplementary1) 2.3 Statistical Analysis Causality was estimated using inverse variance weighting (IVW). Directional pleiotropy was also assessed using IVW (p < 0.05 was regarded as demonstrating statistically significant). Horizontal pleiotropy occurs in addition to the effect of a genetic variant on the exposure in MR. Contrary to the antagonistic pleiotropy hypothesis, horizontal pleiotropy leads to severe bias in MR. MR of pleiotropic residual and outlier (MR-PRESSO) tests were developed to identify pleiotropic level outliers ( 14 ). In the assessment of pleiotropy, p > 0.05 indicates no pleiotropy. The study adopted the MR-PRESSO method in MR in order to further assess and correct for potential pleiotropy. mR-PRESSO identifies and corrects for outliers in IV and reduces the impact of horizontal pleiotropic effects on causal effect estimates.The method helps to provide more dependable and reliable estimates of causal effects ( 15 ). The p-values were all greater than 0.05, indicating that there were no outliers or heterogeneity, which indicates that the results are robust (Supplementary 1 Table 5),in the MR-PRESSO analytical results,. The Cochrane's Q test assessed heterogeneity among genetic variants as IVs.The results of the Q test (p > 0.05) suggested that there was no heterogeneity among IVs.MR-Egger regression was also used to assess potential multiple effects.MR-Egger regression estimated the intercept term, and our results suggest that a P value for the intercept greater than 0.05 does not suggest the presence of pleiotropy. ( 16 ).(The results shows in Table 1) All of the statistical analyses were performed using the “TwoSampleMR version 0.5.6” package and a two-tailed p value of less than 0.05 was recognized statistically significant. 3 Results All 91 inflammatory factors had impact F-statistics of 10 or more, indicating the absence of weak IVs. To determine the primary analytical tool, hypotheses were examined for all 91 inflammatory factors, and the IVW method was employed as the principal analytical approach. A total of 182 SNPs(Single-nucleotide polymorphisms) were identified (The results shows in Fig. 2 ). 3.1 Reverse MR Analysis Reverse MR was performed with PCOS as the exposure and the 91 inflammatory factors identified in the present study as the outcome. The procedure included a total of 16 IVs under the screening conditions of P < 1×10 − 5 and an r of 5 kb for 10,000, but none of the subsequent MR analyses revealed significant reverse causality. The statistical consequences can be summarized in the additional documentation. (Supplementary2 Table 1). 4 Discussion Using the GWAS database, we performed a two-sample bidirectional MR analysis to investigate the causal relationship between inflammatory cytokines and PCOS. The results showed that IL1A and OSM levels are positively associated with the development of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively associated with the development of PCOS. Interleukin-1α (IL1A) gene encodes a protein that is a pleiotropic cytokine participating in diverse immortal reactions and inflamatory procedures. IL1A is differentially expressed in human granulosa cells and cumulus cells, which also suggests that IL1A may affect the process of ovulation. IL1A is involved in the development of PCOS by affecting androgen levels and follicular development in the ovary. In addition, IL1A may also affect insulin resistance, glucose metabolism, and the formation of chronic low-grade inflammation, which are important pathological processes in PCOS. IL1A may be an important factor in the pathogenesis of PCOS and is highly important for elucidating the pathophysiological mechanism, clinical diagnosis and treatment of PCOS. The role of IL1A in the pathogenesis of PCOS and the feasibility of treating PCOS by interfering with the IL1A signaling pathway should be further explored in subsequent studies. Additionally, monocytes and macrophages produce IL-1, a cytokine superfamily that includes IL-1 and IL-18, and IL-1α and IL-1β, which directly affect progesterone and estradiol production in granulosa cells ( 17 ). It has been shown that the presence of polymorphisms in the interleukin-1 gene is associated with the development of PCOS, serum follicle-stimulating hormone (FSH) levels and luteinizing hormone (LH)/FSH ratios in patients with PCOS, and common polymorphisms in the interleukin-1 gene are associated with the presence of PCOS and with the clinical parameters of women affected by this disease ( 18 ). It has been shown that both IL-1A and IL-6 levels are elevated in patients with PCOS. However, there was no correlation between IL-1A levels and IL-1A polymorphisms. Moreover, abnormalities in hormonal and biochemical markers may be associated with IL-6 gene polymorphisms, but not with IL-1A gene polymorphisms ( 19 ). A meta-analysis revealed that IL-1B and IL-1A polymorphisms affect PCOS susceptibility in Asians and Caucasians, respectively ( 20 ). However, the frequency of the IL-1a C (-889) T polymorphism in the Chinese population was not correlated with PCOS susceptibility ( 21 ). Oncostatin M is a member of the IL-6 cytokine family of novel adipokines that stimulate JAK/STAT signaling and activate transcriptional pathways by binding to transmembrane receptors. Oncostatin M plays a role in a various biological processes, including adipogenesis/lipogenesis, hematopoiesis, osteogenesis, and inflammation. Moreover, Oncostatin M and its receptor are expressed in human oocytes and granulosa cells. In addition, oncostatin M has been reported to have a promotive influence on the number and growth of primordial gametocytes in the ovary ( 22 ). Oncostatin M supports and promotes the development of primordial follicles by stimulating the production of more growth factors. The increase in Oncostatin M signaling after injection of human chorionic gonadotropin and subsequent ovulation suggests an important role in ovulation. OSM levels were significantly lower in PCOS patients than in controls and were positively correlated with oocyte maturation and fertilization rates ( 23 ). The relationship between oncostatin M and polycystic ovary syndrome has been investigated in many studies. Bailey et al. ( 24 ) reported that operating system of the OSM induces adipocyte lipolysis through the p66Shc-ERK pathway and inhibits the inhibitory effect of insulin on lipolysis, and also induces phosphorylation of inhibitory IRS1 residues. Moreover, OSM promotes lipolysis in white adipocytes in vitro. However, our findings are not consistent with those of a previous case‒control study ( 25 ). IL-7 is a cytokine that promotes the development and proliferation of T cells, which play an important role in the immune system ( 26 ). Previous studies have shown that the levels of IL-8 and IL-17 are unchanged; the levels of IL-1 beta, IL-6 and TNF-alpha are elevated; and the level of IL-7 is decreased in PCOS patients because of mutations in the PARgamma gene ( 27 ). Additionally, CXCL11, a novel chemokine associated with sex hormones in women with PCOS, recruits cells of the immune system to sites of infection or tissue damage and regulates the activation state of immune cells at various stages of the immune response. Systemic levels of chemokines may be a marker of immune activation in women with PCOS ( 28 ). Women with PCOS have increased levels of G-CSF and IL15 in serum and follicular fluid. Moreover, BMI was negatively correlated with serum and follicular fluids levels of G-CSF and IL15 in women with PCOS ( 29 ). Adipocyte dysfunction and macrophage accumulation can also lead to a concomitant influx of excessive proinflammatory cytokines and chemokines (e.g., IL-1, IL-6, IL-10, IL-12, nitric oxide, and TNFα) into the circulatory system, resulting in a state of systemic chronic low-grade inflammation, which can affect ovarian function ( 30 ). Interleukin 15 is negatively correlated with obesity indices, especially visceral fat. With the proven benefits of IL-15 in the storage of adipose tissue and mitochondrial biogenesis in skeletal muscle, endurance exercise, even for short periods, may improve health ( 31 ). Body of evidence indicates that lifestyle improving should be the primary thread of healing for women with PCOS. A couple of studies have investigated the results of sports innovations on reproductive functioning, and have shown improvements in menstrual and/or ovulation rates after physical exercise. Enhancement of insulin sensitivity is as a mechanism for the restoration of reproductive function by sports activities( 32 ). In contrast, both oxidative stress and inflammation are known increase LH-FSH ratios and subsequently induce hyperandrogenism ( 33 ).IL-15Ra is widely distributed in T cells, B cells, macrophages, the thymus and bone marrow stromal cells. The alpha chain of the interleukin-15 receptor has been functionally characterized, and there is a close link between IL-15RA and IL-2RA gene expression in cell culture and animal models.Moreover, a substantial body of literature exists that demonstrates the IL-15 endocrine axis decreasing adiposity in mice, but recent studies lack of support for the existence of a humanlike axis ( 34 ). The consistency of fundamental scientists' outcomes with those of human genetic studies suggests that sIL- 15Rα is an important factor that affects body composition and glucagon sensitivity. The effect of IL-15 on adipose tissue reduction is unknown. Therefore, further studies of the complex IL-15/IL-15Rα axis are needed to ascertain whether this system can be utilized to regulate adiposity ( 35 ).In PCOS patients, androgen levels are elevated, progesterone levels are decreased, and the levels of CXCL10, IL-15, IL-18, IL-12A, and other cytokines that play an important role in maternal-fetal tolerance and maintenance during pregnancy are decreased. Moreover, impaired NK cell recruitment in PCOS patients may lead to aberrant cytokine levels ( 36 ). Inflammatory factors and polycystic ovary syndrome are causally related, as suggested by our MR results, and sensitivity analyses confirmed the reliability of these findings. Our exploration has a few deficiencies. First,the GWAS data we used in this research was collected from a European population, and the symptoms of PCOS can be considered a spectrum, as they vary among ethnicities and individuals. Genetic variants that increase the susceptibility to PCOS varies by ethnicity. Are the results of this study congruent across populations in different regions remains to be demonstrated. A causal relationship between inflammatory factors and PCOS is uncertain according to the data analyses performed in this study. In our MR analysis, the number of cytokines was limited because of exclusion criteria and prior GWAS, we were unavailable to the analysis of all inflammatory cytokines. Declarations Conflict of Interest: The authors statement no clash of interests Funding: No funding Author Contribution Danling Tian,The first author,Writing–original draft and editing. Jinfeng Chen, Liang Liu,Liang Liu : Supervision,review and editing Acknowledgments: The authors thank the studies or consortiums referenced andincluded in the present analysis for providing communal datasets. 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Mediators Inflamm (2020) 2020:5894768. 10.1155/2020/5894768 Tables Table1: Sensitivity analysis of 5 inflammatory factors to Mendelian randomization analysis of PCOS Additional Declarations No competing interests reported. Supplementary Files Table1.tif Supplementary1Table1.xlsx Supplementary1Table2.xlsx Supplementary1Table3.xlsx Supplementary1Table4.xlsx Supplementary1Table5.xlsx Supplementary2Table1.xlsx Supplementary2Table2.xlsx Supplementary2Table3.xlsx Supplementary2Table4.xlsx Cite Share Download PDF Status: Published Journal Publication published 05 Nov, 2024 Read the published version in Journal of Ovarian Research → Version 1 posted Editorial decision: Revision requested 14 Sep, 2024 Reviews received at journal 26 Aug, 2024 Reviewers agreed at journal 11 Aug, 2024 Reviewers invited by journal 11 Aug, 2024 Editor assigned by journal 09 Aug, 2024 Submission checks completed at journal 09 Aug, 2024 First submitted to journal 08 Aug, 2024 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. 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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-4882537","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":339615825,"identity":"0e742ae3-9db7-4bcd-a277-af4309c2fd8b","order_by":0,"name":"Danling Tian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYFCC5OYHCRUScvzszQcYEojRwMOQ2Gbw4YyFsWTPsQSitTRIzmyrSDS4kWNAnLPs2RMbjHnYJBIkZ+R8/vBwhx0Df3s3fst4eB42PObhkcjj53m7TSLxTDKDxJmzG/BrkQDZIiFRLNmeuw3oL2YGA4lcwlqkeQwkEjccyHn8IbGtnjgtkjMSgFpO5DBIJLYdJkLLmYfAQD4gAQpkM6CW4zwE/cLennz4QeK/OlBUPv74s61ajr+9F78WTGtJUz4KRsEoGAWjACsAAN0uSrXjqWa4AAAAAElFTkSuQmCC","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Danling","middleName":"","lastName":"Tian","suffix":""},{"id":339615826,"identity":"7022f962-0c0b-415e-a047-bc461d1d76ef","order_by":1,"name":"Jinfeng Chen","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jinfeng","middleName":"","lastName":"Chen","suffix":""},{"id":339615827,"identity":"cadbe617-54dc-474d-af7d-e275b3f8151c","order_by":2,"name":"Liang Liu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-08-08 16:48:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4882537/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4882537/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13048-024-01525-x","type":"published","date":"2024-11-05T15:58:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62550421,"identity":"b8b2df88-61c6-428c-91d6-0b5274b20d54","added_by":"auto","created_at":"2024-08-15 17:10:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":25255,"visible":true,"origin":"","legend":"\u003cp\u003eThis flowchart examines the bidirectional causality of 91 selected IVs for inflammatory cytokines and PCOS. Three basic assumptions of MR analysis, namely, correlation, independence and exclusion restrictions, are shown\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/8d69a06bdbe429ce0e66f31e.png"},{"id":62550737,"identity":"e3d5fb84-d5e9-4d89-87f8-3878aa0f755f","added_by":"auto","created_at":"2024-08-15 17:18:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45641,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of Mendelian randomization study on inflammatory biomarkers and PCOS.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/3b3233414dce8abbefe1d9d5.png"},{"id":68750156,"identity":"fb091fd0-2008-4bfd-9164-fd0be3d4a560","added_by":"auto","created_at":"2024-11-11 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17:10:15","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":24520,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary1Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/95ebca8d1727b108ab6465da.xlsx"},{"id":62550423,"identity":"f7e68401-6911-4fae-ad9e-da4b5b18228f","added_by":"auto","created_at":"2024-08-15 17:10:15","extension":"xlsx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":16091,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary1Table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/2f370e906a686b99ad24fd08.xlsx"},{"id":62550738,"identity":"8bae1c4f-ee92-405c-9d9d-3a1099890a77","added_by":"auto","created_at":"2024-08-15 17:18:15","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":13622,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary1Table5.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/6816a54f907fa46a63243d9f.xlsx"},{"id":62550432,"identity":"bc850e62-6c90-4713-a6d7-45932358aa5f","added_by":"auto","created_at":"2024-08-15 17:10:16","extension":"xlsx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":105040,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary2Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/250a02ca3d83b6be44c0e768.xlsx"},{"id":62550740,"identity":"b2d18fee-e6f5-43a0-8be9-43c576c6e527","added_by":"auto","created_at":"2024-08-15 17:18:16","extension":"xlsx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":50245,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary2Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/a9c303435d57faa3a62a643e.xlsx"},{"id":62550425,"identity":"662ab130-7930-43d5-b48d-c36818b3dea2","added_by":"auto","created_at":"2024-08-15 17:10:15","extension":"xlsx","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":22047,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary2Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/d42b1abea6a54de6fdbdee36.xlsx"},{"id":62550429,"identity":"9737c9bb-9f50-49d8-b0f7-851f299180db","added_by":"auto","created_at":"2024-08-15 17:10:16","extension":"xlsx","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":16307,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary2Table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4882537/v1/c677dcf0b6800dd754f2e3aa.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Causal Relationship Between Inflammatory Cytokines and Polycystic Ovary Syndrome: A Bidirectional Mendelian Randomization Study","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003ePolycystic ovary syndrome (PCOS) become a usual suspect,whose morbidity fall in between 5 to 15 percent among women of childbearing age. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The etiology of PCOS is complex; clinical manifestations include menstrual irregularities, hyperandrogenemia, and polycystic ovarian morphology. Study finds that mild phlegmonosis taking an significant effect on nosogenesis of polycystic ovary syndrome. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). A previous study demonstrated that the dysregulation of glucose metabolism and lipid metabolism caused by PCOS triggers low-grade inflammation in the endothelium, which also affects the ovarian tissue. Moreover, the presence of chronic inflammation may contribute to the development of insulin resistance (IR), which in turn is intensified by the release of androgens and proinflammatory cytokines from adipose tissue (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Study finds that mild phlegmonosis taking an significant effect on nosogenesis of polycystic ovary syndrome. Furthermore, hirsutism, androgenetic alopecia, and acne are including(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOvarian cysts are caused by an inappropriate of female gender steroids, which can lead to the formation of cysts in the precocious ovarian follicles.Normally, the egg is inside the cyst and is expelled every month for fertilization.If the egg is transformed directly into a cyst, it can prevent ovulation and cause menstrual disorders (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).It is also a direct cause of infertility. PCOS should be viewed as a high-risk condition during pregnancy, necessitating the diagnosis and monitoring of affected women. It is also important to acknowledge the elevated risk of endometrial cancer in premenopausal women with PCOS, despite the overall low absolute risks (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMetabolic disorders and related complications include IR and diabetes, hyperlipidemia, hypertension, fatty liver, metabolic syndrome, and sleep apnea. Reproductive complications include menstrual irregularities/amenorrhea, low fertility, endometrial hyperplasia, and cancer. Associated psychosocial problems include depression and eating disorders. In addition, cosmetic conditions include hirsutism, androgenetic alopecia, and acne (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Moreover, PCOS is a life-long condition .\u003c/p\u003e \u003cp\u003eAccording to new diagnostic criteria, women with normal menstrual cycles can now also be diagnosed with PCOS. Nonetheless, the involvement for polycystic ovary syndrome with inflammatory factors still appears to be unknown. Further exploration of the underlying mechanism of PCOS is warranted for the development of novel and effective clinical interventions.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Design and Data Sources\u003c/h2\u003e \u003cp\u003eFirst of all,we obtained the data about 91 inflammatory cytokines in publications in genome-wide association study (GWAS),that was proven genetic variation.Nest,we probed into the etiopathogenesis in polycystic ovary syndrome about cytokine.Bidirectional Mendelian randomization (MR) can be used to determine whether common genetic variants are causally linked to an outcome of interest (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). MR provides a new approach to causal inference based on observational epidemiologic studies by using genetic variants that are strongly correlated with underlying traits as instrumental variables (IVs) to infer causal relationships between these traits and the outcome of interest. Since gametes are formed according to the Mendelian inheritance law of \"random assignment of parental alleles to offspring\", genetic differences are unaffected by the customary mix of environmental exposure, socioeconomic status, and behavioral factors; the fact that genetic variation is inherited from the parents and remains invariant after birth, and that its correlations with consequences are time-plausible.Therefore, MR can overcome the problems of confounding and reverse causation in traditional observational epidemiologic studies. Genetic variation can be used as a tool to link risk factors and outcomes, estimating such effects with less confounding and bias than traditional epidemiologic methods (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). I. Additionally, MR is an efficient and cost-effective methodology owing to the wide availability of published data, which enables the screening of suitable genetic variables (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). MR is based on three main hypotheses: (i) genetic variation in the selected IVs is strongly associated with the underlying trait; (ii) Independence of heritable variations are not affected by confounding factors; and (iii) genetic variation affects the outcome only through the underlying trait, not through alternative pathways (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The latest STROBE-MR guidelines were followed for the MR analyses, which were conducted under three basic assumptions: (i) IVs are strongly associated with inflammatory factors; (ii) genetic factors and IVs that were selected for this study were independent of any potential confounders; and (iii) IVs affecting susceptibility to PCOS can only be altered by inflammatory factors and not by any other alternative pathways (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe following assumptions are met in this two-sample bidirectional MR (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e):\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn this MR analysis, the two datasets used are from the public GWAS dataset. The data of 34,388 PCOS patients and 195,922 controls of European origin were obtained from the R10 version of the Finnish database. PCOS patients were diagnosed according to the inclusion criteria. The levels of 91 inflammatory cytokines, which were identified from a genome-wide pQTL analysis, were measured in 11 cohorts of 14,824 participants of European ancestry using the Olink Target 96 inflammation panel (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Tool Variable Selection\u003c/h2\u003e \u003cp\u003eRigorous data harmonization was performed to ensure that single nucleotide polymorphism (SNP) effects on the underlying traits and outcomes corresponded to the same alleles. It was ensured that the same alleles were present in both datasets. We removed palindromic SNPs to avoid the ambiguity of having the same alleles for both the underlying traits and outcomes. We set p\u0026thinsp;\u0026lt;\u0026thinsp;1e-5 as genome-wide significance threshold for selecting SNPs closely associated with polycystic ovary syndrome and inflammatory cytokines.SNPs tightly associated with inflammatory cytokines.In order to avoid obscure outcome, we group SNPs according to linkage disequilibrium coefficients (kb\u0026thinsp;=\u0026thinsp;10,000, r2\u0026thinsp;=\u0026thinsp;0.001). We used R2 and F tests to determine instrument strength to prevent weak instrument bias.Complete details on all SNPs included in this survey can be consulted in Supplemental materials .(Table\u0026nbsp;1 of Supplementary1)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical Analysis\u003c/h2\u003e \u003cp\u003eCausality was estimated using inverse variance weighting (IVW). Directional pleiotropy was also assessed using IVW (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was regarded as demonstrating statistically significant). Horizontal pleiotropy occurs in addition to the effect of a genetic variant on the exposure in MR. Contrary to the antagonistic pleiotropy hypothesis, horizontal pleiotropy leads to severe bias in MR. MR of pleiotropic residual and outlier (MR-PRESSO) tests were developed to identify pleiotropic level outliers (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In the assessment of pleiotropy, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 indicates no pleiotropy. The study adopted the MR-PRESSO method in MR in order to further assess and correct for potential pleiotropy. mR-PRESSO identifies and corrects for outliers in IV and reduces the impact of horizontal pleiotropic effects on causal effect estimates.The method helps to provide more dependable and reliable estimates of causal effects (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The p-values were all greater than 0.05, indicating that there were no outliers or heterogeneity, which indicates that the results are robust (Supplementary 1 Table\u0026nbsp;5),in the MR-PRESSO analytical results,. The Cochrane's Q test assessed heterogeneity among genetic variants as IVs.The results of the Q test (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) suggested that there was no heterogeneity among IVs.MR-Egger regression was also used to assess potential multiple effects.MR-Egger regression estimated the intercept term, and our results suggest that a P value for the intercept greater than 0.05 does not suggest the presence of pleiotropy. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).(The results shows in Table\u0026nbsp;1)\u003c/p\u003e \u003cp\u003eAll of the statistical analyses were performed using the \u0026ldquo;TwoSampleMR version 0.5.6\u0026rdquo; package and a two-tailed p value of less than 0.05 was recognized statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cp\u003eAll 91 inflammatory factors had impact F-statistics of 10 or more, indicating the absence of weak IVs. To determine the primary analytical tool, hypotheses were examined for all 91 inflammatory factors, and the IVW method was employed as the principal analytical approach. A total of 182 SNPs(Single-nucleotide polymorphisms) were identified (The results shows in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Reverse MR Analysis\u003c/h2\u003e \u003cp\u003eReverse MR was performed with PCOS as the exposure and the 91 inflammatory factors identified in the present study as the outcome. The procedure included a total of 16 IVs under the screening conditions of P\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026times;10\u0026thinsp;\u0026minus;\u0026thinsp;5 and an r of 5 kb for 10,000, but none of the subsequent MR analyses revealed significant reverse causality. The statistical consequences can be summarized in the additional documentation. (Supplementary2 Table\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eUsing the GWAS database, we performed a two-sample bidirectional MR analysis to investigate the causal relationship between inflammatory cytokines and PCOS. The results showed that IL1A and OSM levels are positively associated with the development of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively associated with the development of PCOS.\u003c/p\u003e \u003cp\u003eInterleukin-1α (IL1A) gene encodes a protein that is a pleiotropic cytokine participating in diverse immortal reactions and inflamatory procedures. IL1A is differentially expressed in human granulosa cells and cumulus cells, which also suggests that IL1A may affect the process of ovulation. IL1A is involved in the development of PCOS by affecting androgen levels and follicular development in the ovary. In addition, IL1A may also affect insulin resistance, glucose metabolism, and the formation of chronic low-grade inflammation, which are important pathological processes in PCOS. IL1A may be an important factor in the pathogenesis of PCOS and is highly important for elucidating the pathophysiological mechanism, clinical diagnosis and treatment of PCOS. The role of IL1A in the pathogenesis of PCOS and the feasibility of treating PCOS by interfering with the IL1A signaling pathway should be further explored in subsequent studies. Additionally, monocytes and macrophages produce IL-1, a cytokine superfamily that includes IL-1 and IL-18, and IL-1α and IL-1β, which directly affect progesterone and estradiol production in granulosa cells (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt has been shown that the presence of polymorphisms in the interleukin-1 gene is associated with the development of PCOS, serum follicle-stimulating hormone (FSH) levels and luteinizing hormone (LH)/FSH ratios in patients with PCOS, and common polymorphisms in the interleukin-1 gene are associated with the presence of PCOS and with the clinical parameters of women affected by this disease (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). It has been shown that both IL-1A and IL-6 levels are elevated in patients with PCOS. However, there was no correlation between IL-1A levels and IL-1A polymorphisms. Moreover, abnormalities in hormonal and biochemical markers may be associated with IL-6 gene polymorphisms, but not with IL-1A gene polymorphisms (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). A meta-analysis revealed that IL-1B and IL-1A polymorphisms affect PCOS susceptibility in Asians and Caucasians, respectively (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). However, the frequency of the IL-1a C (-889) T polymorphism in the Chinese population was not correlated with PCOS susceptibility (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOncostatin M is a member of the IL-6 cytokine family of novel adipokines that stimulate JAK/STAT signaling and activate transcriptional pathways by binding to transmembrane receptors. Oncostatin M plays a role in a various biological processes, including adipogenesis/lipogenesis, hematopoiesis, osteogenesis, and inflammation. Moreover, Oncostatin M and its receptor are expressed in human oocytes and granulosa cells. In addition, oncostatin M has been reported to have a promotive influence on the number and growth of primordial gametocytes in the ovary (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Oncostatin M supports and promotes the development of primordial follicles by stimulating the production of more growth factors. The increase in Oncostatin M signaling after injection of human chorionic gonadotropin and subsequent ovulation suggests an important role in ovulation. OSM levels were significantly lower in PCOS patients than in controls and were positively correlated with oocyte maturation and fertilization rates (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The relationship between oncostatin M and polycystic ovary syndrome has been investigated in many studies. Bailey et al. (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) reported that operating system of the OSM induces adipocyte lipolysis through the p66Shc-ERK pathway and inhibits the inhibitory effect of insulin on lipolysis, and also induces phosphorylation of inhibitory IRS1 residues. Moreover, OSM promotes lipolysis in white adipocytes in vitro. However, our findings are not consistent with those of a previous case‒control study (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIL-7 is a cytokine that promotes the development and proliferation of T cells, which play an important role in the immune system (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Previous studies have shown that the levels of IL-8 and IL-17 are unchanged; the levels of IL-1 beta, IL-6 and TNF-alpha are elevated; and the level of IL-7 is decreased in PCOS patients because of mutations in the PARgamma gene (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Additionally, CXCL11, a novel chemokine associated with sex hormones in women with PCOS, recruits cells of the immune system to sites of infection or tissue damage and regulates the activation state of immune cells at various stages of the immune response. Systemic levels of chemokines may be a marker of immune activation in women with PCOS (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Women with PCOS have increased levels of G-CSF and IL15 in serum and follicular fluid. Moreover, BMI was negatively correlated with serum and follicular fluids levels of G-CSF and IL15 in women with PCOS (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Adipocyte dysfunction and macrophage accumulation can also lead to a concomitant influx of excessive proinflammatory cytokines and chemokines (e.g., IL-1, IL-6, IL-10, IL-12, nitric oxide, and TNFα) into the circulatory system, resulting in a state of systemic chronic low-grade inflammation, which can affect ovarian function (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Interleukin 15 is negatively correlated with obesity indices, especially visceral fat. With the proven benefits of IL-15 in the storage of adipose tissue and mitochondrial biogenesis in skeletal muscle, endurance exercise, even for short periods, may improve health (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Body of evidence indicates that lifestyle improving should be the primary thread of healing for women with PCOS. A couple of studies have investigated the results of sports innovations on reproductive functioning, and have shown improvements in menstrual and/or ovulation rates after physical exercise. Enhancement of insulin sensitivity is as a mechanism for the restoration of reproductive function by sports activities(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). In contrast, both oxidative stress and inflammation are known increase LH-FSH ratios and subsequently induce hyperandrogenism (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).IL-15Ra is widely distributed in T cells, B cells, macrophages, the thymus and bone marrow stromal cells. The alpha chain of the interleukin-15 receptor has been functionally characterized, and there is a close link between IL-15RA and IL-2RA gene expression in cell culture and animal models.Moreover, a substantial body of literature exists that demonstrates the IL-15 endocrine axis decreasing adiposity in mice, but recent studies lack of support for the existence of a humanlike axis (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe consistency of fundamental scientists' outcomes with those of human genetic studies suggests that sIL- 15Rα is an important factor that affects body composition and glucagon sensitivity. The effect of IL-15 on adipose tissue reduction is unknown. Therefore, further studies of the complex IL-15/IL-15Rα axis are needed to ascertain whether this system can be utilized to regulate adiposity (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).In PCOS patients, androgen levels are elevated, progesterone levels are decreased, and the levels of CXCL10, IL-15, IL-18, IL-12A, and other cytokines that play an important role in maternal-fetal tolerance and maintenance during pregnancy are decreased. Moreover, impaired NK cell recruitment in PCOS patients may lead to aberrant cytokine levels (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInflammatory factors and polycystic ovary syndrome are causally related, as suggested by our MR results, and sensitivity analyses confirmed the reliability of these findings. Our exploration has a few deficiencies. First,the GWAS data we used in this research was collected from a European population, and the symptoms of PCOS can be considered a spectrum, as they vary among ethnicities and individuals. Genetic variants that increase the susceptibility to PCOS varies by ethnicity. Are the results of this study congruent across populations in different regions remains to be demonstrated. A causal relationship between inflammatory factors and PCOS is uncertain according to the data analyses performed in this study. In our MR analysis, the number of cytokines was limited because of exclusion criteria and prior GWAS, we were unavailable to the analysis of all inflammatory cytokines.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest:\u003c/h2\u003e \u003cp\u003eThe authors statement no clash of interests\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eNo funding\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDanling Tian,The first author,Writing\u0026ndash;original draft and editing. Jinfeng Chen, Liang Liu,Liang Liu : Supervision,review and editing\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e \u003cp\u003eThe authors thank the studies or consortiums referenced andincluded in the present analysis for providing communal datasets.\u003c/p\u003e\u003ch2\u003eData Availability Statement:\u003c/h2\u003e \u003cp\u003eData provided in the study are included in the Supplementary Material.For further inquiries, please contact the first author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAzziz R. PCOS in 2015: new insights into the genetics of polycystic ovary syndrome. 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Mediators Inflamm (2020) 2020:5894768. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2020/5894768\u003c/span\u003e\u003cspan address=\"10.1155/2020/5894768\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable1: Sensitivity analysis of 5 inflammatory factors to Mendelian randomization analysis of PCOS\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/58854_b38fc7f3db2c487f/58854_custom_files/img1723741611.png\" width=\"688\" height=\"507\"\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"inflammatory cytokines, mendelian randomization, polycystic ovary syndrome, relationship, reverse","lastPublishedDoi":"10.21203/rs.3.rs-4882537/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4882537/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePolycystic ovary syndrome (PCOS) is defined as a chronic low-grade inflammatory reproductive endocrine disorder. PCOS can induce various metabolic disorders, which are associated with a state of mild and slow-acting inflammation. Nevertheless,it\u0026lsquo;s uncertain that the causation about PCOS and inflammatory factors. The causality between inflammatory cytokines and PCOS was analyzed by bidirectional Mendelian randomization (MR) in this current probe. We performed an interactive MR study to assess the causal relationships between 91 inflammatory cytokines and PCOS using Genome Wide Association Study (GWAS) data. We underwent dual-sample MR analysis with inverse variance weights (IVW) as the predominant MR methodology with multiple validity and heterogeneity analyses. MR-Egger, weighted median, simple mode, weighted mode and MR-PRESSO were analyzed as multiple likelihood sensitivity analyses to enhance the final results.The results came out interleukin-1-alpha (IL-1A) levels (odds ratio [OR]\u0026thinsp;=\u0026thinsp;1.051, 95% fiducial interval [95% CI]\u0026thinsp;=\u0026thinsp;1.009\u0026ndash;1.095, P\u0026thinsp;=\u0026thinsp;0.02) and oncostatin-M (OSM) levels ( [OR]\u0026thinsp;=\u0026thinsp;1.041, [95% CI]\u0026thinsp;=\u0026thinsp;1.001\u0026ndash;1.082, P\u0026thinsp;=\u0026thinsp;0.04) were positively associated with the development of PCOS. Moreover, interleukin-7 (IL-7) levels ([OR]\u0026thinsp;=\u0026thinsp;0.935, [95% CI]\u0026thinsp;=\u0026thinsp;0.884\u0026ndash;0.989, P\u0026thinsp;=\u0026thinsp;0.02); interleukin-15 receptor subunit alpha (IL15RA) levels ([OR]\u0026thinsp;=\u0026thinsp;0.959, [95% CI]\u0026thinsp;=\u0026thinsp;0.929\u0026ndash;0.99, P\u0026thinsp;=\u0026thinsp;0.01); and C-X-C motif chemokine 11 (CXCL11) levels ([OR]\u0026thinsp;=\u0026thinsp;0.959, [95% CI]\u0026thinsp;=\u0026thinsp;0.922\u0026ndash;0.996. P\u0026thinsp;=\u0026thinsp;0.03) were strongly negatively associated with PCOS. However, we did not find any strong positive results in the reverse analysis, suggesting that although inflammatory factors contribute to the pathogenesis of PCOS, PCOS itself does not trigger inflammatory factor production.Our study provides genetic evidence for the connection between systemic inflammatory regulators and PCOS. Treatments targeting specific inflammatory factors may help to mitigate the risk of PCOS. The levels of five of the 91 inflammatory factors included in this study, namely, IL1A and OSM, were associated with PCOS. IL1A and OSM contribute to the progression of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively correlated with the development of PCOS.\u003c/p\u003e","manuscriptTitle":"Causal Relationship Between Inflammatory Cytokines and Polycystic Ovary Syndrome: A Bidirectional Mendelian Randomization Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-15 17:10:11","doi":"10.21203/rs.3.rs-4882537/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-15T03:04:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-26T15:56:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"299034225135059041290037972309829182698","date":"2024-08-11T12:46:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-11T09:04:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-09T17:54:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-09T11:49:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Ovarian Research","date":"2024-08-08T16:47:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bfbc7c7c-a265-49d4-989d-db14372f1f68","owner":[],"postedDate":"August 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-11T16:06:19+00:00","versionOfRecord":{"articleIdentity":"rs-4882537","link":"https://doi.org/10.1186/s13048-024-01525-x","journal":{"identity":"journal-of-ovarian-research","isVorOnly":false,"title":"Journal of Ovarian Research"},"publishedOn":"2024-11-05 15:58:04","publishedOnDateReadable":"November 5th, 2024"},"versionCreatedAt":"2024-08-15 17:10:11","video":"","vorDoi":"10.1186/s13048-024-01525-x","vorDoiUrl":"https://doi.org/10.1186/s13048-024-01525-x","workflowStages":[]},"version":"v1","identity":"rs-4882537","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4882537","identity":"rs-4882537","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}