Endometriosis and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study

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But residual confounding and the potential for reverse causality are inevitable in such routine observational studies. This study used Mendelian randomization (MR) design to evaluate the causal effect of endometriosis on CVD including coronary heart disease (CHD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), hypertension and Stroke. Methods We utilized publicly available summary statistics of genome-wide association studies (GWAS) from European participants in the UK Biobank and Finnish databases. Instrumental variables (IVs) associated with endometriosis and CVD were identified and used IVs to investigate the genetic causal relationship between them. MR analyses were performed using various analytical methods, including Inverse variance weighted (IVW), MR-Egger, and Weighted Median. Tests for pleiotropy and heterogeneity were performed to assess the reliability of causality. Results MR analysis showed that endometriosis was associated with hypertension (odds ratio (OR) = 0.9990, 95% confidence interval (CI) : 0.9981–0.9998, P = 0.0191), which may be a protective factor. However, this significance disappeared after applying the Bonferroni correction. Endometriosis was identified as a risk factor for CHD (OR = 1.0025,95%CI: 1.0005–1.0046, P = 0.0164), but this significance was lost after Bonferroni correction. Endometriosis was identified as a risk factor for MI (OR = 1.0018, 95%CI: 1.0005–1.0032, P = 0.0058), which remained significant after Bonferroni correction. Genetic associations between endometriosis and other CVD were not significant. Conclusions MR studies have shown that genetic predisposition to endometriosis is significantly associated with the risk of myocardial infarction, and may be associated with the risk of CHD and hypertension. However, the causal relationships between endometriosis and AF, HF and Stroke need to be further explored. Mendelian randomization Endometriosis Cardiovascular Diseases causal inference Coronary heart disease Figures Figure 1 Figure 2 Introduction Endometriosis is a chronic, inflammatory, estrogen-dependent disease, which is estimated to burden 10% of women of reproductive age, affecting nearly 190 million women worldwide ( 1 ). The disease occurs when endometrioid tissue is implanted and grows in an ectopic location ( 2 ), which can have a negative impact on quality of life. Endometriosis in women can cause infertility, severe menstrual cramps, pelvic discomfort, and/or pain during intercourse, urination, or bowel movements ( 3 ). It is also linked to sadness and exhaustion, which leads to a loss of employment and fertility ( 4 , 5 ) as well as a strain on economic and medical resources ( 6 , 7 ). Endometriosis should be considered a public health issue in light of these consequences. Studies have shown that inflammation and immune response are involved in the occurrence and development of cardiovascular diseases (CVD) ( 8 , 9 ), which are also the main pathophysiological processes of endometriosis ( 2 ). Thus, as reported in many experimental and observational studies, endometriosis has emerged as a potential risk factor for the development of cardiovascular disease ( 10 – 12 ). These studies have shown that endometriosis is associated with atherosclerosis ( 13 ), hypertension ( 14 ), coronary heart disease ( 15 ), myocardial infarction ( 16 ), heart failure ( 11 ) and other cardiovascular diseases. However, it should be pointed out that due to the limitations of traditional research methods, the potential confounding factors or reverse causality may affect the research results to some extent. Mendelian randomization (MR) is a novel approach that can avoid the limitations of traditional research ( 17 ). In this case, MR eliminates systematic bias by selecting the genetic variable associated with exposure as the IVs, randomly assigning alleles at conception according to Gregor Mendel's second law ( 18 ). Through this, confounding factors are randomly distributed throughout the population. MR uses genetic variants associated with potentially modifiable risk factors to determine their causal effect on disease risk. Currently, studies have used MR to explore causal relationships between endometriosis and clotting factors ( 19 ), anxiety and depressive states ( 20 ), and asthma ( 21 ). However, these studies did not limit the gender of the included population to women, which lead to some bias in the results. In order to overcome the limitations of traditional observational studies and the gender ambiguity of existing MR studies, we used the Two Sample Mendelian randomization (TSMR) method to clarify the causal association between endometriosis and cardiovascular disease. The association between endometriosis-associated single nucleotide polymorphisms (SNPs) and cardiovascular disease risk was evaluated based on two independent publicly available genome-wide association studies (GWAS.) Method In this study, we conducted an analysis of TSMR. SNPs are randomly assigned at conception, a property that establishes that SNPS are not influenced by acquired environmental factors ( 22 ). The increasingly accepted contribution of publicly available databases has facilitated the application of TSMR. In this study, we used exposure data from Finnish database( http://www.finngen.fi/en ) for genetic variants associated with endometriosis (ID: finn-b-N14_ENDOMETRIOSIS) (n case = 15088, n control = 107564); Similarly, the result of cardiovascular disease (CVD) data from UKB database ( http://www.nealelab.is/uk-biobank ). To ensure the accuracy of the results, we only selected the female sample data. Phenotypes were I9_CHD, I9_MI_STRICT, HEARTFAIL, I48 Atrial fibrillation and flutter, I9_HYPTENS, I9_STR_SAH. The potential causal effects of endometriosis on CVD including Coronary heart disease(CHD), Myocardial infarction (MI), Atrial fibrillation (AF), Heart failure (HF), hypertension and Stroke were explored by TSMR. As hypothesized, three assumptions must be met when conducting the MR:1) Association hypothesis: there is a strong association between the IVs and the exposure factors; 2) Independence assumption: IVs were independent of confounding factors affecting exposure and outcome; 3) Exclusivity hypothesis: IVs can affect the outcome only through exposure pathway, not through other pathways. (Fig. 1 ). IVs were selected by the following criteria:1) GWAS associated with a P-value of 5*10 − 8 ;2) filtering linkage disequilibrium(LD) (r 2 < 0.001; distance < 1000 kb).After that, We searched the secondary phenotype of each SNP in PhenoScanner( http://www.phenoscanner.medschl.cam.ac.uk ), with a threshold of P < 1×10 − 5 and deleted 4 SNPs(rs1936805,rs1451385, rs635634,rs3803361), which were associated with CVD confounders. The content relates to blood pressure ( 23 ), waist-to-hip ratio ( 24 ), Low density lipoprotein cholesterol(LDL) and High density lipoprotein cholesterol(HDL) ( 25 ) Removing confounding factors can avoid potential pleiotropic effects ( 26 ). Subsequently, we eliminated three palindrome alleles of SNPs (rs12213593, rs58415480, rs7967229). Finally, we evaluated R 2 and F statistics to detect whether the chosen IVs were strongly associated with exposure. R 2 and F can be calculated by formulas. R 2 = β 2 (1 − EAF)×2EAF F = R 2 (N − K−1)/K(1 − R 2 ) (EAF is the frequency of gene mutation. K is the number of exposure-related SNPs and N is the number of samples in the exposure outcome. Single SNP with F statistic > 10 was defined as reliable and valid IV that prevents MR results from being affected by weak instrument bias ( 27 )) To eliminate false positive findings owing to multiple testing, the Bonferroni correction was utilized. As a result, P value less than 0.008 (0.05/6 outcomes) was deemed robust, P value between 0.008 and 0.05 was considered suggestive, and P value more than 0.05 was supposed nonsignificant. Statistical Analysis Three different MR methods, Inverse variance weighted(IVW), MR Egger and Weighted Median(WM) are used to deal with heterogeneity and pleotropic effects. IVW is used as the primary evaluation method, while MR-Egger and Weighted Median are used to improve IVW estimates as they can provide more reliable results in other scenarios. MR-Egger is a method of analysis assuming that all IVs used in the MR Analysis are invalid. The weighted median allows for the assumption that at least half of the tools used in the MR analysis are valid. IVW is a method for analysis under the assumption that all IVs used in MR analysis are valid. If the results obtained by the three calculation methods are inconsistent, the IVW results are taken as the main result. The scatter plot was then used to display the outcomes of the three approaches. In terms of sensitivity analysis, the MR-PRESSO method was utilized to find and eliminate outliers in IVW linear regression to offer corrected MR estimate; the Cochran's Q test was also used to discover heterogeneity; and the leave-one-out sensitivity test was performed to detect if a single SNP leads to results. All statistical analyses were performed using the "TwoSampleMR", "mr-presso"packages in R software, version 4.2.3. Ethic This study used data from publicly available databases that had been approved by ethics committees. So separate ethical approval was not required in this study. Results After screening for confounders and palindromic SNPs, 20 SNPs were used as IVs to study the causal relationship between endometriosis and CVD, and all of them had F values greater than 10(Supplementary Table S1 ). We primarily employed the IVW method to investigate the genetic link between endometriosis and CVD. Endometriosis genetic prediction was linked to hypertension [odds ratio (OR) = 0.9990, 95% confidence interval (CI): 0.9981–0.9998, P = 0.0191], which might be a protective factor. However, after using the Bonferroni correction, this significance vanished. Endometriosis was shown to be a risk factor for CHD (OR = 1.0025, 95% CI: 1.0005–1.0046, P = 0.0164), although this significance was lost following Bonferroni correction. Endometriosis was shown to be a risk factor for MI (OR = 1.0018, 95% CI: 1.0005–1.0032, P = 0.0058), and the relationship remained robust after Bonferroni correction. However, genetic associations between endometriosis and other CVD were not significant, detailed information can be found in Fig. 2 . Scatter plots are used to display the results of three statistical methods (Supplementary Figures S1 ). Sensitivity analyses were performed to detect the presence of horizontal pleiotropy, confirming the reliability of the IVW results. There was no statistical significance for heterogeneity (P value for Cochran's Q > 0.05), pleiotropy (P value for intercept > 0.05), or outliers (Supplementary Table S2 , Supplementary Table S3 , Supplementary Figures S2 ). Discussion To our knowledge, this is the first MR study to determine causal relationship between endometriosis and CVD. The results show that genetic predisposition to endometriosis is significantly associated with the risk of MI, and may be associated with the risk of coronary heart disease and hypertension. However, there is no evidence of an association between endometriosis and AF, HF and Stroke. Endometriosis is a complex disease influenced by both genetic and environmental factors. Genetic studies have previously reported similar potential associations between endometriosis and atherosclerotic cardiovascular disease, and there is a large body of literature focused on the increased risk of myocardial infarction, ischemic heart disease, and hypertension in women with endometriosis ( 10 , 28 , 29 ). At present, detailed study is needed to fully understand the clinical relevance and underlying pathophysiological mechanisms of the interaction between endometriosis and CVD. The immune system and inflammatory response play important roles in the pathophysiology of endometriosis as well as CVD ( 30 , 31 ). CXC chemokines are cytokines that attract and regulate immune cells, and play a crucial role in inflammatory response and immune homeostasis ( 32 ). Relevant studies have accumulated evidence linking these CXC chemokines and the pathogenesis of female reproductive diseases such as endometriosis ( 33 ). The CXC family member CXCL4 is involved in chemotaxis of neutrophils and monocytes ( 34 ). Both neutrophils and monocytes have been implicated in endometrial healing. CXCL4 inhibits angiogenesis by directly interacting with vascular endothelial growth factor and fibroblast growth factor. In addition, related studies have found that platelet activation in patients with endometriosis further releases CXCL4, which may continue to activate the coagulation process by inducing more platelet aggregation ( 35 ). Many cell types, including mesothelial cells, endometrial cells, and peripheral blood monocytes, among others, produce the chemokine CXCL8, which increases endothelial cell permeability, and increased CXCL-8 secretion also promotes leukocyte adhesion and migration into the subendothelial space, leading to foam cell formation and atherogenesis ( 36 ). Inflammation is part of the non-specific immune response and plays a key role in endometriosis and CVD. Endometriosis is caused by a variety of inflammatory factors such as cytokines, prostaglandins, macrophages, and tumor necrosis factor. A recent study by Rafi et al. ( 17 ) showed that in women with endometriosis, inflammation leads to a hypercoagulable state, which leads to the development of atherosclerosis and other cardiac complications. Various inflammatory factors such as interleukin-1(IL-1), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) are elevated in peritoneal fluid and peripheral blood of patients with endometriosis ( 37 , 38 ). Studies have also shown increased markers of oxidative stress but decreased antioxidants in peritoneal fluid ( 39 , 40 ) and peripheral blood ( 41 , 42 ) in women with endometriosis. In addition, women with endometriosis have higher serum levels ofLDL( 43 ) and HDL ( 42 ). Therefore, the increased incidence of cardiovascular events in women with endometriosis may be related to increased oxidative stress and atherogenic lipids ( 44 ). Many studies have also explained the relationship between the two diseases from the genetic level. Vascular endothelial growth factor, encoded by the human vascular endothelial growth factor gene located on chromosome 6p21.3, is a powerful regulator of angiogenesis and has also been implicated in endothelial cell dysfunction. The rs1570360(-1154G/A)SNP located in the promoter region of transcription factor binding sites (TFBS) has been associated with coronary heart disease ( 45 , 46 ) and endometriosis ( 47 ). Endometriosis shares a common genetic pathway with myocardial infarction and coronary artery disease. For example, variants in the CDKN2CBAS gene on chromosome 9 are significantly associated with the development of endometriosis and acute myocardial infarction. The discovery of MicroRNAs opens up new avenues for investigating the link between endometriosis and ASCVD. MicroRNAs are small non-coding RNA molecules that can regulate gene expression, thereby promoting or preventing protein synthesis, and regulate the expression of adhesion molecules that are highly expressed in the cardiovascular system. Gynecological disorders such as endometriosis are induced under a variety of conditions that affect human reproductive organs and processes ( 44 ). This TSMR analysis has several advantages: ( 1 ) Compared with traditional observational studies, the MR method reduces the influence of confounding factors and reverse causality, making our results more objective and convincing; ( 2 ) The pooled data included were based on women of European ancestry, which mitigated the effects of demographic and sex factors on the results; ( 3 ) IVs were strictly screened to reduce the bias caused by inappropriate IVs. Our study also has certain limitations: ( 1 ) we did not stratify the causal relationship between endometriosis and CVD by age, BMI, and other factors; ( 2 ) The European sample study limited the clinical significance of the results to other populations. Conclusions In conclusion, there is a modest association between endometriosis and CVD in a European female population. Genetic predisposition to endometriosis is significantly associated with the risk of myocardial infarction, and may be associated with the risk of coronary heart disease and hypertension. However, this study did not show evidence of an association between endometriosis and atrial fibrillation, heart failure or Stroke. Declarations Data availability statement The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author Contributions PH designed the study and drafted the article. SF and ZZ collect data. PH, LG, HZ, YL, XM, SF and ZZ performed data analysis and manuscript revisions. All authors contributed to this article and approved the submitted version. 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Epub 2018/05/09. doi: 10.1016/j.gene.2018.04.082. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigures.docx SupplementaryTableS.xlsx STROBEMRchecklistfillable.docx 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-3647756","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":252321595,"identity":"b3cbb7ab-895e-4758-a0c6-449c390a7bd4","order_by":0,"name":"Pingping Huang","email":"","orcid":"","institution":"Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China","correspondingAuthor":false,"prefix":"","firstName":"Pingping","middleName":"","lastName":"Huang","suffix":""},{"id":252321596,"identity":"94865f8c-0945-42f4-9f93-301f16a06d5e","order_by":1,"name":"Yifei Wang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yifei","middleName":"","lastName":"Wang","suffix":""},{"id":252321597,"identity":"83ce295b-1a6d-460c-98b3-dad40519438f","order_by":2,"name":"Yicheng Liu","email":"","orcid":"","institution":"Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China","correspondingAuthor":false,"prefix":"","firstName":"Yicheng","middleName":"","lastName":"Liu","suffix":""},{"id":252321598,"identity":"dcba6d4c-4ba8-4663-bc6b-d00d14e06599","order_by":3,"name":"Hongwei Zhang","email":"","orcid":"","institution":"Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China","correspondingAuthor":false,"prefix":"","firstName":"Hongwei","middleName":"","lastName":"Zhang","suffix":""},{"id":252321599,"identity":"513d35cd-a385-4f48-ac94-4ee1ffd9e153","order_by":4,"name":"Shuangqing Fu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Shuangqing","middleName":"","lastName":"Fu","suffix":""},{"id":252321600,"identity":"d8078951-1104-46ca-88bd-333cc30cba13","order_by":5,"name":"Zhibo Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Zhibo","middleName":"","lastName":"Zhang","suffix":""},{"id":252321601,"identity":"d71691cb-1e05-4c63-8414-aae389ff9e7d","order_by":6,"name":"Lijun Guo","email":"","orcid":"","institution":"Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China","correspondingAuthor":false,"prefix":"","firstName":"Lijun","middleName":"","lastName":"Guo","suffix":""},{"id":252321602,"identity":"a9c34744-caf5-4b33-9c7d-3d36d32cb20e","order_by":7,"name":"Xiaochang Ma","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYJCCA0CcAMSMDxgqbOxI0sJswHAmLRmkt4EYbSAtbBKMbYdAyvFr0W0/Y3jgR4VdHv/s9mvVPGwHmBmkm48/wKfF7ExawsGeM8nFEnfOlN2cwXOHj0HmWCJeW8wOJB84wNt2ILHhRk7ajQ8Sz5gZJHIM8Ws5/7Dh4F+glvlALQUJBocZGyTyP+LXciP5wGGQLRtupB9j+JAA0pKD3/tmN54lHJY5k5y48UYOs+SMA2nJbBJphjPwOyzH+OObCrvEeTfSH37m/Wdjxy+R/OADPi1IgMcATLERqRwE2B+QoHgUjIJRMApGEgAAI0ZX9NHd8ukAAAAASUVORK5CYII=","orcid":"","institution":"Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China","correspondingAuthor":true,"prefix":"","firstName":"Xiaochang","middleName":"","lastName":"Ma","suffix":""}],"badges":[],"createdAt":"2023-11-22 08:59:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3647756/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3647756/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":47224198,"identity":"322f063a-3530-49da-8cef-b9439bf666e8","added_by":"auto","created_at":"2023-11-28 19:19:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55653,"visible":true,"origin":"","legend":"\u003cp\u003eThe Three Hypothetical Laws of Mendelian Randomization Research\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3647756/v1/db0a6424fce70c143f56e36b.png"},{"id":47224200,"identity":"69ee1950-5156-4a2e-baf4-8730d0bd880b","added_by":"auto","created_at":"2023-11-28 19:19:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1573873,"visible":true,"origin":"","legend":"\u003cp\u003eThe correlation between endometriosis and cardiovascular disease detected by a complete set of single nucleotide polymorphisms. OR, odds ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3647756/v1/7417b83b7d1200c32ec210b2.png"},{"id":48045814,"identity":"17a044e0-cf9e-452e-808a-e3d329c98909","added_by":"auto","created_at":"2023-12-12 09:17:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":759610,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3647756/v1/940e8a08-5d54-452e-9ff5-a8dc6c8e1033.pdf"},{"id":47224202,"identity":"9b2e31d4-bdf5-4ec3-a410-ad12b328a21f","added_by":"auto","created_at":"2023-11-28 19:19:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":440889,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-3647756/v1/b4c1a071caf5fbba7e7411f3.docx"},{"id":47224199,"identity":"b7e20610-906f-4879-8eda-9596b16766c5","added_by":"auto","created_at":"2023-11-28 19:19:53","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":15009,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3647756/v1/4bff6b64f2f2682277c2f0ad.xlsx"},{"id":47224201,"identity":"4e46675a-dace-4609-802d-c8a345756875","added_by":"auto","created_at":"2023-11-28 19:19:54","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":43123,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEMRchecklistfillable.docx","url":"https://assets-eu.researchsquare.com/files/rs-3647756/v1/4d3ca375a0381ec4b1555b48.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Endometriosis and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a chronic, inflammatory, estrogen-dependent disease, which is estimated to burden 10% of women of reproductive age, affecting nearly 190\u0026nbsp;million women worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The disease occurs when endometrioid tissue is implanted and grows in an ectopic location (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), which can have a negative impact on quality of life. Endometriosis in women can cause infertility, severe menstrual cramps, pelvic discomfort, and/or pain during intercourse, urination, or bowel movements (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It is also linked to sadness and exhaustion, which leads to a loss of employment and fertility (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) as well as a strain on economic and medical resources (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Endometriosis should be considered a public health issue in light of these consequences.\u003c/p\u003e \u003cp\u003eStudies have shown that inflammation and immune response are involved in the occurrence and development of cardiovascular diseases (CVD) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), which are also the main pathophysiological processes of endometriosis (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Thus, as reported in many experimental and observational studies, endometriosis has emerged as a potential risk factor for the development of cardiovascular disease (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). These studies have shown that endometriosis is associated with atherosclerosis (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), hypertension (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), coronary heart disease (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), myocardial infarction (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), heart failure (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) and other cardiovascular diseases. However, it should be pointed out that due to the limitations of traditional research methods, the potential confounding factors or reverse causality may affect the research results to some extent.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) is a novel approach that can avoid the limitations of traditional research (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In this case, MR eliminates systematic bias by selecting the genetic variable associated with exposure as the IVs, randomly assigning alleles at conception according to Gregor Mendel's second law (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Through this, confounding factors are randomly distributed throughout the population. MR uses genetic variants associated with potentially modifiable risk factors to determine their causal effect on disease risk. Currently, studies have used MR to explore causal relationships between endometriosis and clotting factors (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), anxiety and depressive states (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), and asthma (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). However, these studies did not limit the gender of the included population to women, which lead to some bias in the results.\u003c/p\u003e \u003cp\u003eIn order to overcome the limitations of traditional observational studies and the gender ambiguity of existing MR studies, we used the Two Sample Mendelian randomization (TSMR) method to clarify the causal association between endometriosis and cardiovascular disease. The association between endometriosis-associated single nucleotide polymorphisms (SNPs) and cardiovascular disease risk was evaluated based on two independent publicly available genome-wide association studies (GWAS.)\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eIn this study, we conducted an analysis of TSMR. SNPs are randomly assigned at conception, a property that establishes that SNPS are not influenced by acquired environmental factors (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The increasingly accepted contribution of publicly available databases has facilitated the application of TSMR.\u003c/p\u003e \u003cp\u003eIn this study, we used exposure data from Finnish database(\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.finngen.fi/en\u003c/span\u003e\u003cspan address=\"http://www.finngen.fi/en\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) for genetic variants associated with endometriosis (ID: finn-b-N14_ENDOMETRIOSIS) (n case\u0026thinsp;=\u0026thinsp;15088, n control\u0026thinsp;=\u0026thinsp;107564); Similarly, the result of cardiovascular disease (CVD) data from UKB database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.nealelab.is/uk-biobank\u003c/span\u003e\u003cspan address=\"http://www.nealelab.is/uk-biobank\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). To ensure the accuracy of the results, we only selected the female sample data. Phenotypes were I9_CHD, I9_MI_STRICT, HEARTFAIL, I48 Atrial fibrillation and flutter, I9_HYPTENS, I9_STR_SAH.\u003c/p\u003e \u003cp\u003eThe potential causal effects of endometriosis on CVD including Coronary heart disease(CHD), Myocardial infarction (MI), Atrial fibrillation (AF), Heart failure (HF), hypertension and Stroke were explored by TSMR. As hypothesized, three assumptions must be met when conducting the MR:1) Association hypothesis: there is a strong association between the IVs and the exposure factors; 2) Independence assumption: IVs were independent of confounding factors affecting exposure and outcome; 3) Exclusivity hypothesis: IVs can affect the outcome only through exposure pathway, not through other pathways. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIVs were selected by the following criteria:1) GWAS associated with a P-value of 5*10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e ;2) filtering linkage disequilibrium(LD) (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; distance\u0026thinsp;\u0026lt;\u0026thinsp;1000 kb).After that, We searched the secondary phenotype of each SNP in PhenoScanner(\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.phenoscanner.medschl.cam.ac.uk\u003c/span\u003e\u003cspan address=\"http://www.phenoscanner.medschl.cam.ac.uk\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), with a threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e and deleted 4 SNPs(rs1936805,rs1451385, rs635634,rs3803361), which were associated with CVD confounders. The content relates to blood pressure (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), waist-to-hip ratio (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), Low density lipoprotein cholesterol(LDL) and High density lipoprotein cholesterol(HDL) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) Removing confounding factors can avoid potential pleiotropic effects (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Subsequently, we eliminated three palindrome alleles of SNPs (rs12213593, rs58415480, rs7967229). Finally, we evaluated R\u003csup\u003e2\u003c/sup\u003e and F statistics to detect whether the chosen IVs were strongly associated with exposure. R\u003csup\u003e2\u003c/sup\u003e and F can be calculated by formulas.\u003c/p\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;β\u003csup\u003e2\u003c/sup\u003e(1\u0026thinsp;\u0026minus;\u0026thinsp;EAF)\u0026times;2EAF\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eF\u0026thinsp;=\u0026thinsp;R\u003csup\u003e2\u003c/sup\u003e(N\u0026thinsp;\u0026minus;\u0026thinsp;K\u0026minus;1)/K(1\u0026thinsp;\u0026minus;\u0026thinsp;R\u003csup\u003e2\u003c/sup\u003e)\u003c/h2\u003e \u003cp\u003e(EAF is the frequency of gene mutation. K is the number of exposure-related SNPs and N is the number of samples in the exposure outcome. Single SNP with F statistic\u0026thinsp;\u0026gt;\u0026thinsp;10 was defined as reliable and valid IV that prevents MR results from being affected by weak instrument bias (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e))\u003c/p\u003e \u003cp\u003eTo eliminate false positive findings owing to multiple testing, the Bonferroni correction was utilized. As a result, P value less than 0.008 (0.05/6 outcomes) was deemed robust, P value between 0.008 and 0.05 was considered suggestive, and P value more than 0.05 was supposed nonsignificant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThree different MR methods, Inverse variance weighted(IVW), MR Egger and Weighted Median(WM) are used to deal with heterogeneity and pleotropic effects. IVW is used as the primary evaluation method, while MR-Egger and Weighted Median are used to improve IVW estimates as they can provide more reliable results in other scenarios. MR-Egger is a method of analysis assuming that all IVs used in the MR Analysis are invalid. The weighted median allows for the assumption that at least half of the tools used in the MR analysis are valid. IVW is a method for analysis under the assumption that all IVs used in MR analysis are valid. If the results obtained by the three calculation methods are inconsistent, the IVW results are taken as the main result. The scatter plot was then used to display the outcomes of the three approaches. In terms of sensitivity analysis, the MR-PRESSO method was utilized to find and eliminate outliers in IVW linear regression to offer corrected MR estimate; the Cochran's Q test was also used to discover heterogeneity; and the leave-one-out sensitivity test was performed to detect if a single SNP leads to results. All statistical analyses were performed using the \"TwoSampleMR\", \"mr-presso\"packages in R software, version 4.2.3.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEthic\u003c/h2\u003e \u003cp\u003eThis study used data from publicly available databases that had been approved by ethics committees. So separate ethical approval was not required in this study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAfter screening for confounders and palindromic SNPs, 20 SNPs were used as IVs to study the causal relationship between endometriosis and CVD, and all of them had F values greater than 10(Supplementary Table\u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe primarily employed the IVW method to investigate the genetic link between endometriosis and CVD. Endometriosis genetic prediction was linked to hypertension [odds ratio (OR)\u0026thinsp;=\u0026thinsp;0.9990, 95% confidence interval (CI): 0.9981\u0026ndash;0.9998, P\u0026thinsp;=\u0026thinsp;0.0191], which might be a protective factor. However, after using the Bonferroni correction, this significance vanished. Endometriosis was shown to be a risk factor for CHD (OR\u0026thinsp;=\u0026thinsp;1.0025, 95% CI: 1.0005\u0026ndash;1.0046, P\u0026thinsp;=\u0026thinsp;0.0164), although this significance was lost following Bonferroni correction. Endometriosis was shown to be a risk factor for MI (OR\u0026thinsp;=\u0026thinsp;1.0018, 95% CI: 1.0005\u0026ndash;1.0032, P\u0026thinsp;=\u0026thinsp;0.0058), and the relationship remained robust after Bonferroni correction. However, genetic associations between endometriosis and other CVD were not significant, detailed information can be found in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Scatter plots are used to display the results of three statistical methods (Supplementary Figures \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Sensitivity analyses were performed to detect the presence of horizontal pleiotropy, confirming the reliability of the IVW results. There was no statistical significance for heterogeneity (P value for Cochran's Q\u0026thinsp;\u0026gt;\u0026thinsp;0.05), pleiotropy (P value for intercept\u0026thinsp;\u0026gt;\u0026thinsp;0.05), or outliers (Supplementary Table\u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e, Supplementary Table\u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e, Supplementary Figures \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first MR study to determine causal relationship between endometriosis and CVD. The results show that genetic predisposition to endometriosis is significantly associated with the risk of MI, and may be associated with the risk of coronary heart disease and hypertension. However, there is no evidence of an association between endometriosis and AF, HF and Stroke.\u003c/p\u003e \u003cp\u003eEndometriosis is a complex disease influenced by both genetic and environmental factors. Genetic studies have previously reported similar potential associations between endometriosis and atherosclerotic cardiovascular disease, and there is a large body of literature focused on the increased risk of myocardial infarction, ischemic heart disease, and hypertension in women with endometriosis (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). At present, detailed study is needed to fully understand the clinical relevance and underlying pathophysiological mechanisms of the interaction between endometriosis and CVD.\u003c/p\u003e \u003cp\u003eThe immune system and inflammatory response play important roles in the pathophysiology of endometriosis as well as CVD (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e31\u003c/span\u003e). CXC chemokines are cytokines that attract and regulate immune cells, and play a crucial role in inflammatory response and immune homeostasis (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Relevant studies have accumulated evidence linking these CXC chemokines and the pathogenesis of female reproductive diseases such as endometriosis (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The CXC family member CXCL4 is involved in chemotaxis of neutrophils and monocytes (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Both neutrophils and monocytes have been implicated in endometrial healing. CXCL4 inhibits angiogenesis by directly interacting with vascular endothelial growth factor and fibroblast growth factor. In addition, related studies have found that platelet activation in patients with endometriosis further releases CXCL4, which may continue to activate the coagulation process by inducing more platelet aggregation (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Many cell types, including mesothelial cells, endometrial cells, and peripheral blood monocytes, among others, produce the chemokine CXCL8, which increases endothelial cell permeability, and increased CXCL-8 secretion also promotes leukocyte adhesion and migration into the subendothelial space, leading to foam cell formation and atherogenesis (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInflammation is part of the non-specific immune response and plays a key role in endometriosis and CVD. Endometriosis is caused by a variety of inflammatory factors such as cytokines, prostaglandins, macrophages, and tumor necrosis factor. A recent study by Rafi et al. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) showed that in women with endometriosis, inflammation leads to a hypercoagulable state, which leads to the development of atherosclerosis and other cardiac complications. Various inflammatory factors such as interleukin-1(IL-1), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) are elevated in peritoneal fluid and peripheral blood of patients with endometriosis (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Studies have also shown increased markers of oxidative stress but decreased antioxidants in peritoneal fluid (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e) and peripheral blood (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e42\u003c/span\u003e) in women with endometriosis. In addition, women with endometriosis have higher serum levels ofLDL(\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e43\u003c/span\u003e) and HDL (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Therefore, the increased incidence of cardiovascular events in women with endometriosis may be related to increased oxidative stress and atherogenic lipids (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMany studies have also explained the relationship between the two diseases from the genetic level. Vascular endothelial growth factor, encoded by the human vascular endothelial growth factor gene located on chromosome 6p21.3, is a powerful regulator of angiogenesis and has also been implicated in endothelial cell dysfunction. The rs1570360(-1154G/A)SNP located in the promoter region of transcription factor binding sites (TFBS) has been associated with coronary heart disease (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e46\u003c/span\u003e) and endometriosis (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e47\u003c/span\u003e). Endometriosis shares a common genetic pathway with myocardial infarction and coronary artery disease. For example, variants in the CDKN2CBAS gene on chromosome 9 are significantly associated with the development of endometriosis and acute myocardial infarction. The discovery of MicroRNAs opens up new avenues for investigating the link between endometriosis and ASCVD. MicroRNAs are small non-coding RNA molecules that can regulate gene expression, thereby promoting or preventing protein synthesis, and regulate the expression of adhesion molecules that are highly expressed in the cardiovascular system. Gynecological disorders such as endometriosis are induced under a variety of conditions that affect human reproductive organs and processes (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis TSMR analysis has several advantages: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Compared with traditional observational studies, the MR method reduces the influence of confounding factors and reverse causality, making our results more objective and convincing; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) The pooled data included were based on women of European ancestry, which mitigated the effects of demographic and sex factors on the results; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) IVs were strictly screened to reduce the bias caused by inappropriate IVs.\u003c/p\u003e \u003cp\u003eOur study also has certain limitations: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) we did not stratify the causal relationship between endometriosis and CVD by age, BMI, and other factors; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) The European sample study limited the clinical significance of the results to other populations.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, there is a modest association between endometriosis and CVD in a European female population. Genetic predisposition to endometriosis is significantly associated with the risk of myocardial infarction, and may be associated with the risk of coronary heart disease and hypertension. However, this study did not show evidence of an association between endometriosis and atrial fibrillation, heart failure or Stroke.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included\u0026nbsp;in the article/Supplementary Material. Further inquiries can be\u0026nbsp;directed to the corresponding authors.\u003c/p\u003e\n\u003cp\u003eConflict of Interest\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the\u0026nbsp;absence of any commercial or financial relationships that could be\u0026nbsp;construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003ePH designed the study and drafted the article. SF and ZZ collect data. PH, LG, HZ, YL, XM, SF and ZZ performed data analysis and manuscript revisions. All authors contributed to this article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe are thankful to all of the participants in the UK Biobank and FinnGen studies, as well as all of the researchers who assisted with data collecting.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med (2020) 382(13):1244-1256. Epub 2020/03/27. doi: 10.1056/NEJMra1810764.\u003c/li\u003e\n\u003cli\u003eSaunders PTK, Horne AW. Endometriosis: Etiology, Pathobiology, and Therapeutic Prospects. Cell (2021) 184(11):2807-2824. Epub 2021/05/29. doi: 10.1016/j.cell.2021.04.041.\u003c/li\u003e\n\u003cli\u003eHorne AW, Missmer SA. Pathophysiology, Diagnosis, and Management of Endometriosis. BMJ (2022) 379:e070750. Epub 2022/11/15. doi: 10.1136/bmj-2022-070750.\u003c/li\u003e\n\u003cli\u003eSoliman AM, Coyne KS, Gries KS, Castelli-Haley J, Snabes MC, Surrey ES. The Effect of Endometriosis Symptoms on Absenteeism and Presenteeism in the Workplace and at Home. J Manag Care Spec Pharm (2017) 23(7):745-754. doi: 10.18553/jmcp.2017.23.7.745.\u003c/li\u003e\n\u003cli\u003eSmolarz B, Szyłło K, Romanowicz H. Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature). 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Guidelines for Performing Mendelian Randomization Investigations: Update for Summer 2023. Wellcome Open Res (2019) 4:186.doi: 10.12688/wellcomeopenres.15555.3\u003c/li\u003e\n\u003cli\u003eHai-Feng T, Wei W, Yuan-Yuan Y, Jun Z, Su-Ping G, Hui-Ming L. Association between Polymorphisms in Il-16 Genes and Coronary Heart Disease Risk. Pak J Med Sci (2013) 29(4):1033-1037.doi: 10.12669/pjms.294.3650\u003c/li\u003e\n\u003cli\u003eChiang HJ, Lan KC, Yang YH, Chiang JY, Kung FT, Huang FJ, et al. Risk of Major Adverse Cardiovascular and Cerebrovascular Events in Taiwanese Women with Endometriosis. J Formos Med Assoc (2021) 120(1 Pt 2):327-336. Epub 2020/12/04. doi: 10.1016/j.jfma.2020.10.005.\u003c/li\u003e\n\u003cli\u003eMoghaddam MZ, Ansariniya H, Seifati SM, Zare F, Fesahat F. Immunopathogenesis of Endometriosis: An Overview of the Role of Innate and Adaptive Immune Cells and Their Mediators. Am J Reprod Immunol (2022) 87(5):e13537. 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Epub 2019/04/21. doi: 10.1002/jcp.28666.\u003c/li\u003e\n\u003cli\u003eVerit FF, Erel O, Celik N. Serum Paraoxonase-1 Activity in Women with Endometriosis and Its Relationship with the Stage of the Disease. Hum Reprod (2008) 23(1):100-4. Epub 2007/11/15. doi: 10.1093/humrep/dem340.\u003c/li\u003e\n\u003cli\u003eMelo AS, Rosa-e-Silva JC, Rosa-e-Silva AC, Poli-Neto OB, Ferriani RA, Vieira CS. Unfavorable Lipid Profile in Women with Endometriosis. Fertil Steril (2010) 93(7):2433-2436. Epub 2009/12/09. doi: 10.1016/j.fertnstert.2009.08.043.\u003c/li\u003e\n\u003cli\u003ede Ziegler D, Borghese B, Chapron C. Endometriosis and Infertility: Pathophysiology and Management. Lancet (2010) 376(9742):730-738. Epub 2010/08/31. doi: 10.1016/s0140-6736(10)60490-4.\u003c/li\u003e\n\u003cli\u003eLiu D, Song J, Ji X, Liu Z, Cong M, Hu B. Association of Genetic Polymorphisms on Vegfa and Vegfr2 with Risk of Coronary Heart Disease. Medicine (Baltimore) (2016) 95(19):e3413.doi: 10.1097/MD.0000000000003413.\u003c/li\u003e\n\u003cli\u003eZhao N, Zhang J. Role of Alternative Splicing of Vegf-a in the Development of Atherosclerosis. Aging (Albany NY) (2018) 10(10):2695-2708. doi: 10.18632/aging.204732 \u003c/li\u003e\n\u003cli\u003eZhao W, Li Y, Zhao J, Kang S. A Functional Promoter Polymorphism in Interleukin 12b Gene Is Associated with an Increased Risk of Ovarian Endometriosis. Gene (2018) 666:27-31. Epub 2018/05/09. doi: 10.1016/j.gene.2018.04.082. \u003c/li\u003e\n\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":"Mendelian randomization, Endometriosis, Cardiovascular Diseases, causal inference, Coronary heart disease","lastPublishedDoi":"10.21203/rs.3.rs-3647756/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3647756/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eObservational studies have shown associations between endometriosis and cardiovascular disease (CVD). But residual confounding and the potential for reverse causality are inevitable in such routine observational studies. This study used Mendelian randomization (MR) design to evaluate the causal effect of endometriosis on CVD including coronary heart disease (CHD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), hypertension and Stroke.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe utilized publicly available summary statistics of genome-wide association studies (GWAS) from European participants in the UK Biobank and Finnish databases. Instrumental variables (IVs) associated with endometriosis and CVD were identified and used IVs to investigate the genetic causal relationship between them. MR analyses were performed using various analytical methods, including Inverse variance weighted (IVW), MR-Egger, and Weighted Median. Tests for pleiotropy and heterogeneity were performed to assess the reliability of causality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMR analysis showed that endometriosis was associated with hypertension (odds ratio (OR)\u0026thinsp;=\u0026thinsp;0.9990, 95% confidence interval (CI) : 0.9981\u0026ndash;0.9998, P\u0026thinsp;=\u0026thinsp;0.0191), which may be a protective factor. However, this significance disappeared after applying the Bonferroni correction. Endometriosis was identified as a risk factor for CHD (OR\u0026thinsp;=\u0026thinsp;1.0025,95%CI: 1.0005\u0026ndash;1.0046, P\u0026thinsp;=\u0026thinsp;0.0164), but this significance was lost after Bonferroni correction. Endometriosis was identified as a risk factor for MI (OR\u0026thinsp;=\u0026thinsp;1.0018, 95%CI: 1.0005\u0026ndash;1.0032, P\u0026thinsp;=\u0026thinsp;0.0058), which remained significant after Bonferroni correction. Genetic associations between endometriosis and other CVD were not significant.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMR studies have shown that genetic predisposition to endometriosis is significantly associated with the risk of myocardial infarction, and may be associated with the risk of CHD and hypertension. However, the causal relationships between endometriosis and AF, HF and Stroke need to be further explored.\u003c/p\u003e","manuscriptTitle":"Endometriosis and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-28 19:19:49","doi":"10.21203/rs.3.rs-3647756/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":"0ac13abb-2656-4da7-9357-267c9ebc6c51","owner":[],"postedDate":"November 28th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-12-12T09:16:44+00:00","versionOfRecord":[],"versionCreatedAt":"2023-11-28 19:19:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3647756","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3647756","identity":"rs-3647756","version":["v1"]},"buildId":"WvIrzKhiLBfengagbw6Ux","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}