Endometriosis Increases the Risk of Stroke: A Mendelian Randomization Study

HomeStrokeVol. 54, No. 2Endometriosis Increases the Risk of Stroke: A Mendelian Randomization Study Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBEndometriosis Increases the Risk of Stroke: A Mendelian Randomization Study Ming Zheng and Shaoping Zheng Ming ZhengMing Zheng Correspondence to: Ming Zheng, MD, PhD, Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, 27 Taiping Rd, Beijing 100850, China. Email E-mail Address: [email protected] or E-mail Address: [email protected] https://orcid.org/0000-0002-3651-7701 Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing, China (M.Z.). Beijing Institute of Basic Medical Sciences, China (M.Z.). and Shaoping ZhengShaoping Zheng https://orcid.org/0000-0002-3544-0431 Departments of Obstetrics and Gynecology, Fuzhou General Hospital, Fujian, China (S.Z.). Originally published23 Jan 2023https://doi.org/10.1161/STROKEAHA.122.041163Stroke. 2023;54:e30–e33AbstractDownload figureDownload PowerPointEndometriosis affects ≈10% of women of reproductive age worldwide. Recently, there has been increasing evidence that endometriosis is a multifactorial disease and affects different organs throughout the body. Among the heterogeneous manifestations of endometriosis, its association with cardiovascular disease is increasingly recognized. In a recent study published in Stroke, women with endometriosis had a 34% higher risk of stroke than those without endometriosis.1 However, stroke is a complex entity with different clinical subtypes. Heterogeneous stroke subtypes were not considered in prior research.1 Additionally, observational studies could be biased by potential confounders.Since 1986, an elegant and reliable statistical technique, Mendelian randomization (MR), has been developed and continuously modified to assess the causal inference of modifiable factors (exposure) on disease risk (outcome).2 The MR technique evaluates causal relationships using genetic variants. According to Mendel's second law of inheritance, genetic variants are randomly assorted and allocated, which remains unchanged throughout an individual's lifetime. Thus, MR studies are less susceptible to confounding bias or reverse causation.MethodsTo investigate the causal inference of the endometriosis-to-stroke relationship, this MR study analyzed genetically determined endometriosis in a stroke cohort of 521 612 participants.3 This study followed the Strengthening the Reporting of Observational Studies in Epidemiology using MR guidelines.4 Using data from a genome-wide association study of an endometriosis cohort of 77 257 participants,5 genetic instruments of single nucleotide polymorphisms for endometriosis were selected using a P<5×10-7 and an independent inheritance with a minimal level of linkage disequilibrium of r2<0.001. Instrumental strength was quantified using the F statistic, with an F statistic>10 being considered sufficiently informative.6 Finally, 46 single nucleotide polymorphisms were selected with an average F statistic of 38.7 (range=25.3–111.4), thus representing sufficient instrumental strength; variances explained ranged from 6.2% to 34.2% (average=16.7%) for different endometriosis features (Figure [A]). See the Supplemental Material for the checklist required by the journal.Download figureDownload PowerPointFigure. Mendelian randomization (MR) study of endometriosis and stroke. A, The graphical illustration of the MR study. The MR analysis was conducted using the genetic instrument to estimate the causal role of endometriosis exposure in stroke outcomes. This MR analysis tested the 46 genetic variants of endometriosis against stroke in genome-wide association study (GWAS) cohorts to evaluate the stroke risk following endometriosis. B, MR results show the causal effect of endometriosis exposure in stroke susceptibility. MR estimated causal effects were calculated using the MR pleiotropy residual sum and outlier (MR-PRESSO) test, with horizontal pleiotropy corrected when MR-PRESSO Global test P<0.05. The causal estimates were shown by heatmap, with the dot color and size representing the β coefficients of MR analysis. A positive β coefficient indicates that endometriosis exposure is associated with an increased risk of stroke. The × symbol represents adjusted P≥0.05; and the * symbol represents false discovery rate (FDR)–adjusted P<0.05. C, Causal estimates of genetically determined endometriosis on ischemic stroke (IS) risk. Causal estimates were analyzed by 3 different MR tests: weighted median, inverse-variance weighting, and MR-PRESSO. The significance of P<0.05 were indicated by √ symbol. Power (%)=the statistical power of MR analysis to detect the corresponding causal effect at α=0.05, represented by bar length. The MR causal effect was shown by the color gradient.ResultsIn a stroke cohort of people with different subtypes of ischemic stroke (IS),3 MR analysis was performed to estimate the risk of stroke (outcome) following endometriosis (exposure). Using the MR pleiotropy residual sum and outlier (MR-PRESSO) test, horizontal pleiotropy was corrected when the MR-PRESSO global test P value was <0.05.7 As shown in Figure [B], endometriosis was significantly associated with increased risks of IS, including total IS and cardioembolic IS (PMR-PRESSO<0.05). Significantly increased IS risks were found for endometriosis subtypes of the ovary, pelvic peritoneum, rectovaginal septum and vagina, and occurring infertility. The most significant causality was found between infertility-related endometriosis and cardioembolic IS (causal estimate=0.18; PMR-PRESSO<0.001).Furthermore, the robustness of the MR results was investigated using different MR methods: weighted median, inverse-variance weighting, and MR-PRESSO tests. A power calculation was performed to evaluate statistical power.8 The causal effect of infertility-related endometriosis on cardioembolic IS was significant across different MR tests (Pweighted median=0.009, Pinverse-variance weighting=0.001, PMR-PRESSO<0.001; power=100%; Figure [C]). Additionally, the causalities of ovary endometriosis on total IS and cardioembolic IS were significant in inverse-variance weighting and MR-PRESSO tests but not in the weighted median test. Nevertheless, there was a universal trend toward increased IS risks following endometriosis exposure (Figure [C]).DiscussionTo our knowledge, this study analyzed the largest available stroke cohort, providing sufficient power to detect the causality of endometriosis on stroke risk. This finding is consistent with previous research1 while further providing convincing evidence at the genetic level. Moreover, adding important new knowledge to the field, we discovered that different endometriosis subtypes could also lead to an increased risk of cardioembolic-specific IS. Thus, the relationship between endometriosis and stroke is attributable to site-specific and comorbidity-related disease subtypes.Previous studies have been hampered by difficulties in determining the true prevalence of endometriosis, which has been reported to vary from 2% to 75% due to different diagnostic methods, as a definitive diagnosis of endometriosis requires surgical visualization. Currently, there is no accurate noninvasive biomarker of endometriosis. This study analyzed genetically determined endometriosis using genetic variants, offering an alternative solution to overcome this problem.This study has limitations that should be noted. (1) Using MR-PRESSO, the horizontal pleiotropy effect was minimized, but it could be corrected in some but not all instances.7 (2) Although correction for multiple testing was performed, there is still a possibility of false-negative results due to overcorrection. (3) The sample sizes of IS subtypes were relatively small, so power calculations were performed to determine adequately powered results.Further studies are warranted to replicate our findings in an independent cohort of different ethnic groups and to determine the extent to which a prior history of endometriosis predicts the future risk of stroke. Given the causal inference of the endometriosis-to-stroke relationship, it is reasonable to assume that early treatment of endometriosis might be a potential preventive strategy to reduce stroke risk before disease onset. Among the different subtypes of endometriosis and stroke, the most pronounced increase in stroke risk was caused by infertility-related endometriosis. Infertility is one of the most important symptoms of endometriosis, affecting approximately one-third of women with endometriosis.9 For women who wish to become pregnant, surgical treatment using laparoscopy to remove endometriotic lesions is highly recommended to increase pregnancy rates.10 As such, there are ample opportunities to explore whether surgical removal of endometriosis could reduce stroke risk in further research. Of note, we should be more cautious about suggesting that the surgical treatment of endometriosis might reduce future stroke risk. We should also call for more studies examining the relationship between endometriosis and common stroke-related comorbidities, such as atherosclerosis.ConclusionsEndometriosis, characterized by the presence of endometrial tissue outside the uterus, has been classically defined as a gynecological disease for decades. In this study, we strongly suggest a shift in the perception of endometriosis from a purely gynecological disease to a complex systemic disease involving increased stroke risk. It is necessary to raise clinical awareness of considering endometriosis in the risk assessment and primary prevention of cardiovascular disease.Article InformationAcknowledgmentsThe authors acknowledge the participants and investigators of the FinnGen project and the MEGASTROKE project (International Stroke Genetics Consortium). S. Zheng provided the original clinical experience of endometriosis-related stroke, and conceived the project with Dr M. Zheng; Dr M. Zheng and S. Zheng designed the study, developed the method, conducted data analysis, and wrote the manuscript. Dr M. Zheng supervised this project and is responsible for the overall content.Sources of FundingThis project was supported by the National Natural Science Foundation of China (32100739) received by Dr. Ming Zheng.Disclosures No human subjects were directly involved in this study. All the data used in this study was derived from existing de-identified biological samples from prior studies. Thus, ethical and patient consent was not required in this study. The funders had no role in the study design, data analysis, data interpretation, and writing of this manuscript. This study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The data that support the findings of this study will be available from the corresponding author upon reasonable request.Footnotes*M. Zheng and S. Zheng contributed equally.For Sources of Funding and Disclosures, see page e32.Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.122.041163.Correspondence to: Ming Zheng, MD, PhD, Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, 27 Taiping Rd, Beijing 100850, China. Email mmzheng@fmmu.edu.cn or zhengming_china@163.comReferences1. Farland LV, Degnan WJ, Bell ML, Kasner SE, Liberman AL, Shah DK, Rexrode KM, Missmer SA. Laparoscopically confirmed endometriosis and risk of incident stroke: a prospective cohort study.Stroke. 2022;53:3116–3122. doi: 10.1161/STROKEAHA.122.039250LinkGoogle Scholar2. Katan MB. Apolipoprotein E isoforms, serum cholesterol, and cancer.Lancet. 1986; 1:507–508. doi: 10.1016/s0140-6736(86)92972-7CrossrefMedlineGoogle Scholar3. Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, et al. 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Endometriosis.N Engl J Med. 2020; 382:1244–1256. doi: 10.1056/nejmra1810764CrossrefGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. 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