Role of Immune Cell in Mendiating the Effect of Lipids on Female Infertility

Role of Immune Cell in Mendiating the Effect of Lipids on Female Infertility | 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 Role of Immune Cell in Mendiating the Effect of Lipids on Female Infertility Yafei Xie, Zhelin Zhang, Qiaozhi Yin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4379152/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Observational and retrospective studies suggest that liposomes may be associated with female infertility. The exact relationship between different liposomes and female infertility remains difficult to determine. In addition, modulation of the immune system is a key measure of the impact of lipids on disease development, but it remains uncertain whether the causality of this association is mediated by immune cells. Method: In this study, we performed a two-step two-sample Mendelian randomization (MR) analysis to investigate the causal role of lipids on female infertility and the mediating role of immune cells between lipids and female infertility. The inverse variance weighting method was employed as the primary estimator, complemented by MR-Egger, Weighted median, Simple mode, and Weighted mode approaches. To address potential bias from single nucleotide polymorphisms (SNPs), we utilized MR-PRESSO. Additionally, Cochran's Q test and MR-Egger intercept analysis were performed to detect heterogeneity and horizontal pleiotropy. Results: MR analysis identified a causal relationship between 18 lipid species and female infertility. In addition,14 immune cell traits suggested an association with female infertility. Notably, mediated MR showed that the causal effect of phosphatidylcholine on female infertility (Total effect IVW: OR=1.069,95% CI [1.008,1.134], P=0.030) was largely mediated by HLA DR++ monocyte AC (OR=0.888,95% CI [0.790,0.998] , P=0.046). Conclusion: This study demonstrates a causal relationship between liposomes and female infertility, which may be mediated by HLA DR++ monocyte AC, thereby identifying novel drug targets for the prevention and treatment of this condition. Lipid species Immune cell Female infertility Mendelian randomization Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Infertility is defined as the inability to achieve pregnancy following 12 months of regular, unprotected sexual intercourse[ 1 ]. Approximately 85% of infertile couples have an identifiable cause; the most common causes are ovulatory dysfunction, male factor infertility, and tubal disease. The remaining 15% of infertile couples suffer from "unexplained infertility"[ 2 ]. According to a report by the World Health Organization, approximately 17% of individuals worldwide experience infertility, affecting one in every six people globally [ 3 ]. Lipids play a vital role in the regulation of numerous biological processes, such as energy conversion, material transport, information recognition and transmission, cell development and differentiation, and apoptosis. In recent years, there has been increasing evidence that dysregulation of lipid metabolism may affect female conception[ 4 ]. A study conducted on normal-weight women with polycystic ovary syndrome revealed that lipid changes in their follicular fluid affected the oocyte's microenvironment, affecting oocyte quality[ 5 ]. Lipid metabolism and immune function seem to be two different systems that are closely linked. Lipids and their mediators have been found to affect different immune cell subpopulations by regulating membrane fluidity, acting as precursors of bioactive oxygenated phospholipid derivatives, and directly activating membrane-associated pattern recognition receptors (PRRs)[ 6 ], and are crucial signaling molecules for intracellular and intercellular signaling, which regulate the development, differentiation, activation, and proliferation of immune cells[ 7 ]. MR is a method that uses indices of genetic variance to measure the causality of disease-associated risk factors while minimizing the bias caused by confounding or reverse causality inherent in observational studies [ 8 ]. Many studies have shown that lipid metabolism induces female infertility and modulates the immune system, but whether lipid metabolism can influence the progression of female infertility by modulating the immune system remains unknown. Therefore, we would like to determine the causal role of 179 lipid types in female infertility and whether it can be mediated by immune cells. Methods Study design We performed two-step two-sample Mendelian randomization to determine the association of 179 lipid species with the genetically predicted risk of female infertility and whether immune cell signatures could mediate this association(Fig. 1 ). The first step was to assess the causal effects of 179 lipid species and 731 immune cell signatures on female infertility using two-sample MR, to screen for lipid species and immune cell signatures that are highly correlated with female infertility risk and to investigate whether they are reverse causality. The second step is to assess the causal effect of the screened liposomes on the characteristics of the screened immune cells as well as reverse causality. Data sources Pooled data on lipids were obtained from a genome-wide association analysis of 179 plasma lipid groups from 7,174 Finnish individuals, covering four main lipid classes: glycerolipids, glycerophospholipids, sphingolipids, and sterols [ 9 ]. Data on female infertility were obtained from the FinnGen Consortium version R10 [ 10 ], which included a total of 75,450 Europeans (6,481 cases and 68.969 controls). The original GWAS for the immune traits used data from 3,757 European descendants. The summary statistics for the 731 immunophenotypes disclosed in the GWAS catalog [ 11 ] included 118 absolute cell counts, 389 mean fluorescence intensities (MFI) of surface antigens, 32 morphological parameters, and 192 relative counts (ratios between cellular levels). The MFI, absolute cell count, and relative count characteristics included B cells, CDCs, T cell maturation stage, monocytes, myeloid cells, TBNK (T cells, B cells, natural killer cells), and Treg groups, and morphological parameter characteristics included CDC and TBNK groups. The threshold significance level for SNP selection was P < 5e-8, and all relevant data were obtained from studies analyzing only populations of European ancestry to remove the potential bias due to population stratification. Genetic instrumental variable (IV)selection criteria The IV significance level for each immunological trait and lipid groups ware set at 1×10 − 5 and these SNPs (linkage disequilibrium [LD] R2 < 0.1, kb = 500) [ 12 ], where LD R2 was calculated based on 1000 Genomes Projects as a reference panel. The significance level for infertility was adjusted to 5×10 − 8 .To avoid bias due to weak IV, we use the F-statistic to measure the strength of IV. MR analysis In the MR analysis, we employed five methodologies, namely random effects Inverse variance Weighting (IVW), MR-Egger, Weighted median, Simple mode, and Weighted mode. The IVW approach yielded robust causal estimates in the absence of directional pleiotropy and was utilized as the primary method for estimating causal effects between exposure and outcome. MR-Egger and weighted median were employed as supplementary analyses. For instrumental variables (IVs) with P values < 0.05 from the IVW analysis, we conducted MR-PRESSO using the MRPRESSO package to identify and eliminate potentially polymorphic IVs (outliers), thereby providing outlier-adjusted estimates. Sensitivity analysis To ensure the stability of the MR analysis results, we performed tests for heterogeneity and pleiotropy. Cochran's Q test was used to calculate the level of heterogeneity, and MR-Egger regression and IVW methods were used to detect heterogeneity in IVS, with P < 0.05 reflecting the presence of significant heterogeneity. We checked for pleiotropy by MR-Egger intercept regression, and a P value < 0.05 was considered significant pleiotropy, and then the study results were unreliable. In addition, we performed a "leave-one-out" sensitivity analysis, in which one SNP was sequentially missing from the MR reanalysis to tease out the potential effects of SNPs. Result The total effect of 179 lipid species on female infertility Dual-sample MR analysis confirmed the causal association of 18 lipid species with female infertility (Fig. 2 ). Although other methods did not reflect statistical significance, the IVW method showed that the level of Phosphatidylcholine (17:0_18:2) in blood serum was positively associated with female infertility(odds ratio (OR) = 1.098,95% Confidence Interval (CI)[1.030,1.170], P = 0.004). Similar results were observed in triacylglycerol 52:4 measurement(OR = 1.080,95% CI[1.018,1.146],P = 0.010), level of Phosphatidylcholine (18:0_0:0) in blood serum(OR = 1.088,95%CI[1.020,1.162],P = 0.011),Triacylglycerol (50:4) levels(OR = 1.075,95% CI[1.014,1.139],P = 0.015), triacylglycerol 52:3 measurement(OR = 1.067,95%CI[1.010,1.128],P = 0.020), level of Phosphatidylethanolamine (16:0_18:2) in blood serum(OR = 1.051,95% CI[1.007,1.098],P = 0.023), level of Diacylglycerol (18:1_18:2) in blood serum(OR = 1.059,95% CI[1.007,1.114],P = 0.6),level of Phosphatidylcholine (16:1_18:1) in blood serum(OR = 1.069,95% CI[1.009,1.134],P = 0.027),level of Phosphatidylinositol (18:1_20:4) in blood serum(OR = 1.067,95% CI[1.005,1.133],P = 0.035),level of Phosphatidylcholine (16:0_0:0) in blood serum(OR = 1.070,95% CI[1.003,1.141],P = 0.040),Triacylglycerol (54:5) levels,(OR = 1.067,95% CI[1.003,1.135],P = 0.040),level of Phosphatidylcholine (18:0_20:2) in blood serum(OR = 1.065,95% CI[1.001,1.133],P = 0.045).In addition, IVW and MR Egger found that level of Sterol ester (27:1/16:1) in blood serum increased the risk of infertility in women(IVW,(OR) = 1.082,95%CI[1.011,1.158], P = 0.022), (MR Egger, odds ratio (OR) = 1.120,95% Confidence Interval (CI)[1.019,1.413], P = 0.040). Interestingly, the study also found the level of Phosphatidylcholine (O-16:0_16:0) in blood serum to be protective against female infertility(OR = 0.912,95% CI[0.846,0.984], P = 0.017).Similar results were observed in level of Phosphatidylcholine (O-18:1_20:4) in blood serum(OR = 0.935,95% CI[0.881,0.993],P = 0.030), level of Sphingomyelin (d38:1) in blood serum(OR = 0.953,95% CI[0.912,0.996],P = 0.032),level of Phosphatidylcholine (O-16:0_22:5) in blood serum(OR = 0.924,95% CI[0.858,0.995],P = 0.037) and Phosphatidylcholine (16:0_20:4) levels(OR = 0.958,95% CI[0.919,0.999],P = 0.042).The results of the MR-PRESSO method were also consistent and there was no heterogeneity or horizontal polytropy. In addition, there was no inverse causality between 179 lipid types and female infertility. Effect of immune cell signatures on female infertility To explore the causal relationship between immune phenotypes and female infertility, two-sample MR analysis was used, with the IVW method as the main analysis method, and genetically predicted six immune cell traits that would promote female pregnancy as well as eight immune cell traits that would increase the risk of infertility in women (Fig. 3). In the sensitivity analyses of the causal relationship between the 14 immune phenotypes and female infertility, the results of both MR Egger and IVW analyses were not statistically significant (p > 0.05) and there was no significant heterogeneity. In addition, the MR-Egger intercept regression test for horizontal pleiotropy was performed and the results showed that horizontal pleiotropy did not exist. In our study, no abnormal snp was found using MR-PRESSO. reverse magnetic resonance analysis did not reveal a causal effect of female infertility on immune cells. Effects of lipid species on immune cell traits Previously, we screened 18 lipid species and 14 immune cell traits critical for female infertility, and the level of Phosphatidylcholine (16:1_18:1) in blood serum was highly correlated with HLA DR + + monocyte AC (OR = 0.888,95% CI [ 0.790,0.998], P = 0.046, Fig. 4 ). Heterogeneity and horizontal pleiotropy were not observed, and specific SNPs did not drive causal estimates. The mediating role of lipids in female infertility We analyzed the causal effect of the level of Phosphatidylcholine (16:1_18:1) in blood serum on female infertility and HLA DR + + monocyte AC. We performed mediation analyses to describe the lipid and female infertility mediating effects of HLA DR + + monocyte AC pairs, with a mediation effect of -0.004 (95% CI [-0.018, 0.009]). We found no reverse causality between the serum phosphatidylcholine levels (16:1_18:1) and HLA DR + + monocyte AC. Discussion With recent advances in microarray technology, lipidomics, and proteomics analyses may be used as assessment tools for embryo implantation in the future. Lipidomics is defined as the large-scale study of lipid metabolites and their associated networks [ 13 ]. Pregnancy success is impacted by lipids and lipid metabolism, according to an increasing number of research conducted in recent years [ 14 ]. Women with infertility that cannot be explained had notably higher levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) [ 15 ]. It has been demonstrated that certain lipid mediators are essential for female reproduction, including triglycerides, lysophosphatidic acid, and arachidonic acid-like[ 16 , 17 , 18 ]. Therefore, we performed a two-sample MR to examine the causal relationship between lipids and female infertility. We found that 18 lipids have an impact on female conception, including the level of Phosphatidylcholine (17:0_18:2), Triacylglycerol 52:4 level, level of Phosphatidylcholine (18:0_0:0), Triacylglycerol (50:4) levels, Triacylglycerol 52:3 level,level of Phosphatidylethanolamine (16:0_18:2), level of Diacylglycerol (18:1_18:2), level of Phosphatidylcholine (16:1_18:1), level of Phosphatidylinositol (18:1_20:4), level of Phosphatidylcholine (16:0_0:0), Triacylglycerol (54:5) levels, level of Phosphatidylcholine (18:0_20:2), level of Sterol ester (27:1/16:1), level of Phosphatidylcholine (O-16:0_16:0), level of Phosphatidylcholine (O-18:1_20:4), level of Sphingomyelin (d38:1), level of Phosphatidylcholine (O-16:0_22:5) and Phosphatidylcholine (16:0_20:4) levels. Interestingly, a cohort analysis discovered that lipids might be involved in immunological homeostasis and inflammation control [ 19 ]. To investigate whether these 18 lipids modulate the immune system to influence female infertility, we performed a two-step MR, detecting six immune cell traits that reduce the risk of female infertility, and eight immune cell traits that can be detrimental to a woman's pregnancy. Subsequently, causal relationships between 18 lipids on 14 immune cells were analysed. The results showed that HLA DR + + monocyte AC was closely related to the level of Phosphatidylcholine (16:1_18:1). It was discovered that HLA DR + + monocyte AC may be a key factor mediating the causal relationship between the level of Phosphatidylcholine (16:1_18:1) and female infertility. Phosphatidylcholine (PC) is an important membrane component involved in intracellular and intercellular signaling and promotes the regulation of a wide range of immune cells [ 20 ]. A large number of phospholipids were found to be present in the peri-embryonic mouse uterus immediately adjacent to the site of embryo implantation, mainly containing 18:1 phosphatidylcholine and phosphatidylethanolamines, and phosphatidylinositol 20:4, which are important for endometrial tolerance, embryo implantation, and post-implantation growth [ 21 ]. Our study revealed that HLA DR + + monocyte AC may be the key immune cell trait mediating the causal relationship between the level of Phosphatidylcholine (16:1_18:1) and female infertility. HLA-DR is an MHC-II class molecule expressed on B lymphocytes, monocytes, macrophages, activated T-lymphocytes, activated NK-lymphocytes, and human progenitor cells[ 22 ]. Research has shown that HLA-DR expression is linked to both successful IVF implantations, and the mechanism underlying this relationship may be the down-regulation of HLA-DRs, which reflects the absence of antigen-presenting cells in the endometrium and causes infertility[ 23 , 24 ]. Interestingly, however, HLA class II antigens were not found in couples with unexplained infertility in early observational studies [ 25 , 26 ]. This may be due to small sample sizes or studies. This study demonstrates the causal role of lipids in female infertility and the mediating effect of immune cells in the association between lipids and female infertility.The advantage of MR is that SNP is randomly distributed at conception and the method is not subject to confounding and reverse causality as in traditional epidemiological studies, making the results more reliable. However, the population analyzed was limited to Europeans and is not generalizable to other populations, and future research directions should be extended to different ethnicities. The results obtained from this study provide valuable literature support for further investigations into reproductive immunity. However, additional studies are warranted to elucidate the underlying mechanisms involved. Conclusion Our results add to the understanding of the causative relationship between immune cells, lipids, and female infertility by demonstrating that female infertility is more likely in women with levels of phosphatidylcholine (16:1_18:1), which may be mediated by HLA DR + + monocyte AC. Early illness development and progression may be shown by examining the dynamic range of lipid changes, including which lipids change and over what time in response to disease. These novel insights contribute to a deeper exploration of immune-related infertility and offer potential drug targets and research directions for the prevention and treatment of female infertility. Declarations Funding This study was supported by the Chengdu Science and Technology Bureau(2021-YF05-02042-SN). Author Contribution YFX, ZLZ and QZY contributed to the concept and design of the study; YFX was responsible for statistical analysis and writing of the manuscript; ZLZ and QZY assisted with the statistical analysis. All authors have read and approved the final manuscript. Data Availability Data can be found in public open access repositories. Data URLs: the GWAS summary statistics for 179 lipid species and the 731 immune traits are available for download from the GWAS catalogue(study logins: GCST90277238-GCST90277416, GCST90001001 ~ GCST90002000 https://www.ebi.ac.uk/gwas/home ); the summary statistics for female infertility are available from https://r10.finngen.fi/pheno/N14_FEMALEINFERT . All codes used in the study are available from the corresponding author. References Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected] . Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2020;113(3):533–5. 10.1016/j.fertnstert.2019.11.025 . Sang Q, Ray PF, Wang L. Understanding the genetics of human infertility. Science. 2023;380(6641):158–63. 10.1126/science.adf7760 . Harris E. Infertility Affects 1 in 6 People Globally. JAMA Published online April. 2023;12. 10.1001/jama.2023.6251 . Yang T, Zhao J, et al. Lipid metabolism and endometrial receptivity. Hum Reprod Update. 2022;28(6):858–89. 10.1093/humupd/dmac026 . Ban Y, Ran H et al. Lipidomics analysis of human follicular fluid form normal-weight patients with polycystic ovary syndrome: a pilot study. J Ovarian Res. 2021;14(1):135. Published 2021 Oct 13. 10.1186/s13048-021-00885-y . Andersen CJ. Lipid Metabolism in Inflammation and Immune Function. Nutrients. 2022;14(7):1414. 10.3390/nu14071414 . Published 2022 Mar 28. Baumruker T, Prieschl EE. Sphingolipids and the regulation of the immune response. Semin Immunol. 2002;14(1):57–63. 10.1006/smim.2001.0342 . Birney E. Mendelian Randomization. Cold Spring Harb Perspect Med. 2022;12(4):a041302. 10.1101/cshperspect.a041302 . Ottensmann L, Tabassum R, Ruotsalainen SE et al. Genome-wide association analysis of plasma lipidome identifies 495 genetic associations. Nat Commun. 2023;14(1):6934. Published 2023 Oct 31. 10.1038/s41467-023-42532-8 . The FinnGen Consortium FinnGen Documentation of R10 Release. 2024. [(accessed on 23 April 2024)]. Available online: https://finngen.gitbook.io/documentation/ . Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy [published correction appears in Nat Genet. 2020]. Nat Genet. 2020;52(10):1036–45. 10.1038/s41588-020-0684-4 . 1000 Genomes Project Consortium, Auton A, Brooks LD, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68–74. 10.1038/nature15393 . Demiral İ, Doğan M, Baştu E, Buyru F. Genomic, proteomic and lipidomic evaluation of endometrial receptivity. Turk J Obstet Gynecol. 2015;12(4):237–43. 10.4274/tjod.98475 . Tianli Yang J, Zhao F, Liu Y, Li. Lipid metabolism and endometrial receptivity. Hum Reprod Update. 2022;28(6):858–89. November-December. Verit FF, Yildiz Zeyrek F, Zebitay AG, Akyol H. Cardiovascular risk may be increased in women with unexplained infertility. Clin Exp Reprod Med. 2017;44(1):28–32. 10.5653/cerm.2017.44.1.28 . Paria BC, Ma W, Tan J, et al. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci U S A. 2001;98(3):1047–52. 10.1073/pnas.98.3.1047 . Mizugishi K, Li C, Olivera A, et al. Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice. J Clin Invest. 2007;117(10):2993–3006. 10.1172/JCI30674 . Ye X, Hama K, Contos JJ, et al. LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature. 2005;435(7038):104–8. 10.1038/nature03505 . Hornburg D, Wu S, Moqri M, et al. Dynamic lipidome alterations associated with human health, disease and ageing. Nat Metab. 2023;5(9):1578–94. 10.1038/s42255-023-00880-1 . Nishiyama-Naruke A, Curi R. Phosphatidylcholine participates in the interaction between macrophages and lymphocytes. Am J Physiol Cell Physiol. 2000;278(3):C554–60. 10.1152/ajpcell.2000.278.3.C554 . Burnum-Johnson KE, Baker ES, Metz TO. Characterizing the lipid and metabolite changes associated with placental function and pregnancy complications using ion mobility spectrometry-mass spectrometry and mass spectrometry imaging. Placenta. 2017;60(Suppl 1):S67–72. 10.1016/j.placenta.2017.03.016 . Abualrous ET, Stolzenberg S, Sticht J, et al. MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange. Nat Chem Biol. 2023;19(10):1196–204. 10.1038/s41589-023-01316-3 . Chernyshov VP, Dons'koi BV, Sudoma IO, Goncharova YO. Favorable immune phenotype predicts successful implantation and pregnancy. Immunol Lett. 2014;162(2 Pt B):217–21. 10.1016/j.imlet.2014.10.022 . Jiang L, Wang X, Zhang T, et al. Down-regulation of HLA-DRs and HLA-DPs reflects the deficiency of antigen-presenting cells in endometrium from infertile women with and without ovarian endometriosis. Hum Fertil (Camb). 2022;25(4):716–27. 10.1080/14647273.2021.1902576 . Martín-Villa JM, De Juan D, Vicario JL, et al. HLA class I, class II, and class III antigen sharing is not found in couples with unexplained infertility. Int J Fertil Menopausal Stud. 1993;38(5):280–8. Coulam CB, Stern JJ. Evaluation of immunological infertility. Am J Reprod Immunol. 1992;27(3–4):130–5. 10.1111/j.1600-0897.1992.tb00740.x . Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure1Causalassociationsbetween18lipidspeciesandfemaleinfertility.pdf SupplementaryFigure2Causalassociationsbetween14immunecellsignaturesandfemaleinfertility.pdf SupplementaryFigure3CausalassociationsbetweenPhosphatidylcholineandHLADRmonocyteAC..pdf 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-4379152","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":301433157,"identity":"c7c68a38-b9e5-4bd9-89ca-3cca6af3f98d","order_by":0,"name":"Yafei Xie","email":"","orcid":"","institution":"Chengdu University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yafei","middleName":"","lastName":"Xie","suffix":""},{"id":301433158,"identity":"c8a8867f-bb7f-4861-b82f-cf29ebae3253","order_by":1,"name":"Zhelin Zhang","email":"","orcid":"","institution":"Chengdu University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Zhelin","middleName":"","lastName":"Zhang","suffix":""},{"id":301433159,"identity":"866c2f0c-745d-450a-a1f2-3df83a956b68","order_by":2,"name":"Qiaozhi Yin","email":"data:image/png;base64,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","orcid":"","institution":"Chengdu University of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Qiaozhi","middleName":"","lastName":"Yin","suffix":""}],"badges":[],"createdAt":"2024-05-06 22:09:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4379152/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4379152/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56361443,"identity":"1a980aa0-dc5d-4cdc-b347-74524d4b04a0","added_by":"auto","created_at":"2024-05-13 07:42:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":220713,"visible":true,"origin":"","legend":"\u003cp\u003eMR analysis revealed that 179 lipid species on immune cell-mediated A two-step Mendelian randomisation study of female infertility.IVs: instrumental variables.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4379152/v1/f017ef8418e1ba2b2d3ddb33.jpg"},{"id":56361441,"identity":"e7b7195f-3ac5-4dba-bfe8-5fec9e9ccdef","added_by":"auto","created_at":"2024-05-13 07:42:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":329497,"visible":true,"origin":"","legend":"\u003cp\u003eMR analysis revealed a causal association between 18 lipid species and female infertility.CI: confidence interval; MR: Mendelian randomization; OR: ratio ratio; SNP: single nucleotide polymorphism.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4379152/v1/ac3b3bfcc342c4ce909dcf50.jpg"},{"id":56361442,"identity":"eeb21962-8d5e-4983-8279-ce4f91bcdee2","added_by":"auto","created_at":"2024-05-13 07:42:18","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":231037,"visible":true,"origin":"","legend":"\u003cp\u003eMR analysis revealed a causal association between 14 immune cell signatures and female infertility.CI: confidence interval; MR: Mendelian randomization; OR: ratio ratio; SNP: single nucleotide polymorphism.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4379152/v1/efb64d572bc2954d9711bc7e.jpg"},{"id":56361444,"identity":"8730fff8-c570-45dd-bdf5-1029e4995829","added_by":"auto","created_at":"2024-05-13 07:42:18","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":52603,"visible":true,"origin":"","legend":"\u003cp\u003eMR analysis revealed a causal association between the level of Phosphatidylcholine (16:1_18:1) in blood serum and \u0026nbsp;HLA DR++ monocyte AC.CI: confidence interval; MR: Mendelian randomization; OR: ratio ratio; SNP: single nucleotide polymorphism.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4379152/v1/850b86a597476a0964a91067.jpg"},{"id":56854903,"identity":"5d11a805-5a77-455a-99fb-9ee88d6b1557","added_by":"auto","created_at":"2024-05-21 09:51:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1189442,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4379152/v1/35722aab-b5f9-4091-a479-ab6936e82cf4.pdf"},{"id":56361822,"identity":"d3b339ce-714b-41da-8731-d3f2d768a128","added_by":"auto","created_at":"2024-05-13 07:50:18","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2692506,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1Causalassociationsbetween18lipidspeciesandfemaleinfertility.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4379152/v1/340b754fcdd196ee72561628.pdf"},{"id":56361439,"identity":"d34df265-46a4-47f6-9d27-be78d505db98","added_by":"auto","created_at":"2024-05-13 07:42:18","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1521029,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure2Causalassociationsbetween14immunecellsignaturesandfemaleinfertility.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4379152/v1/12853eb0c091be210f879967.pdf"},{"id":56361445,"identity":"8ed3fb24-5e10-4c89-aa5f-1718e711e272","added_by":"auto","created_at":"2024-05-13 07:42:18","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":179751,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure3CausalassociationsbetweenPhosphatidylcholineandHLADRmonocyteAC..pdf","url":"https://assets-eu.researchsquare.com/files/rs-4379152/v1/8a807febac253b21b1f37c97.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Role of Immune Cell in Mendiating the Effect of Lipids on Female Infertility","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInfertility is defined as the inability to achieve pregnancy following 12 months of regular, unprotected sexual intercourse[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately 85% of infertile couples have an identifiable cause; the most common causes are ovulatory dysfunction, male factor infertility, and tubal disease. The remaining 15% of infertile couples suffer from \"unexplained infertility\"[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. According to a report by the World Health Organization, approximately 17% of individuals worldwide experience infertility, affecting one in every six people globally [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLipids play a vital role in the regulation of numerous biological processes, such as energy conversion, material transport, information recognition and transmission, cell development and differentiation, and apoptosis. In recent years, there has been increasing evidence that dysregulation of lipid metabolism may affect female conception[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A study conducted on normal-weight women with polycystic ovary syndrome revealed that lipid changes in their follicular fluid affected the oocyte's microenvironment, affecting oocyte quality[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLipid metabolism and immune function seem to be two different systems that are closely linked. Lipids and their mediators have been found to affect different immune cell subpopulations by regulating membrane fluidity, acting as precursors of bioactive oxygenated phospholipid derivatives, and directly activating membrane-associated pattern recognition receptors (PRRs)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and are crucial signaling molecules for intracellular and intercellular signaling, which regulate the development, differentiation, activation, and proliferation of immune cells[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMR is a method that uses indices of genetic variance to measure the causality of disease-associated risk factors while minimizing the bias caused by confounding or reverse causality inherent in observational studies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Many studies have shown that lipid metabolism induces female infertility and modulates the immune system, but whether lipid metabolism can influence the progression of female infertility by modulating the immune system remains unknown. Therefore, we would like to determine the causal role of 179 lipid types in female infertility and whether it can be mediated by immune cells.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eWe performed two-step two-sample Mendelian randomization to determine the association of 179 lipid species with the genetically predicted risk of female infertility and whether immune cell signatures could mediate this association(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The first step was to assess the causal effects of 179 lipid species and 731 immune cell signatures on female infertility using two-sample MR, to screen for lipid species and immune cell signatures that are highly correlated with female infertility risk and to investigate whether they are reverse causality. The second step is to assess the causal effect of the screened liposomes on the characteristics of the screened immune cells as well as reverse causality.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData sources\u003c/h2\u003e \u003cp\u003ePooled data on lipids were obtained from a genome-wide association analysis of 179 plasma lipid groups from 7,174 Finnish individuals, covering four main lipid classes: glycerolipids, glycerophospholipids, sphingolipids, and sterols [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Data on female infertility were obtained from the FinnGen Consortium version R10 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], which included a total of 75,450 Europeans (6,481 cases and 68.969 controls). The original GWAS for the immune traits used data from 3,757 European descendants. The summary statistics for the 731 immunophenotypes disclosed in the GWAS catalog [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] included 118 absolute cell counts, 389 mean fluorescence intensities (MFI) of surface antigens, 32 morphological parameters, and 192 relative counts (ratios between cellular levels). The MFI, absolute cell count, and relative count characteristics included B cells, CDCs, T cell maturation stage, monocytes, myeloid cells, TBNK (T cells, B cells, natural killer cells), and Treg groups, and morphological parameter characteristics included CDC and TBNK groups. The threshold significance level for SNP selection was P\u0026thinsp;\u0026lt;\u0026thinsp;5e-8, and all relevant data were obtained from studies analyzing only populations of European ancestry to remove the potential bias due to population stratification.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eGenetic instrumental variable (IV)selection criteria\u003c/h2\u003e \u003cp\u003eThe IV significance level for each immunological trait and lipid groups ware set at 1\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e and these SNPs (linkage disequilibrium [LD] R2\u0026thinsp;\u0026lt;\u0026thinsp;0.1, kb\u0026thinsp;=\u0026thinsp;500) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], where LD R2 was calculated based on 1000 Genomes Projects as a reference panel. The significance level for infertility was adjusted to 5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e.To avoid bias due to weak IV, we use the F-statistic to measure the strength of IV.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eMR analysis\u003c/h2\u003e \u003cp\u003eIn the MR analysis, we employed five methodologies, namely random effects Inverse variance Weighting (IVW), MR-Egger, Weighted median, Simple mode, and Weighted mode. The IVW approach yielded robust causal estimates in the absence of directional pleiotropy and was utilized as the primary method for estimating causal effects between exposure and outcome. MR-Egger and weighted median were employed as supplementary analyses. For instrumental variables (IVs) with P values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 from the IVW analysis, we conducted MR-PRESSO using the MRPRESSO package to identify and eliminate potentially polymorphic IVs (outliers), thereby providing outlier-adjusted estimates.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eTo ensure the stability of the MR analysis results, we performed tests for heterogeneity and pleiotropy. Cochran's Q test was used to calculate the level of heterogeneity, and MR-Egger regression and IVW methods were used to detect heterogeneity in IVS, with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 reflecting the presence of significant heterogeneity. We checked for pleiotropy by MR-Egger intercept regression, and a P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant pleiotropy, and then the study results were unreliable. In addition, we performed a \"leave-one-out\" sensitivity analysis, in which one SNP was sequentially missing from the MR reanalysis to tease out the potential effects of SNPs.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eThe total effect of 179 lipid species on female infertility\u003c/h2\u003e \u003cp\u003eDual-sample MR analysis confirmed the causal association of 18 lipid species with female infertility (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Although other methods did not reflect statistical significance, the IVW method showed that the level of Phosphatidylcholine (17:0_18:2) in blood serum was positively associated with female infertility(odds ratio (OR)\u0026thinsp;=\u0026thinsp;1.098,95% Confidence Interval (CI)[1.030,1.170], P\u0026thinsp;=\u0026thinsp;0.004). Similar results were observed in triacylglycerol 52:4 measurement(OR\u0026thinsp;=\u0026thinsp;1.080,95% CI[1.018,1.146],P\u0026thinsp;=\u0026thinsp;0.010), level of Phosphatidylcholine (18:0_0:0) in blood serum(OR\u0026thinsp;=\u0026thinsp;1.088,95%CI[1.020,1.162],P\u0026thinsp;=\u0026thinsp;0.011),Triacylglycerol (50:4) levels(OR\u0026thinsp;=\u0026thinsp;1.075,95% CI[1.014,1.139],P\u0026thinsp;=\u0026thinsp;0.015), triacylglycerol 52:3 measurement(OR\u0026thinsp;=\u0026thinsp;1.067,95%CI[1.010,1.128],P\u0026thinsp;=\u0026thinsp;0.020), level of Phosphatidylethanolamine (16:0_18:2) in blood serum(OR\u0026thinsp;=\u0026thinsp;1.051,95% CI[1.007,1.098],P\u0026thinsp;=\u0026thinsp;0.023), level of Diacylglycerol (18:1_18:2) in blood serum(OR\u0026thinsp;=\u0026thinsp;1.059,95% CI[1.007,1.114],P\u0026thinsp;=\u0026thinsp;0.6),level of Phosphatidylcholine (16:1_18:1) in blood serum(OR\u0026thinsp;=\u0026thinsp;1.069,95% CI[1.009,1.134],P\u0026thinsp;=\u0026thinsp;0.027),level of Phosphatidylinositol (18:1_20:4) in blood serum(OR\u0026thinsp;=\u0026thinsp;1.067,95% CI[1.005,1.133],P\u0026thinsp;=\u0026thinsp;0.035),level of Phosphatidylcholine (16:0_0:0) in blood serum(OR\u0026thinsp;=\u0026thinsp;1.070,95% CI[1.003,1.141],P\u0026thinsp;=\u0026thinsp;0.040),Triacylglycerol (54:5) levels,(OR\u0026thinsp;=\u0026thinsp;1.067,95% CI[1.003,1.135],P\u0026thinsp;=\u0026thinsp;0.040),level of Phosphatidylcholine (18:0_20:2) in blood serum(OR\u0026thinsp;=\u0026thinsp;1.065,95% CI[1.001,1.133],P\u0026thinsp;=\u0026thinsp;0.045).In addition, IVW and MR Egger found that level of Sterol ester (27:1/16:1) in blood serum increased the risk of infertility in women(IVW,(OR)\u0026thinsp;=\u0026thinsp;1.082,95%CI[1.011,1.158], P\u0026thinsp;=\u0026thinsp;0.022), (MR Egger, odds ratio (OR)\u0026thinsp;=\u0026thinsp;1.120,95% Confidence Interval (CI)[1.019,1.413], P\u0026thinsp;=\u0026thinsp;0.040). Interestingly, the study also found the level of Phosphatidylcholine (O-16:0_16:0) in blood serum to be protective against female infertility(OR\u0026thinsp;=\u0026thinsp;0.912,95% CI[0.846,0.984], P\u0026thinsp;=\u0026thinsp;0.017).Similar results were observed in level of Phosphatidylcholine (O-18:1_20:4) in blood serum(OR\u0026thinsp;=\u0026thinsp;0.935,95% CI[0.881,0.993],P\u0026thinsp;=\u0026thinsp;0.030), level of Sphingomyelin (d38:1) in blood serum(OR\u0026thinsp;=\u0026thinsp;0.953,95% CI[0.912,0.996],P\u0026thinsp;=\u0026thinsp;0.032),level of Phosphatidylcholine (O-16:0_22:5) in blood serum(OR\u0026thinsp;=\u0026thinsp;0.924,95% CI[0.858,0.995],P\u0026thinsp;=\u0026thinsp;0.037) and Phosphatidylcholine (16:0_20:4) levels(OR\u0026thinsp;=\u0026thinsp;0.958,95% CI[0.919,0.999],P\u0026thinsp;=\u0026thinsp;0.042).The results of the MR-PRESSO method were also consistent and there was no heterogeneity or horizontal polytropy. In addition, there was no inverse causality between 179 lipid types and female infertility.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEffect of immune cell signatures on female infertility\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo explore the causal relationship between immune phenotypes and female infertility, two-sample MR analysis was used, with the IVW method as the main analysis method, and genetically predicted six immune cell traits that would promote female pregnancy as well as eight immune cell traits that would increase the risk of infertility in women (Fig.\u0026nbsp;3). In the sensitivity analyses of the causal relationship between the 14 immune phenotypes and female infertility, the results of both MR Egger and IVW analyses were not statistically significant (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and there was no significant heterogeneity. In addition, the MR-Egger intercept regression test for horizontal pleiotropy was performed and the results showed that horizontal pleiotropy did not exist. In our study, no abnormal snp was found using MR-PRESSO. reverse magnetic resonance analysis did not reveal a causal effect of female infertility on immune cells.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEffects of lipid species on immune cell traits\u003c/h2\u003e \u003cp\u003ePreviously, we screened 18 lipid species and 14 immune cell traits critical for female infertility, and the level of Phosphatidylcholine (16:1_18:1) in blood serum was highly correlated with HLA DR\u0026thinsp;+\u0026thinsp;+\u0026thinsp;monocyte AC (OR\u0026thinsp;=\u0026thinsp;0.888,95% CI [ 0.790,0.998], P\u0026thinsp;=\u0026thinsp;0.046, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Heterogeneity and horizontal pleiotropy were not observed, and specific SNPs did not drive causal estimates.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eThe mediating role of lipids in female infertility\u003c/h2\u003e \u003cp\u003eWe analyzed the causal effect of the level of Phosphatidylcholine (16:1_18:1) in blood serum on female infertility and HLA DR\u0026thinsp;+\u0026thinsp;+\u0026thinsp;monocyte AC. We performed mediation analyses to describe the lipid and female infertility mediating effects of HLA DR\u0026thinsp;+\u0026thinsp;+\u0026thinsp;monocyte AC pairs, with a mediation effect of -0.004 (95% CI [-0.018, 0.009]). We found no reverse causality between the serum phosphatidylcholine levels (16:1_18:1) and HLA DR\u0026thinsp;+\u0026thinsp;+\u0026thinsp;monocyte AC.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWith recent advances in microarray technology, lipidomics, and proteomics analyses may be used as assessment tools for embryo implantation in the future. Lipidomics is defined as the large-scale study of lipid metabolites and their associated networks [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Pregnancy success is impacted by lipids and lipid metabolism, according to an increasing number of research conducted in recent years [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Women with infertility that cannot be explained had notably higher levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. It has been demonstrated that certain lipid mediators are essential for female reproduction, including triglycerides, lysophosphatidic acid, and arachidonic acid-like[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Therefore, we performed a two-sample MR to examine the causal relationship between lipids and female infertility. We found that 18 lipids have an impact on female conception, including the level of Phosphatidylcholine (17:0_18:2), Triacylglycerol 52:4 level, level of Phosphatidylcholine (18:0_0:0), Triacylglycerol (50:4) levels, Triacylglycerol 52:3 level,level of Phosphatidylethanolamine (16:0_18:2), level of Diacylglycerol (18:1_18:2), level of Phosphatidylcholine (16:1_18:1), level of Phosphatidylinositol (18:1_20:4), level of Phosphatidylcholine (16:0_0:0), Triacylglycerol (54:5) levels, level of Phosphatidylcholine (18:0_20:2), level of Sterol ester (27:1/16:1), level of Phosphatidylcholine (O-16:0_16:0), level of Phosphatidylcholine (O-18:1_20:4), level of Sphingomyelin (d38:1), level of Phosphatidylcholine (O-16:0_22:5) and Phosphatidylcholine (16:0_20:4) levels. Interestingly, a cohort analysis discovered that lipids might be involved in immunological homeostasis and inflammation control [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. To investigate whether these 18 lipids modulate the immune system to influence female infertility, we performed a two-step MR, detecting six immune cell traits that reduce the risk of female infertility, and eight immune cell traits that can be detrimental to a woman's pregnancy. Subsequently, causal relationships between 18 lipids on 14 immune cells were analysed. The results showed that HLA DR\u0026thinsp;+\u0026thinsp;+\u0026thinsp;monocyte AC was closely related to the level of Phosphatidylcholine (16:1_18:1). It was discovered that HLA DR\u0026thinsp;+\u0026thinsp;+\u0026thinsp;monocyte AC may be a key factor mediating the causal relationship between the level of Phosphatidylcholine (16:1_18:1) and female infertility.\u003c/p\u003e \u003cp\u003ePhosphatidylcholine (PC) is an important membrane component involved in intracellular and intercellular signaling and promotes the regulation of a wide range of immune cells [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. A large number of phospholipids were found to be present in the peri-embryonic mouse uterus immediately adjacent to the site of embryo implantation, mainly containing 18:1 phosphatidylcholine and phosphatidylethanolamines, and phosphatidylinositol 20:4, which are important for endometrial tolerance, embryo implantation, and post-implantation growth [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our study revealed that HLA DR\u0026thinsp;+\u0026thinsp;+\u0026thinsp;monocyte AC may be the key immune cell trait mediating the causal relationship between the level of Phosphatidylcholine (16:1_18:1) and female infertility. HLA-DR is an MHC-II class molecule expressed on B lymphocytes, monocytes, macrophages, activated T-lymphocytes, activated NK-lymphocytes, and human progenitor cells[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Research has shown that HLA-DR expression is linked to both successful IVF implantations, and the mechanism underlying this relationship may be the down-regulation of HLA-DRs, which reflects the absence of antigen-presenting cells in the endometrium and causes infertility[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Interestingly, however, HLA class II antigens were not found in couples with unexplained infertility in early observational studies [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This may be due to small sample sizes or studies.\u003c/p\u003e \u003cp\u003eThis study demonstrates the causal role of lipids in female infertility and the mediating effect of immune cells in the association between lipids and female infertility.The advantage of MR is that SNP is randomly distributed at conception and the method is not subject to confounding and reverse causality as in traditional epidemiological studies, making the results more reliable. However, the population analyzed was limited to Europeans and is not generalizable to other populations, and future research directions should be extended to different ethnicities. The results obtained from this study provide valuable literature support for further investigations into reproductive immunity. However, additional studies are warranted to elucidate the underlying mechanisms involved.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur results add to the understanding of the causative relationship between immune cells, lipids, and female infertility by demonstrating that female infertility is more likely in women with levels of phosphatidylcholine (16:1_18:1), which may be mediated by HLA DR\u0026thinsp;+\u0026thinsp;+\u0026thinsp;monocyte AC. Early illness development and progression may be shown by examining the dynamic range of lipid changes, including which lipids change and over what time in response to disease. These novel insights contribute to a deeper exploration of immune-related infertility and offer potential drug targets and research directions for the prevention and treatment of female infertility.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was supported by the Chengdu Science and Technology Bureau(2021-YF05-02042-SN).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYFX, ZLZ and QZY contributed to the concept and design of the study; YFX was responsible for statistical analysis and writing of the manuscript; ZLZ and QZY assisted with the statistical analysis. All authors have read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e \u003cp\u003eData can be found in public open access repositories. Data URLs: the GWAS summary statistics for 179 lipid species and the 731 immune traits are available for download from the GWAS catalogue(study logins: GCST90277238-GCST90277416, GCST90001001\u0026thinsp;~\u0026thinsp;GCST90002000 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ebi.ac.uk/gwas/home\u003c/span\u003e\u003cspan address=\"https://www.ebi.ac.uk/gwas/home\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e); the summary statistics for female infertility are available from \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://r10.finngen.fi/pheno/N14_FEMALEINFERT\u003c/span\u003e\u003cspan address=\"https://r10.finngen.fi/pheno/N14_FEMALEINFERT\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. All codes used in the study are available from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePractice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected]. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2020;113(3):533\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.fertnstert.2019.11.025\u003c/span\u003e\u003cspan address=\"10.1016/j.fertnstert.2019.11.025\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSang Q, Ray PF, Wang L. Understanding the genetics of human infertility. 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HLA class I, class II, and class III antigen sharing is not found in couples with unexplained infertility. Int J Fertil Menopausal Stud. 1993;38(5):280\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoulam CB, Stern JJ. Evaluation of immunological infertility. Am J Reprod Immunol. 1992;27(3\u0026ndash;4):130\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1600-0897.1992.tb00740.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1600-0897.1992.tb00740.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lipid species, Immune cell, Female infertility, Mendelian randomization","lastPublishedDoi":"10.21203/rs.3.rs-4379152/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4379152/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eObservational and retrospective studies suggest that liposomes may be associated with female infertility. The exact relationship between different liposomes and female infertility remains difficult to determine. In addition, modulation of the immune system is a key measure of the impact of lipids on disease development, but it remains uncertain whether the causality of this association is mediated by immune cells.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod:\u003c/strong\u003eIn this study, we performed a two-step two-sample Mendelian randomization (MR) analysis to investigate the causal role of lipids on female infertility and the mediating role of immune cells between lipids and female infertility. The inverse variance weighting method was employed as the primary estimator, complemented by MR-Egger, Weighted median, Simple mode, and Weighted mode approaches. To address potential bias from single nucleotide polymorphisms (SNPs), we utilized MR-PRESSO. Additionally, Cochran's Q test and MR-Egger intercept analysis were performed to detect heterogeneity and horizontal pleiotropy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eMR analysis identified a causal relationship between 18 lipid species and female infertility. In addition,14 immune cell traits suggested an association with female infertility. Notably, mediated MR showed that the causal effect of phosphatidylcholine on female infertility (Total effect IVW: OR=1.069,95% CI [1.008,1.134], P=0.030) was largely mediated by HLA DR++ monocyte AC (OR=0.888,95% CI [0.790,0.998] , P=0.046).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003eThis study demonstrates a causal relationship between liposomes and female infertility, which may be mediated by HLA DR++ monocyte AC, thereby identifying novel drug targets for the prevention and treatment of this condition.\u003c/p\u003e","manuscriptTitle":"Role of Immune Cell in Mendiating the Effect of Lipids on Female Infertility","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-13 07:42:13","doi":"10.21203/rs.3.rs-4379152/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":"500ee94a-ce6f-4854-a1fa-4a38910217fa","owner":[],"postedDate":"May 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-21T09:51:43+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-13 07:42:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4379152","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4379152","identity":"rs-4379152","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}