Analysis of the Genetic Association Between Immune Cell Phenotypes and Chronic Rhinosinusitis

Analysis of the Genetic Association Between Immune Cell Phenotypes and Chronic Rhinosinusitis | 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 Analysis of the Genetic Association Between Immune Cell Phenotypes and Chronic Rhinosinusitis Enze Wang, Yingxuan Sun, He Zhao, Meng Wang, Zhiwei Cao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6026517/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 Chronic rhinosinusitis (CRS), a prevalent and debilitating disorder, is characterized by persistent sinus inflammation and a complex interplay of immune cell phenotypes, inflammatory cytokines, and genetic factors. This study employed bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between 731 immune cell phenotypes and CRS, utilizing data from the FinnGen and OPEN GWAS public databases. The analysis revealed significant associations between CRS and specific immune cell phenotypes, including HLA-DR on CD14 monocytes (OR=1.118, p_adj_fdr=0.0003), CD14_CD16 monocytes (OR=1.116, p_adj_fdr=0.0002), dendritic cells (OR=1.085673909, p_adj_fdr=0.00118315), CD33 myeloid cell differentiation antigens (OR=1.110, p_adj_fdr=0.000195), and plasmacytoid dendritic cells (pDC) (OR=1.069, p_adj_fdr=0.00118). These findings suggest that aberrant immune cell function and genetic predisposition are pivotal in the onset and progression of CRS. The insights gained from this study provide a foundation for the development of novel, precision medicine-based therapeutic strategies for CRS, targeting specific immune cell phenotypes and inflammatory pathways to enhance treatment efficacy and minimize side effects. Genetic analyses Immune cells Immunology Mendelian randomization Chronic sinusitis Figures Figure 1 Figure 2 Figure 3 1. Background Chronic rhinosinusitis (CRS), a heterogeneous disorder, is defined by persistent sinus inflammation exceeding 12 weeks[ 1 ], accompanied by at least two symptoms such as nasal obstruction/congestion, anterior or posterior (mucoid) nasal drainage, hyposmia or anosmia, and facial pressure/pain/distension, with diagnosis confirmed through endoscopic or imaging findings[ 2 , 3 ]. The condition is prevalent in the population, significantly impacting quality of life and imposing considerable health economic burdens. CRS is primarily categorized into two types: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP)[ 4 ]. Based on inflammatory cell infiltration, CRS can be further classified into subtypes such as neutrophilic, eosinophilic, lymphocytic/plasmacytic, and mixe[ 5 ]. The phenotypic expression of immune cells plays a crucial role in the pathogenesis of CRS. Various immune cells, including neutrophils, macrophages, eosinophils, lymphocytes, and mast cells[ 6 ], regulate inflammatory responses, tissue remodeling, and chronic disease progression through the expression of specific markers and the secretion of inflammatory mediators[ 7 ]. The aberrant expression of these cell phenotypes is closely associated with the onset, progression, and refractory nature of the disease, underscoring the significance of in-depth research for elucidating pathogenic mechanisms and developing novel therapeutic strategies. CRS exhibits marked genetic susceptibility and familial aggregation[ 8 ]. Genome-wide association studies (GWAS) have identified multiple genetic variants associated with CRS, including genes related to both innate and adaptive immunity[ 9 , 10 ]. However, elucidating these associations in traditional population-based surveys remains challenging due to the presence of unmeasurable confounding or mediating factors[ 11 ]. The shared genetic characteristics between CRS and autoimmune diseases may provide evidence for their correlation. In conclusion, the pathogenesis of CRS is complex, involving immune cell phenotypes, inflammatory cytokines, and genetic factors. Our team has investigated the genetic association between CRS and autoimmune diseases[ 12 ]. Although existing research has highlighted the significant roles of these factors, further comprehensive studies are warranted to delineate their specific causal relationships and potential therapeutic targets. 2. Methods 2.1. Mendelian randomization (MR) analysis This study employed bidirectional two-sample Mendelian randomization analysis[ 13 ] to assess the causal relationship between 731 immune cell phenotypes (collectively grouped into seven categories) and epithelial barrier injury-related nasal diseases. The analysis was based on three primary assumptions: (1) the relevance assumption, wherein the instrumental variables (IVs) are closely associated with the exposure factors; (2) the independence hypothesis, stating that IVs should not be influenced by known or unknown confounders; and (3) the exclusion restriction hypothesis, which posits that IVs affect the outcome variables solely through the exposure factors[ 14 , 15 ]. The data utilized in this study were sourced from the FinnGen and OPEN GWAS public databases, pre-processed to ensure anonymization, thereby excluding any personal privacy or identifying information. Given the nature of the study, which did not involve informed consent or data sharing with institutions, ethical review was not required. 2.2. Data Collection for Exposure and Outcome: The GWAS Catalog (ranging from GCST90001391 to GCST90002121) provided an overview of GWAS statistical data for each immunological characteristic. This dataset encompassed comprehensive data from 3,757 Europeans, covering 731 immune phenotypes. When selecting CRS data from the Finnish database, considerations included sample size, publication year, the number of single nucleotide polymorphisms (SNPs), and ethnicity. The dataset ultimately included 359,399 European participants, comprising 19,856 cases and 337,881 controls. 2.3. Selection of Instrumental Variables: Initially, GWAS data were screened to include relevant SNPs that met the P < 1×10 − 5 threshold. To mitigate the impact of linkage disequilibrium (LD) on the analysis, the parameter r threshold was set at 0.001, and the distance between SNPs was set to 10,000 Kb for analysis. Subsequently, the PhenoScanner V2 database was used to further validate these SNP loci for the presence of other confounding variables. To assess whether the included SNPs were affected by weak IVs, the F-statistic was employed, excluding values greater than 10. SNPs with an F-statistic less than 10, indicating a potential for weak instrument bias, were excluded to prevent influencing the results. Following this, outcome information was extracted through the IEU OpenGWAS database or FinnGen database, and the exposure and generated datasets were merged, with palindromic sequences removed. The remaining SNPs constituted the final IVs for exposure. 2.4. Statistical Analysis: The MR analysis in this study was conducted using the TwoSampleMR package in R version 4.3.3. Initially, the selected IVs were extracted from the outcome variables, followed by MR analysis using the TwoSampleMR package. Five commonly used MR analysis methods were employed: inverse variance weighting (IVW), weighted median, simple mode, weighted mode, and MR-Egger regression, with IVW as the primary method and the others as supplementary. The IVW method is characterized by its disregard for the intercept term and use of the inverse of the end variance (square of the standard error) as the fitting weight. A series of sensitivity analyses were conducted to further interpret potential pleiotropy, with IVW-derived p-values less than 0.05 considered indicative of correlation, and FDR-adjusted p-values (p_adj_fdr) less than 0.05 as the criterion for significant correlation. At the conclusion of the MR analysis, sensitivity analyses were performed, including heterogeneity and horizontal pleiotropy tests. Cochran's Q test quantified the heterogeneity of IVs, with P-values less than 0.05 indicating heterogeneity. The MR-Egger method, a weighted linear regression with an intercept, was used to assess the presence of horizontal pleiotropy among IVs. Additionally, the leave-one-out sensitivity test was employed to evaluate whether the causal effect was significantly influenced by individual SNPs. All results are presented as odds ratios (OR) with 95% confidence intervals (CI), and results were considered statistically significant when P-values were less than 0.05. 3. Outcomes We identified 64 immune phenotypes associated with chronic rhinosinusitis (CRS), of which six demonstrated more significant correlations. Reverse MR analysis of the immune phenotypes and CRS identified 27 phenotypes with correlations (p < 0.05), but none reached significant correlation (p_adj_fdr < 0.05). (Fig. 1 ) (Fig. 2 ) The IVW model revealed positive associations between CRS and the surface expression of HLA-DR on CD14 monocytes (OR = 1.118, p_adj_fdr = 0.0003), CD14_CD16 monocytes (OR = 1.116, p_adj_fdr = 0.0002), dendritic cells (OR = 1.085673909, p_adj_fdr = 0.00118315), CD33 myeloid cell differentiation antigens (OR = 1.110, p_adj_fdr = 0.000195), and plasmacytoid dendritic cells (pDC) (OR = 1.069, p_adj_fdr = 0.00118). HLA-DR, a major histocompatibility complex (MHC) II molecule, reflects the activation state of monocytes when expressed on their surface[ 16 ], aiding in the assessment of immune status[ 17 ]. Additionally, CD25 on activated CD4 regulatory T cells also had a positive effect on CRS (OR = 1.101, p_adj_fdr = 0.001183). (Fig. 3 ) (Table 1) 4. Discussion Mendelian randomization studies offer significant advantages in exploring the causal relationship between immune cell phenotypes and diseases[ 18 ]. By utilizing genetic variants as instrumental variables, this method effectively mitigates the confounding biases and reverse causality issues common in traditional observational studies, thereby providing a more accurate assessment of the direct impact of specific immune cell phenotypes on disease risk. Moreover, Mendelian randomization studies can leverage large-scale genetic data to enhance statistical power, offering robust evidence for understanding the role of immune cells in disease pathogenesis, which is crucial for identifying new therapeutic targets and developing more effective prevention and treatment strategies[ 19 ]. The epithelial barrier, comprising epithelial cells and their tight junctions (TJs), serves as the first line of defense for the nasal and sinus mucosa, primarily functioning to protect against external pathogens, allergens, and other harmful substances, while also regulating immune responses and maintaining the health and homeostasis of the nasal mucosa[ 20 ]. In chronic rhinosinusitis (CRS), epithelial barrier dysfunction is considered a key factor in the onset and progression of the disease. Particularly in chronic rhinosinusitis with nasal polyps (CRSwNP), the disruption of the epithelial barrier is closely linked to disease occurrence. Research indicates that CRSwNP patients exhibit significant impairment in the barrier function of nasal mucosal epithelial cells, associated with altered expression of tight junction proteins. For instance, gene transcriptome analyses have identified multiple differentially expressed genes between CRSwNP patients and controls, involved in regulating cell adhesion functions and the composition of microtubule-related complexes, thereby affecting barrier function. CD14 monocytes can be divided into three distinct subpopulations: classical monocytes (CD14 + + CD16-), intermediate monocytes (CD14 + + CD16+), and non-classical monocytes (CD14 + CD16++). These subpopulations are further classified based on varying levels of HLA-DR and CD195, as well as receptors TNFR1 and TNFR2[ 21 ]. CD14, an important immunomodulatory molecule, is primarily expressed on the surface of monocytes, macrophages, and dendritic cells. It recognizes pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharide (LPS) and activates downstream immune responses through the TLR4 signaling pathway[ 22 ]. Studies have found that specific single nucleotide polymorphisms (SNPs) in the CD14 promoter gene may be associated with the pathogenesis of sinusitis and the incidence of asthma[ 23 ], and that CD14 is upregulated in the nasal mucosa of CRS patients, suggesting a potential pro-inflammatory role in the disease process[ 24 ]. Research on CD14 as a target has primarily focused on the correlation between HLA-DR expression on CD14-positive monocytes and disease states, particularly in cancer and immune system disorders. For example, in non-Hodgkin lymphoma[ 25 ] and pancreatic cancer[ 26 ], the relative proportion of CD14 + HLA-DRlo/neg monocytes is associated with clinical characteristics and prognosis of patients. However, there are no clear reports on the application of HLA-DR-targeted drugs on CD14-positive monocytes in the treatment of chronic rhinosinusitis. Current research mainly employs single-cell transcriptomics to unravel the complex cellular and genetic interactions in chronic rhinosinusitis, aiming to discover new therapeutic targets. CD25 holds significant expression and functional importance on activated CD4 regulatory T cells (Tregs)[ 27 ]. As the alpha chain of the interleukin-2 (IL-2) receptor, CD25 is expressed in CD4 + T cells. Notably, CD4 + CD25 + Tregs constitute a specific subset of CD4 + T cells, characterized by their high expression of CD25[ 28 ]. These CD4 + CD25 + Treg cells primarily modulate the immune response by suppressively regulating CD8 T cells and the helper functions of CD4 + T cells, encompassing the entire immune system’s response, including antigen-presenting cells (APCs) and B cells [ 29 ]. This suppression predominantly targets activated effector cells, rather than the activation process of naive T cells. Research on CD4 + CD25 + Tregs in chronic rhinosinusitis (CRS) has largely focused on their immunomodulatory functions and their role in disease pathogenesis [ 30 ]. Studies indicate that in CRS patients, the expression levels of Tregs undergo changes [ 31 ], potentially affecting both the quantity and function of these cells, thereby disrupting immune regulatory balance[ 32 ]. Tregs maintain immune homeostasis through the suppression of excessive immune responses; however, in CRS, dysfunctional Tregs may lead to an imbalance in immune reactions, promoting disease progression. Research has demonstrated that different subsets of CD4 + T cells (such as Th1, Th2, Th17, and Tregs) play varied roles in the pathogenesis of CRS. For instance, Th2 cells are primarily involved in chronic rhinosinusitis with nasal polyps (CRSwNP), while the regulatory functions of Tregs may be compromised in the pathogenesis of CRSwNP[ 33 ]. CD33 is commonly used to identify myeloid-derived suppressor cells (MDSCs), which play a role in immunosuppression[ 34 ]. The expression of HLA-DR in CD33-positive cells may indirectly relate to epithelial barrier damage by influencing immune cell activity and inflammatory responses [ 35 ]. Chronic inflammatory responses resulting from epithelial barrier damage may be associated with the activity of these immune cells[ 20 ], necessitating further research to elucidate the specific mechanisms involved. However, no direct studies or literature establish a direct association between CD33 + cell surface HLA-DR and CRS. The impact of dendritic cells (DCs) on CRS has been a focal point of research, given their efficacy as antigen-presenting cells capable of initiating antigen-specific helper T cell responses[ 36 ]. CRS endotypes are typically defined based on the balance of inflammatory helper T cell patterns, categorized into Th2 and non-Th2 endotypes[ 37 ]. DCs play a crucial role in the polarization of Th2 or non-Th2 biased immune responses, with some studies indicating an increase in DCs in the mucosa of CRS patients, underscoring their significant role in the onset and progression of CRS. Elevated levels of CCL2 and CCL20 in the nasal mucosa of CRS patients may be related to DC recruitment[ 38 ]. Additionally, increased expression of osteopontin (OPN) in CRS patients is associated with DC-mediated promotion of Th1/Th17 immune responses[ 39 ]. OPN can induce the production of IL-6, IL-12, and IL-23 in intestinal cells, thereby promoting the differentiation of Th1 and Th17 cells, a process that may also occur in CRS[ 40 ]. Nevertheless, no definitive studies have established a direct and clear relationship between HLA-DR expression on pDCs and chronic rhinosinusitis. DCs play a pivotal role in nasal mucosal immunity and are considered potential therapeutic targets for CRS. However, current treatments lack specific methods to target DC pathways, such as biologic agents and corticosteroids[ 41 ], which only partially modulate DC function and do not specifically target DC pathways in CRS. Vitamin D3 (VD3), with its immunomodulatory potential, has been implicated in CRS patients with VD3 deficiency, but further research is needed to confirm its efficacy[ 42 ]. Additionally, CCR1 antagonists such as CCX354-C[ 43 ] and BMS-817399[ 44 ], which have entered clinical trials for rheumatoid arthritis, may also be considered potential therapeutic agents for CRS, warranting further investigation. Translation and Polishing: Although Mendelian randomization studies offer unique advantages in elucidating the causal relationship between immune cell phenotypes and diseases, they are not without limitations. Firstly, these studies rely on a strong association between genetic variants and immune cell phenotypes, which may not always be present or sufficiently robust, leading to inefficient instrumental variables[ 45 ]. Secondly, Mendelian randomization assumes that genetic variants act on the disease solely through their impact on the target immune cell phenotype, termed the "exclusivity assumption." However, in reality, genetic variants may influence multiple biological pathways, thereby introducing confounding effects. Additionally, insufficient sample sizes, population-specific genetic variations, and potential gene-environment interactions may also compromise the accuracy and generalizability of the findings. Therefore, caution is warranted when interpreting Mendelian randomization results, and a comprehensive analysis incorporating other research methods is advisable[ 46 ]. In-depth exploration of immune cell phenotypes, inflammatory factors, and genetic associations can provide novel insights and strategies for the precise treatment of chronic rhinosinusitis (CRS). For instance, therapies targeting specific immune cell phenotypes and inflammatory factors may enhance treatment efficacy while minimizing side effects. In summary, immune cell phenotypes, inflammatory factors, and genetic associations play crucial roles in the pathogenesis and immunomodulation of CRS. Further investigation into these phenotypes holds promise for advancing the precise treatment of chronic rhinosinusitis. 5. Conclusion This study underscores the intricate relationship between immune cell phenotypes and the pathogenesis of chronic rhinosinusitis (CRS), highlighting the potential of genetic associations in guiding precision medicine approaches. Through Mendelian randomization analysis, we identified significant correlations between CRS and specific immune cell phenotypes, such as HLA-DR expression on monocytes and dendritic cells, and CD25 on activated CD4 regulatory T cells. These findings suggest that aberrant immune cell function and genetic predisposition are pivotal in the onset and progression of CRS. The insights gained from this analysis pave the way for novel therapeutic strategies targeting specific immune cell phenotypes and inflammatory pathways. By leveraging these genetic and immunological insights, we can aspire to develop more effective and personalized treatments for CRS, ultimately aiming to alleviate the burden of this chronic condition on patient quality of life and healthcare systems. Future research should continue to explore the complex interplay between genetics, immune cell function, and CRS pathogenesis, fostering a deeper understanding that could lead to innovative therapeutic interventions. Declarations 6.1.Ethical Approval and Participant Consent Given that the study utilizes exclusively public databases and does not involve human subjects or personal data, ethical approval and participant consent are not required. 6.2.Consent for Publication All authors have given their consent for the manuscript to be published in its current form. 6.3.Availability of Data and Materials The datasets analyzed during the current study are publicly available and have been deposited in FAERS database (https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers-database), Drugbank database (https://go.drugbank.com), Details of the specific datasets and accession numbers are provided in the Materials and Methods section of the manuscript. 6.4.Competing Interests The authors declare that they have no competing interests. 6.5.Funding No funding body had role in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript. 6.6.The Authors’ full name(s) and affiliation: Enze Wang M.Med（First Author）, 0009-0006-7893-6310 Department of Otolaryngology Head and Neck Surgery，Shengjing Hospital of China Medical University , Shenyang City, China； Yingxuan Sun, M.Med, （Co-first Author）0009-0000-3823-1494 Department of Neurology, The First Affiliation Hospital of China Medical University , Shenyang City, China; He Zhao, Ph.D, 0000-0002-9212-7628 Department of Otolaryngology Head and Neck Surgery，Shengjing Hospital of China Medical University , Shenyang City, China； Meng Wang, Ph.D, 0000-0002-3178-7382 Department of Otolaryngology Head and Neck Surgery，Shengjing Hospital of China Medical University , Shenyang City, China； Zhiwei Cao*, Ph.D, 0000-0002-2221-9260 Department of Otolaryngology Head and Neck Surgery，Shengjing Hospital of China Medical University , Shenyang City, China 6.7.Authors' Contributions Enze Wang and Yingxuan Sun conceived the study, designed the analysis, and drafted the manuscript. Meng Wang and He Zhao performed the data analysis and contributed to the interpretation of the results. Zhiwei Cao provided critical input and helped revise the manuscript. All authors read and approved the final manuscript. 6.8.Confirmation The author Yingxuan Sun has made significant contributions to this article. Enze Wang is the first author of this paper, with Yingxuan Sun as the co-first author. We, the authors of this manuscript, confirm that the work described has been conducted in accordance with the relevant guidelines and regulations. We also confirm that the manuscript has not been published previously, nor is it under consideration for publication elsewhere. References Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, Cervin A, Douglas R, Gevaert P et al : EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists . Rhinology 2012, 50 (1). 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Tak PP, Balanescu A, Tseluyko V, Bojin S, Drescher E, Dairaghi D, Miao S, Marchesin V, Jaen J, Schall TJ et al : Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial . Ann Rheum Dis 2013, 72 (3):337-344. Santella JB, Gardner DS, Duncia JV, Wu H, Dhar M, Cavallaro C, Tebben AJ, Carter PH, Barrish JC, Yarde M et al : Discovery of the CCR1 antagonist, BMS-817399, for the treatment of rheumatoid arthritis . J Med Chem 2014, 57 (18):7550-7564. Brion M-JA, Shakhbazov K, Visscher PM: Calculating statistical power in Mendelian randomization studies . Int J Epidemiol 2013, 42 (5):1497-1501. Yang Q, Sanderson E, Tilling K, Borges MC, Lawlor DA: Exploring and mitigating potential bias when genetic instrumental variables are associated with multiple non-exposure traits in Mendelian randomization . Eur J Epidemiol 2022, 37 (7):683-700. Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.jpg 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-6026517","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":415785255,"identity":"facfc50c-6790-482c-a2af-c118176271bb","order_by":0,"name":"Enze Wang","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Enze","middleName":"","lastName":"Wang","suffix":""},{"id":415785256,"identity":"4214dbac-a808-44df-9f42-3a37615b7390","order_by":1,"name":"Yingxuan Sun","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yingxuan","middleName":"","lastName":"Sun","suffix":""},{"id":415785257,"identity":"005859fd-5838-45ed-b1b2-fd243548f8c6","order_by":2,"name":"He Zhao","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"He","middleName":"","lastName":"Zhao","suffix":""},{"id":415785258,"identity":"3a9c3498-fb70-4fb8-a233-35cf7b85cd39","order_by":3,"name":"Meng Wang","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Meng","middleName":"","lastName":"Wang","suffix":""},{"id":415785259,"identity":"6d90682a-6436-487c-bc31-4a76f3c68c23","order_by":4,"name":"Zhiwei Cao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIie3QMWvCQBTA8RcexCU260Gk/QpPAt2qX0V5kCkBxw4SCoE4ugpKP4azcJDJD+AncHKopINDBt+1pW7XGwvef3hk+d3lHYDP9297BQRlPgjgwY3sfwlB6CSCWsYXAQcSL7Ru++9lD5JKt7NZ9xQCNudPC1H7bJL2txph0GTJimhYQ8jrgYUQ5MTFdofjQ/6MEZH8ZJSispH4RLrYlLJ+nrZCxn8TlQ+r4g0NoUTI1JDgw7bL4cjYNbKLyswuKdcYMloExEvW59W8ZFAsL9Y9vix7lQ4uNvMTm/F9uEyMHMjoRiSnW3w+n+9uugI90D21uE5NqAAAAABJRU5ErkJggg==","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":true,"prefix":"","firstName":"Zhiwei","middleName":"","lastName":"Cao","suffix":""}],"badges":[],"createdAt":"2025-02-14 01:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6026517/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6026517/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76441411,"identity":"72eb76c0-8ed2-42cc-81cc-8b62f63192c7","added_by":"auto","created_at":"2025-02-17 08:18:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3198782,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot Illustrating Positive Outcomes in Forward MR Analysis\u003c/p\u003e","description":"","filename":"Figure100.png","url":"https://assets-eu.researchsquare.com/files/rs-6026517/v1/1599317e2782656b0415b6bc.png"},{"id":76440944,"identity":"094eb26c-cbb2-41f4-9a44-9aa6e631c71c","added_by":"auto","created_at":"2025-02-17 08:10:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1586162,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot Illustrating Positive Outcomes in Reverse MR Analysis\u003c/p\u003e","description":"","filename":"Figure200.png","url":"https://assets-eu.researchsquare.com/files/rs-6026517/v1/b449ee26fd4d9912d7a2bc79.png"},{"id":76440882,"identity":"cd811102-2789-4a11-b6eb-bf3c36d68fa9","added_by":"auto","created_at":"2025-02-17 08:09:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3194656,"visible":true,"origin":"","legend":"\u003cp\u003eShowcasing a Forest Plot of Strongly Positive Results\u003c/p\u003e","description":"","filename":"Figure300.png","url":"https://assets-eu.researchsquare.com/files/rs-6026517/v1/f0907eaff120638548175bd1.png"},{"id":77152860,"identity":"9d1a3947-144b-4aef-9dd9-b5c826b4f5c3","added_by":"auto","created_at":"2025-02-25 15:31:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10113421,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6026517/v1/258be339-3477-45ae-9cc9-22705a7dfe9a.pdf"},{"id":76440950,"identity":"a446d5b3-0d64-4d89-b006-f620ec0d4c28","added_by":"auto","created_at":"2025-02-17 08:10:04","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7048539,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6026517/v1/bcc379f0a6c16e3af0862588.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Analysis of the Genetic Association Between Immune Cell Phenotypes and Chronic Rhinosinusitis","fulltext":[{"header":"1. Background","content":"\u003cp\u003eChronic rhinosinusitis (CRS), a heterogeneous disorder, is defined by persistent sinus inflammation exceeding 12 weeks[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], accompanied by at least two symptoms such as nasal obstruction/congestion, anterior or posterior (mucoid) nasal drainage, hyposmia or anosmia, and facial pressure/pain/distension, with diagnosis confirmed through endoscopic or imaging findings[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The condition is prevalent in the population, significantly impacting quality of life and imposing considerable health economic burdens. CRS is primarily categorized into two types: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Based on inflammatory cell infiltration, CRS can be further classified into subtypes such as neutrophilic, eosinophilic, lymphocytic/plasmacytic, and mixe[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe phenotypic expression of immune cells plays a crucial role in the pathogenesis of CRS. Various immune cells, including neutrophils, macrophages, eosinophils, lymphocytes, and mast cells[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], regulate inflammatory responses, tissue remodeling, and chronic disease progression through the expression of specific markers and the secretion of inflammatory mediators[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The aberrant expression of these cell phenotypes is closely associated with the onset, progression, and refractory nature of the disease, underscoring the significance of in-depth research for elucidating pathogenic mechanisms and developing novel therapeutic strategies.\u003c/p\u003e \u003cp\u003eCRS exhibits marked genetic susceptibility and familial aggregation[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Genome-wide association studies (GWAS) have identified multiple genetic variants associated with CRS, including genes related to both innate and adaptive immunity[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, elucidating these associations in traditional population-based surveys remains challenging due to the presence of unmeasurable confounding or mediating factors[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The shared genetic characteristics between CRS and autoimmune diseases may provide evidence for their correlation.\u003c/p\u003e \u003cp\u003eIn conclusion, the pathogenesis of CRS is complex, involving immune cell phenotypes, inflammatory cytokines, and genetic factors. Our team has investigated the genetic association between CRS and autoimmune diseases[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although existing research has highlighted the significant roles of these factors, further comprehensive studies are warranted to delineate their specific causal relationships and potential therapeutic targets.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Mendelian randomization (MR) analysis\u003c/h2\u003e \u003cp\u003eThis study employed bidirectional two-sample Mendelian randomization analysis[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] to assess the causal relationship between 731 immune cell phenotypes (collectively grouped into seven categories) and epithelial barrier injury-related nasal diseases. The analysis was based on three primary assumptions: (1) the relevance assumption, wherein the instrumental variables (IVs) are closely associated with the exposure factors; (2) the independence hypothesis, stating that IVs should not be influenced by known or unknown confounders; and (3) the exclusion restriction hypothesis, which posits that IVs affect the outcome variables solely through the exposure factors[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The data utilized in this study were sourced from the FinnGen and OPEN GWAS public databases, pre-processed to ensure anonymization, thereby excluding any personal privacy or identifying information. Given the nature of the study, which did not involve informed consent or data sharing with institutions, ethical review was not required.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Data Collection for Exposure and Outcome:\u003c/h2\u003e \u003cp\u003eThe GWAS Catalog (ranging from GCST90001391 to GCST90002121) provided an overview of GWAS statistical data for each immunological characteristic. This dataset encompassed comprehensive data from 3,757 Europeans, covering 731 immune phenotypes. When selecting CRS data from the Finnish database, considerations included sample size, publication year, the number of single nucleotide polymorphisms (SNPs), and ethnicity. The dataset ultimately included 359,399 European participants, comprising 19,856 cases and 337,881 controls.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Selection of Instrumental Variables:\u003c/h2\u003e \u003cp\u003eInitially, GWAS data were screened to include relevant SNPs that met the P\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026times;10\u0026thinsp;\u0026minus;\u0026thinsp;5 threshold. To mitigate the impact of linkage disequilibrium (LD) on the analysis, the parameter r threshold was set at 0.001, and the distance between SNPs was set to 10,000 Kb for analysis. Subsequently, the PhenoScanner V2 database was used to further validate these SNP loci for the presence of other confounding variables. To assess whether the included SNPs were affected by weak IVs, the F-statistic was employed, excluding values greater than 10. SNPs with an F-statistic less than 10, indicating a potential for weak instrument bias, were excluded to prevent influencing the results. Following this, outcome information was extracted through the IEU OpenGWAS database or FinnGen database, and the exposure and generated datasets were merged, with palindromic sequences removed. The remaining SNPs constituted the final IVs for exposure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Statistical Analysis:\u003c/h2\u003e \u003cp\u003eThe MR analysis in this study was conducted using the TwoSampleMR package in R version 4.3.3. Initially, the selected IVs were extracted from the outcome variables, followed by MR analysis using the TwoSampleMR package. Five commonly used MR analysis methods were employed: inverse variance weighting (IVW), weighted median, simple mode, weighted mode, and MR-Egger regression, with IVW as the primary method and the others as supplementary. The IVW method is characterized by its disregard for the intercept term and use of the inverse of the end variance (square of the standard error) as the fitting weight. A series of sensitivity analyses were conducted to further interpret potential pleiotropy, with IVW-derived p-values less than 0.05 considered indicative of correlation, and FDR-adjusted p-values (p_adj_fdr) less than 0.05 as the criterion for significant correlation.\u003c/p\u003e \u003cp\u003eAt the conclusion of the MR analysis, sensitivity analyses were performed, including heterogeneity and horizontal pleiotropy tests. Cochran's Q test quantified the heterogeneity of IVs, with P-values less than 0.05 indicating heterogeneity. The MR-Egger method, a weighted linear regression with an intercept, was used to assess the presence of horizontal pleiotropy among IVs. Additionally, the leave-one-out sensitivity test was employed to evaluate whether the causal effect was significantly influenced by individual SNPs. All results are presented as odds ratios (OR) with 95% confidence intervals (CI), and results were considered statistically significant when P-values were less than 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Outcomes","content":"\u003cp\u003eWe identified 64 immune phenotypes associated with chronic rhinosinusitis (CRS), of which six demonstrated more significant correlations. Reverse MR analysis of the immune phenotypes and CRS identified 27 phenotypes with correlations (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but none reached significant correlation (p_adj_fdr\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe IVW model revealed positive associations between CRS and the surface expression of HLA-DR on CD14 monocytes (OR\u0026thinsp;=\u0026thinsp;1.118, p_adj_fdr\u0026thinsp;=\u0026thinsp;0.0003), CD14_CD16 monocytes (OR\u0026thinsp;=\u0026thinsp;1.116, p_adj_fdr\u0026thinsp;=\u0026thinsp;0.0002), dendritic cells (OR\u0026thinsp;=\u0026thinsp;1.085673909, p_adj_fdr\u0026thinsp;=\u0026thinsp;0.00118315), CD33 myeloid cell differentiation antigens (OR\u0026thinsp;=\u0026thinsp;1.110, p_adj_fdr\u0026thinsp;=\u0026thinsp;0.000195), and plasmacytoid dendritic cells (pDC) (OR\u0026thinsp;=\u0026thinsp;1.069, p_adj_fdr\u0026thinsp;=\u0026thinsp;0.00118). HLA-DR, a major histocompatibility complex (MHC) II molecule, reflects the activation state of monocytes when expressed on their surface[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], aiding in the assessment of immune status[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, CD25 on activated CD4 regulatory T cells also had a positive effect on CRS (OR\u0026thinsp;=\u0026thinsp;1.101, p_adj_fdr\u0026thinsp;=\u0026thinsp;0.001183).\u003c/p\u003e \u003cp\u003e(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) (Table\u0026nbsp;1)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eMendelian randomization studies offer significant advantages in exploring the causal relationship between immune cell phenotypes and diseases[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. By utilizing genetic variants as instrumental variables, this method effectively mitigates the confounding biases and reverse causality issues common in traditional observational studies, thereby providing a more accurate assessment of the direct impact of specific immune cell phenotypes on disease risk. Moreover, Mendelian randomization studies can leverage large-scale genetic data to enhance statistical power, offering robust evidence for understanding the role of immune cells in disease pathogenesis, which is crucial for identifying new therapeutic targets and developing more effective prevention and treatment strategies[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe epithelial barrier, comprising epithelial cells and their tight junctions (TJs), serves as the first line of defense for the nasal and sinus mucosa, primarily functioning to protect against external pathogens, allergens, and other harmful substances, while also regulating immune responses and maintaining the health and homeostasis of the nasal mucosa[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In chronic rhinosinusitis (CRS), epithelial barrier dysfunction is considered a key factor in the onset and progression of the disease. Particularly in chronic rhinosinusitis with nasal polyps (CRSwNP), the disruption of the epithelial barrier is closely linked to disease occurrence. Research indicates that CRSwNP patients exhibit significant impairment in the barrier function of nasal mucosal epithelial cells, associated with altered expression of tight junction proteins. For instance, gene transcriptome analyses have identified multiple differentially expressed genes between CRSwNP patients and controls, involved in regulating cell adhesion functions and the composition of microtubule-related complexes, thereby affecting barrier function.\u003c/p\u003e \u003cp\u003eCD14 monocytes can be divided into three distinct subpopulations: classical monocytes (CD14\u0026thinsp;+\u0026thinsp;+\u0026thinsp;CD16-), intermediate monocytes (CD14\u0026thinsp;+\u0026thinsp;+\u0026thinsp;CD16+), and non-classical monocytes (CD14\u0026thinsp;+\u0026thinsp;CD16++). These subpopulations are further classified based on varying levels of HLA-DR and CD195, as well as receptors TNFR1 and TNFR2[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. CD14, an important immunomodulatory molecule, is primarily expressed on the surface of monocytes, macrophages, and dendritic cells. It recognizes pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharide (LPS) and activates downstream immune responses through the TLR4 signaling pathway[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Studies have found that specific single nucleotide polymorphisms (SNPs) in the CD14 promoter gene may be associated with the pathogenesis of sinusitis and the incidence of asthma[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and that CD14 is upregulated in the nasal mucosa of CRS patients, suggesting a potential pro-inflammatory role in the disease process[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eResearch on CD14 as a target has primarily focused on the correlation between HLA-DR expression on CD14-positive monocytes and disease states, particularly in cancer and immune system disorders. For example, in non-Hodgkin lymphoma[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and pancreatic cancer[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], the relative proportion of CD14\u0026thinsp;+\u0026thinsp;HLA-DRlo/neg monocytes is associated with clinical characteristics and prognosis of patients. However, there are no clear reports on the application of HLA-DR-targeted drugs on CD14-positive monocytes in the treatment of chronic rhinosinusitis. Current research mainly employs single-cell transcriptomics to unravel the complex cellular and genetic interactions in chronic rhinosinusitis, aiming to discover new therapeutic targets.\u003c/p\u003e \u003cp\u003eCD25 holds significant expression and functional importance on activated CD4 regulatory T cells (Tregs)[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. As the alpha chain of the interleukin-2 (IL-2) receptor, CD25 is expressed in CD4\u0026thinsp;+\u0026thinsp;T cells. Notably, CD4\u0026thinsp;+\u0026thinsp;CD25\u0026thinsp;+\u0026thinsp;Tregs constitute a specific subset of CD4\u0026thinsp;+\u0026thinsp;T cells, characterized by their high expression of CD25[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These CD4\u0026thinsp;+\u0026thinsp;CD25\u0026thinsp;+\u0026thinsp;Treg cells primarily modulate the immune response by suppressively regulating CD8 T cells and the helper functions of CD4\u0026thinsp;+\u0026thinsp;T cells, encompassing the entire immune system\u0026rsquo;s response, including antigen-presenting cells (APCs) and B cells [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. This suppression predominantly targets activated effector cells, rather than the activation process of naive T cells. Research on CD4\u0026thinsp;+\u0026thinsp;CD25\u0026thinsp;+\u0026thinsp;Tregs in chronic rhinosinusitis (CRS) has largely focused on their immunomodulatory functions and their role in disease pathogenesis [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Studies indicate that in CRS patients, the expression levels of Tregs undergo changes [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], potentially affecting both the quantity and function of these cells, thereby disrupting immune regulatory balance[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Tregs maintain immune homeostasis through the suppression of excessive immune responses; however, in CRS, dysfunctional Tregs may lead to an imbalance in immune reactions, promoting disease progression.\u003c/p\u003e \u003cp\u003eResearch has demonstrated that different subsets of CD4\u0026thinsp;+\u0026thinsp;T cells (such as Th1, Th2, Th17, and Tregs) play varied roles in the pathogenesis of CRS. For instance, Th2 cells are primarily involved in chronic rhinosinusitis with nasal polyps (CRSwNP), while the regulatory functions of Tregs may be compromised in the pathogenesis of CRSwNP[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. CD33 is commonly used to identify myeloid-derived suppressor cells (MDSCs), which play a role in immunosuppression[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The expression of HLA-DR in CD33-positive cells may indirectly relate to epithelial barrier damage by influencing immune cell activity and inflammatory responses [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Chronic inflammatory responses resulting from epithelial barrier damage may be associated with the activity of these immune cells[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], necessitating further research to elucidate the specific mechanisms involved. However, no direct studies or literature establish a direct association between CD33\u0026thinsp;+\u0026thinsp;cell surface HLA-DR and CRS.\u003c/p\u003e \u003cp\u003eThe impact of dendritic cells (DCs) on CRS has been a focal point of research, given their efficacy as antigen-presenting cells capable of initiating antigen-specific helper T cell responses[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. CRS endotypes are typically defined based on the balance of inflammatory helper T cell patterns, categorized into Th2 and non-Th2 endotypes[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. DCs play a crucial role in the polarization of Th2 or non-Th2 biased immune responses, with some studies indicating an increase in DCs in the mucosa of CRS patients, underscoring their significant role in the onset and progression of CRS. Elevated levels of CCL2 and CCL20 in the nasal mucosa of CRS patients may be related to DC recruitment[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Additionally, increased expression of osteopontin (OPN) in CRS patients is associated with DC-mediated promotion of Th1/Th17 immune responses[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. OPN can induce the production of IL-6, IL-12, and IL-23 in intestinal cells, thereby promoting the differentiation of Th1 and Th17 cells, a process that may also occur in CRS[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Nevertheless, no definitive studies have established a direct and clear relationship between HLA-DR expression on pDCs and chronic rhinosinusitis.\u003c/p\u003e \u003cp\u003eDCs play a pivotal role in nasal mucosal immunity and are considered potential therapeutic targets for CRS. However, current treatments lack specific methods to target DC pathways, such as biologic agents and corticosteroids[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], which only partially modulate DC function and do not specifically target DC pathways in CRS. Vitamin D3 (VD3), with its immunomodulatory potential, has been implicated in CRS patients with VD3 deficiency, but further research is needed to confirm its efficacy[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Additionally, CCR1 antagonists such as CCX354-C[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] and BMS-817399[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], which have entered clinical trials for rheumatoid arthritis, may also be considered potential therapeutic agents for CRS, warranting further investigation.\u003c/p\u003e \u003cp\u003eTranslation and Polishing:\u003c/p\u003e \u003cp\u003eAlthough Mendelian randomization studies offer unique advantages in elucidating the causal relationship between immune cell phenotypes and diseases, they are not without limitations. Firstly, these studies rely on a strong association between genetic variants and immune cell phenotypes, which may not always be present or sufficiently robust, leading to inefficient instrumental variables[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Secondly, Mendelian randomization assumes that genetic variants act on the disease solely through their impact on the target immune cell phenotype, termed the \"exclusivity assumption.\" However, in reality, genetic variants may influence multiple biological pathways, thereby introducing confounding effects. Additionally, insufficient sample sizes, population-specific genetic variations, and potential gene-environment interactions may also compromise the accuracy and generalizability of the findings. Therefore, caution is warranted when interpreting Mendelian randomization results, and a comprehensive analysis incorporating other research methods is advisable[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn-depth exploration of immune cell phenotypes, inflammatory factors, and genetic associations can provide novel insights and strategies for the precise treatment of chronic rhinosinusitis (CRS). For instance, therapies targeting specific immune cell phenotypes and inflammatory factors may enhance treatment efficacy while minimizing side effects. In summary, immune cell phenotypes, inflammatory factors, and genetic associations play crucial roles in the pathogenesis and immunomodulation of CRS. Further investigation into these phenotypes holds promise for advancing the precise treatment of chronic rhinosinusitis.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study underscores the intricate relationship between immune cell phenotypes and the pathogenesis of chronic rhinosinusitis (CRS), highlighting the potential of genetic associations in guiding precision medicine approaches. Through Mendelian randomization analysis, we identified significant correlations between CRS and specific immune cell phenotypes, such as HLA-DR expression on monocytes and dendritic cells, and CD25 on activated CD4 regulatory T cells. These findings suggest that aberrant immune cell function and genetic predisposition are pivotal in the onset and progression of CRS.\u003c/p\u003e \u003cp\u003eThe insights gained from this analysis pave the way for novel therapeutic strategies targeting specific immune cell phenotypes and inflammatory pathways. By leveraging these genetic and immunological insights, we can aspire to develop more effective and personalized treatments for CRS, ultimately aiming to alleviate the burden of this chronic condition on patient quality of life and healthcare systems. Future research should continue to explore the complex interplay between genetics, immune cell function, and CRS pathogenesis, fostering a deeper understanding that could lead to innovative therapeutic interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e6.1.Ethical Approval and Participant Consent\u003c/p\u003e\n\u003cp\u003eGiven that the study utilizes exclusively public databases and does not involve human subjects or personal data, ethical approval and participant consent are not required.\u003c/p\u003e\n\u003cp\u003e6.2.Consent for Publication\u003c/p\u003e\n\u003cp\u003eAll authors have given their consent for the manuscript to be published in its current form.\u003c/p\u003e\n\u003cp\u003e6.3.Availability of Data and Materials\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during the current study are publicly available and have been deposited in FAERS database (https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers-database), Drugbank database (https://go.drugbank.com), \u0026nbsp; Details of the specific datasets and accession numbers are provided in the Materials and Methods section of the manuscript.\u003c/p\u003e\n\u003cp\u003e6.4.Competing Interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e6.5.Funding\u003c/p\u003e\n\u003cp\u003eNo funding body had role in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript.\u003c/p\u003e\n\u003cp\u003e6.6.The Authors’ full name(s) and affiliation:\u003c/p\u003e\n\u003cp\u003eEnze Wang M.Med（First Author）, 0009-0006-7893-6310\u003c/p\u003e\n\u003cp\u003eDepartment of Otolaryngology Head and Neck Surgery，Shengjing Hospital of China Medical University , Shenyang City, China；\u003c/p\u003e\n\u003cp\u003eYingxuan Sun, M.Med, （Co-first Author）0009-0000-3823-1494\u003c/p\u003e\n\u003cp\u003eDepartment of Neurology, The First Affiliation Hospital of China Medical University , Shenyang City, China;\u003c/p\u003e\n\u003cp\u003eHe Zhao, Ph.D, 0000-0002-9212-7628\u003c/p\u003e\n\u003cp\u003eDepartment of Otolaryngology Head and Neck Surgery，Shengjing Hospital of China Medical University , Shenyang City, China；\u003c/p\u003e\n\u003cp\u003eMeng Wang, Ph.D, 0000-0002-3178-7382\u003c/p\u003e\n\u003cp\u003eDepartment of Otolaryngology Head and Neck Surgery，Shengjing Hospital of China Medical University , Shenyang City, China；\u003c/p\u003e\n\u003cp\u003eZhiwei Cao*, Ph.D, 0000-0002-2221-9260\u003c/p\u003e\n\u003cp\u003eDepartment of Otolaryngology Head and Neck Surgery，Shengjing Hospital of China Medical University , Shenyang City, China\u003c/p\u003e\n\u003cp\u003e6.7.Authors' Contributions\u003c/p\u003e\n\u003cp\u003eEnze Wang and Yingxuan Sun conceived the study, designed the analysis, and drafted the manuscript. Meng Wang and He Zhao performed the data analysis and contributed to the interpretation of the results. Zhiwei Cao provided critical input and helped revise the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e6.8.Confirmation\u003c/p\u003e\n\u003cp\u003eThe author Yingxuan Sun has made significant contributions to this article. Enze Wang is the first author of this paper, with Yingxuan Sun as the co-first author. We, the authors of this manuscript, confirm that the work described has been conducted in accordance with the relevant guidelines and regulations. We also confirm that the manuscript has not been published previously, nor is it under consideration for publication elsewhere.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, Cervin A, Douglas R, Gevaert P\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. 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\u003cstrong\u003e37\u003c/strong\u003e(7):683-700.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\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":"Genetic analyses, Immune cells, Immunology, Mendelian randomization, Chronic sinusitis","lastPublishedDoi":"10.21203/rs.3.rs-6026517/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6026517/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChronic rhinosinusitis (CRS), a prevalent and debilitating disorder, is characterized by persistent sinus inflammation and a complex interplay of immune cell phenotypes, inflammatory cytokines, and genetic factors.\u003c/p\u003e\n\u003cp\u003eThis study employed bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between 731 immune cell phenotypes and CRS, utilizing data from the FinnGen and OPEN GWAS public databases.\u003c/p\u003e\n\u003cp\u003eThe analysis revealed significant associations between CRS and specific immune cell phenotypes, including HLA-DR on CD14 monocytes (OR=1.118, p_adj_fdr=0.0003), CD14_CD16 monocytes (OR=1.116, p_adj_fdr=0.0002), dendritic cells (OR=1.085673909, p_adj_fdr=0.00118315), CD33 myeloid cell differentiation antigens (OR=1.110, p_adj_fdr=0.000195), and plasmacytoid dendritic cells (pDC) (OR=1.069, p_adj_fdr=0.00118). \u0026nbsp;These findings suggest that aberrant immune cell function and genetic predisposition are pivotal in the onset and progression of CRS.\u003c/p\u003e\n\u003cp\u003eThe insights gained from this study provide a foundation for the development of novel, precision medicine-based therapeutic strategies for CRS, targeting specific immune cell phenotypes and inflammatory pathways to enhance treatment efficacy and minimize side effects.\u003c/p\u003e","manuscriptTitle":"Analysis of the Genetic Association Between Immune Cell Phenotypes and 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