The causality between chronic rhinosinusitis and inflammatory bowel disease: a bi-directional two-sample Mendelian randomization analysis

The causality between chronic rhinosinusitis and inflammatory bowel disease: a bi-directional two-sample Mendelian randomization analysis | 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 The causality between chronic rhinosinusitis and inflammatory bowel disease: a bi-directional two-sample Mendelian randomization analysis Junyu Huang, Zan Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4447676/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: Prior studies have shown that chronic rhinosinusitis(CRS) was associated with inflammatory bowel disease(IBD) consisted of Crohn's disease (CD) and ulcerative colitis (UC). However, the causality needs to be further verified. We performed a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal effect between CRS and IBD. Methods: We obtained CRS database from the IEU Open GWAS project and IBD database from FinnGen. Inverse-variance weighted (IVW) method was used as the primary statistical method, while weighted median and MR-Egger methods were used to examine the robustness of our results. Furthermore, Cochran’s Q test, MR-Egger intercept, MR-PRESSO and leave-one-out methods were used to examine pleiotropy and heterogeneity. Results: IVW method revealed that CRS was associated with an increased risk of UC(OR=3.44E+08, 95% CI=3.01-3.94+16, p=0.038). Reverse MR analysis revealed that IBD was associated with a decreased risk of CRS(OR=0.999, 95% CI=0.998-1.000, p=0.020). Conclusion: Our findings revealed that CRS was associated with an increased risk of UC, while IBD was associated with a decreased risk of CRS and the effect is mild. We suggested that clinicians should pay attention to the intestinal symptoms in CRS patients and a timely screening colonoscopy to detect early lesions. chronic rhinosinusitis inflammatory bowel disease Crohn’s disease ulcerative colitis Mendelian randomization Introduction Inflammatory bowel disease (IBD) is a chronic and recurrent gastrointestinal inflammatory disease, caused by the interaction of multiple factors including host genetics, environmental factors, immune disorders, and the intestinal microbiota [ 1 – 4 ] , mainly classified into Crohn’s disease (CD) and ulcerative colitis (UC) according to symptoms, endoscopic findings and pathological results [ 5 ] . Currently, IBD has become a growing concern and serious public health problem as the increasing incidence and prevalence globally [ 6 , 7 ] . Chronic rhinosinusitis (CRS) is a common disease with chronic inflammation of the nose and paranasal sinuse characterized by symptoms including nasal obstruction, rhinorrhoea, smell loss and facial pressure or pain, and these symptoms last longer than 12 weeks [ 8 ] ,which severely impact the quality of life [ 9 , 10 ] . Recent evidence has shown that epithelial barrier dysfunction and immune dysregulation play an important role in the development of CRS [ 11 ] , which was similar to IBD [ 12 ] . In addition, it has been briefly reported that a great improvement of UC after CRS treatment in some patients who suffered from both CRS and UC [ 13 ] . Therefore, it is worthy of further studying the relationship between CRS and IBD. Actually, there are several studies having already evaluated the relationship between CRS and IBD [ 14 – 17 ] , but the results are inconsistent. However, it is noteworthy that these evidence come only from observational studies, which are hard to infer causality and avoid the impact of confounding factors [ 18 ] . Mendelian randomization (MR) analysis is a novel epidemiological method for assessing the causality between an exposure and an outcome through using genetic variants as instrumental variables (IVs), which follow Mendel’s law of inheritance, and thus avoiding the reverse causation and the influence of confounding factors. [ 18 ] . Consequently, our study applied a bi-directional two-sample MR analysis to better clarify the causality between CRS and IBD. Materials and Methods For a causal interpretation of MR, the single nucleotide polymorphisms (SNPs) were selected as IVs and must satisfy three assumptions [ 19 ] : (1) SNPs are closely correlated with the exposure; (2) SNPs must be independent of any confounding factors between the exposure and the outcome; (3) SNPs only affect the outcome via the exposure. Data source Summary statistics for CRS were obtained from the IEU Open GWAS project ( https://gwas.mrcieu.ac.uk/datasets/ ), and the GWAS dataset with ID: ebi-a-GCST90038673, comprising 3,014 CRS patients and 481,584 controls from the United Kingdom Biobank (UKBB). Summary statistics for IBD, CD and UC were all obtained from the FinnGen data release 9 ( https://r9.finngen.fi/ ), the GWAS dataset of IBD were comprising 7,625 IBD patients and 369,652 controls, the GWAS dataset of CD were comprising 1,665 CD patients and 375,445 controls, and the GWAS dataset of UC were comprising 5,034 UC patients and 371,530 controls. SNPs selection To identify eligible SNPs as IVs, the following steps were carried out. Firstly, given the insufficient number of SNPs with p < 5×10 − 8 available from the GWAS dataset of CRS, we adopted an alternative threshold of p < 5×10 − 6[ 20 ] , while the GWAS dataset of IBD, CD and UC were adopted a threshold of p < 5×10 − 8 . Secondly, to avoid the effect of linkage disequilibrium in SNPs, we set the clumping process with a distance of 10,000 kb and r 2 < 0.001 [ 21 ] . Thirdly, both the exposure and outcome data were harmonized to guarantee the consistency of alleles, and meanwhile the ambiguous or palindromic variants should be removed. Fourthly, we exclude confounder factors related to the exposure SNPs, including body mass index, obesity, smoking, and autoimmune diseases, via visiting the PhenoScanner database [ 22 ] . Fifthly, we calculated the F statistic for indicating instrument strength of individual SNPs, and SNP was considered a strong instrument strongly associated with exposure when the F statistic was greater than 10 [ 23 ] . Statistical analysis Our study was performed using inverse variance weighted (IVW) as the major analyses method, which provides a convincing causal estimate in the absence of horizontal pleiotropy between the exposure and outcome, divided into the fixed-effects and the random-effects models. Besides, weighted median and MR-Egger methods were used for supplementary methods to enhance accuracy and stability [ 24 , 25 ] . In addition, we used Cochran’s Q test to assess the heterogeneity, and if heterogeneity(P < 0.05) was existed, a random-effects IVW model was applied, otherwise a fixed-effect IVW model. We also MR-Egger regression to assess the horizontal pleiotropy and MR-PRESSO method to check potential outliers. [ 26 ] . At last, leave-one-out analysis was performed to assess whether the possibility of result was driven by a single SNP [ 27 ] . All analyses were carried out by TwoSampleMR and MR-PRESSO packages in R software(version 4.3.1). Results After SNP dataset filtering, we obtained all the detailed information on SNPs for this study, which were shown in Supplementary Tables 1–6. Causal effects of CRS on IBD As shown in Table 1 , the IVW fixed-effects model was used due to the absence of heterogeneity. We found CRS was significantly associated with an increased risk of UC(OR = 3.44E + 08, 95% CI = 3.01–3.94 + 16, p = 0.038). Additionally, we found CRS was positively associated with IBD (OR = 1710.96, 95% CI = 4.57E-04-6.40E + 09, p = 0.335), but negatively associated with CD (OR = 7.27E-04, 95% CI = 8.08E-18-6.54E + 10, p = 0.659), and these results had no statistical significance. The same effect directions were observed in weighted median and MR-Egger methods, but the results had no statistical significance either. The scatter plots were shown in Supplementary Fig. 1–3. Table 1 MR analysis of the causality of CRS on IBD. Exposure Outcome SNPs Methods OR 95% CI P CRS IBD 6 IVW 1710.96 (4.57E-04-6.40E + 09) 0.335 MR Egger 379468.95 (2.15E-06-6.70E + 16) 0.386 WM 7002.13 (5.94E-05-8.25E + 11) 0.347 CRS CD 6 IVW 7.27E-04 (8.08E-18-6.54E + 10) 0.659 MR Egger 7.03E-09 (2.45E-40-2.02E + 23) 0.638 WM 2.81E-01 (1.18E-18-6.72 + 16) 0.952 CRS UC 6 IVW 3.44E + 08 (3.01–3.94 + 16) 0.038 MR Egger 1.36E + 12 (2.21E-02-8.35E + 25) 0.16 WM 5.02E + 06 (7.04E-05-3.57E + 17) 0.226 CRS, chronic rhinosinusitis; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; IVW, inverse variance weighted; OR, odds ratio; CI, confidence interval Causal effects of IBD on CRS As shown in Table 2 , the IVW fixed-effects model was used due to the absence of heterogeneity. We found IBD was associated with a decreased risk of CRS(OR = 0.999, 95% CI = 0.998-1.000, p = 0.020). Likewise, we also found CRS was negatively associated with CD and UC, but these results had no statistical significance. The same effect directions were observed in weighted median and MR-Egger methods, but the results had no statistical significance either. The scatter plots were shown in Supplementary Fig. 4–6. Table 2 MR analysis of the causality of IBD on CRS. Exposure Outcome SNPs Methods OR 95% CI P IBD CRS 20 IVW 0.999 (0.998, 1.000) 0.020 MR Egger 0.999 (0.998, 1.000) 0.312 WM 0.999 (0.998, 1.000) 0.084 CD CRS 5 IVW 0.999 (0.998, 1.000) 0.281 MR Egger 0.999 (0.998, 1.000) 0.977 WM 0.999 (0.998, 1.000) 0.452 UC CRS 16 IVW 1 (0.999,1.000) 0.437 MR Egger 0.999 (0.998, 1.000) 0.487 WM 0.999 (0.998, 1.000) 0.115 IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; CRS, chronic rhinosinusitis; IVW, inverse variance weighted; OR, odds ratio; CI, confidence interval Sensitivity analyses Tables 3 shown that there were no significant heterogeneity observed across the above studies (all P -values for Cochran’s Q test > 0.05) and no significant horizontal pleiotropy based on the analysis results of intercept of MR-Egger regression. Additionally, there were no SNP outliers indicated by MR-PRESSO analysis. Moreover, leave-one-out plots were shown in Supplementary Fig. 1–6, we found that a SNP (rs74753441) may affect the result of the causality of CRS on CD, and an opposite result that CRS was positively associated with CD (OR = 15.404, 95% CI = 5.74E-14-4.140E + 15, p = 0.659) after removing above SNP, but it had no statistical significance. Table 3 Sensitivity analyses of MR Exposure Outcome Cochran's Q-derived P value MR-Egger intercept-derived P value CRS IBD 0.981 0.641 CRS CD 0.206 0.72 CRS UC 0.709 0.563 IBD CRS 0.249 0.841 CD CRS 0.734 0.629 UC CRS 0.554 0.631 CRS, chronic rhinosinusitis; IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis Discussion To our knowledge, this is the first MR study to investigate the causality between CRS and IBD, and we found CRS was significantly associated with an increased risk of UC, while IBD was associated with a decreased risk of CRS. Several studies have explored the link between CRS and IBD previously. A small single-center retrospective study from UChicago Medicine suggested that the diagnosis and duration of UC may be more associated with development of CRS, while CRS may be considered as an extraintestinal manifestation of IBD due to CRS precedes IBD in some patients [ 14 ] . Besides, Lin et al. found that patients with IBD history, especially UC, had an increased risk of subsequent development of CRS [ 16 ] . A 10-year-long retrospective cohort study by Lee et al. including 15,175 CRS patients and 30,350 controls to assess the subsequent incidence of IBD, shown that CRS was significantly related to the risk of UC(adjusted HR = 1.72, 95% CI = 1.26–2.36) after adjusting for sex, age, residence, income level, and comorbidities, but not CD, and more precisely, the subgroup analysis shown that CRS without nasal polyps was related to an increased incidence of UC(adjusted HR = 1.71, 95% CI = 1.24–2.35) [ 15 ] . However, not all observational studies have found a correlation between CRS and IBD [ 17 , 28 ] . Regrettably, causality could not be addressed through the above studies. Rather, our MR study overcame these limitations. The epithelial barrier integrity plays a critical role in maintaining homeostasis in the nose and paranasal sinuses [ 11 ] . There are multiple factors such as geographical, ethnic, environmental exposure, changed sinonasal microbiota, decreased mucociliary clearance, abnormal epithelial barrier and immune response are involved in the development of CRS [ 29 ] , which leads to chronic inflammation in several pathways, like activating inflammatory cytokines, releasing exosome, dysregulating Vitamin D3 and so on [ 30 – 32 ] . Additionally, some reports suggested that S. aureus, a bacterium can secrete a variety of virulence factors such as superantigens, hemolysins, enterotoxins and so on, colonizes in the nasal cavity, may also have played a key role in the development of CRS [ 33 ] . Surprisingly, S. aureus superantigens deriving from sinuses may reach the gut via swallowing and impair the intestinal mucosal barrier to induce ulcerative colitis [ 13 , 34 ] . On the other hand, there are not only in the nasal cavity [ 35 ] , but in the gut existing microbiota dysbiosis in CRS patients, which may be caused by the treatment of CRS, especially antibiotic use [ 36 ] , or by the lung-gut crosstalk, a certain pathophysiological correlation between the respiratory and gastrointestinal system [ 37 ] . These suggest a possible association between CRS and IBD. In conclusion, our MR study revealed that CRS was associated with an increased risk of UC, and we suggested that clinicians should pay attention to the intestinal symptoms in CRS patients and a timely screening colonoscopy to detect early lesions. Additionally, our reverse MR analysis revealed that IBD was associated with a decreased risk of CRS, although the effect is mild as the OR is very close to 1, and the specific mechanism is not completely clear, which may be associated with microbiota dysbiosis. It had the following strengths in our study. Firstly, our study drawn a convincing causality between CRS and IBD by implementing MR analysis compared with conventional observational studies. Secondly, our study was limited to individuals of European ancestry for minimizing the population structure bias. Thirdly, there was no pleiotropy observed suggesting that the results were robust. However, there are also limitations. Firstly, the results of this study might not be appropriate to other ancestry besides European. Secondly, the large OR and CI were observed due to the limited sample size possibly. Therefore, in order to verify the accuracy of our results, future studies with larger sample GWAS datasets are needed. Declarations Data Availability Statement The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors. Author Contributions ZL conceived the study, participated in its design and coordination, and critically revised the manuscript. JH finished data collection and analysis and drafted the manuscript. Both authors contributed to the article and approved the submitted version. Funding No funding was provided for this study. 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Front Cell Infect Microbiol 13:1218565 Additional Declarations No competing interests reported. Supplementary Files SupplementarymaterialFigures.pdf SupplementarymaterialTable.xls 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-4447676","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":308047751,"identity":"2153063d-eda3-4842-a365-f6b1563b2985","order_by":0,"name":"Junyu Huang","email":"","orcid":"","institution":"Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Junyu","middleName":"","lastName":"Huang","suffix":""},{"id":308047752,"identity":"9952202f-a438-4d7a-b389-abee9c1cb77a","order_by":1,"name":"Zan Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYBACA4YDDMw//9jw8DMzH35AvBbGhjQ5yXa2NAMitTCAtBw2NjjPoyBBlBZzxjNm0oU7mBM3H+YB6q+xiSaoxbIBqGXmGbbEbYd5DzxgOJaW20DQYQfOmEnwsPEAtfAlGABdSLQWicTNzTwGEkRrkeZtMzA2YCZey7FiyxlnEuQkDgMDOYEov9w4vPHGh4r/PPz9hw8/+FBjQ1gLg8QJpAhMIKgcBPjbHxClbhSMglEwCkYwAABtpkLogUJ3OQAAAABJRU5ErkJggg==","orcid":"","institution":"Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Zan","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-05-20 08:22:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4447676/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4447676/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58390939,"identity":"91bc2721-5889-43bd-9fee-8e6893a69a52","added_by":"auto","created_at":"2024-06-14 20:35:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":418633,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4447676/v1/914ff9d7-bf6c-4ddc-9632-d398bad26fa1.pdf"},{"id":57613664,"identity":"05fd8b28-08c4-4fed-8606-a99594ccf55f","added_by":"auto","created_at":"2024-06-03 10:53:52","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":596312,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarymaterialFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4447676/v1/1facaf4f597ae54487745951.pdf"},{"id":57614355,"identity":"aa0d0c8c-8f74-4561-9ffc-3a309cd3804f","added_by":"auto","created_at":"2024-06-03 11:01:52","extension":"xls","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":44032,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarymaterialTable.xls","url":"https://assets-eu.researchsquare.com/files/rs-4447676/v1/7003020b5412f86eb64a182d.xls"}],"financialInterests":"No competing interests reported.","formattedTitle":"The causality between chronic rhinosinusitis and inflammatory bowel disease: a bi-directional two-sample Mendelian randomization analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInflammatory bowel disease (IBD) is a chronic and recurrent gastrointestinal inflammatory disease, caused by the interaction of multiple factors including host genetics, environmental factors, immune disorders, and the intestinal microbiota\u003csup\u003e[\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e, mainly classified into Crohn\u0026rsquo;s disease (CD) and ulcerative colitis (UC) according to symptoms, endoscopic findings and pathological results\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Currently, IBD has become a growing concern and serious public health problem as the increasing incidence and prevalence globally\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eChronic rhinosinusitis (CRS) is a common disease with chronic inflammation of the nose and paranasal sinuse characterized by symptoms including nasal obstruction, rhinorrhoea, smell loss and facial pressure or pain, and these symptoms last longer than 12 weeks\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e,which severely impact the quality of life\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Recent evidence has shown that epithelial barrier dysfunction and immune dysregulation play an important role in the development of CRS\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e, which was similar to IBD\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. In addition, it has been briefly reported that a great improvement of UC after CRS treatment in some patients who suffered from both CRS and UC\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Therefore, it is worthy of further studying the relationship between CRS and IBD. Actually, there are several studies having already evaluated the relationship between CRS and IBD\u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, but the results are inconsistent. However, it is noteworthy that these evidence come only from observational studies, which are hard to infer causality and avoid the impact of confounding factors\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) analysis is a novel epidemiological method for assessing the causality between an exposure and an outcome through using genetic variants as instrumental variables (IVs), which follow Mendel\u0026rsquo;s law of inheritance, and thus avoiding the reverse causation and the influence of confounding factors.\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Consequently, our study applied a bi-directional two-sample MR analysis to better clarify the causality between CRS and IBD.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eFor a causal interpretation of MR, the single nucleotide polymorphisms (SNPs) were selected as IVs and must satisfy three assumptions\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e: (1) SNPs are closely correlated with the exposure; (2) SNPs must be independent of any confounding factors between the exposure and the outcome; (3) SNPs only affect the outcome via the exposure.\u003c/p\u003e \u003cp\u003eData source\u003c/p\u003e \u003cp\u003eSummary statistics for CRS were obtained from the IEU Open GWAS project (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/datasets/\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk/datasets/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and the GWAS dataset with ID: ebi-a-GCST90038673, comprising 3,014 CRS patients and 481,584 controls from the United Kingdom Biobank (UKBB).\u003c/p\u003e \u003cp\u003eSummary statistics for IBD, CD and UC were all obtained from the FinnGen data release 9 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://r9.finngen.fi/\u003c/span\u003e\u003cspan address=\"https://r9.finngen.fi/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), the GWAS dataset of IBD were comprising 7,625 IBD patients and 369,652 controls, the GWAS dataset of CD were comprising 1,665 CD patients and 375,445 controls, and the GWAS dataset of UC were comprising 5,034 UC patients and 371,530 controls.\u003c/p\u003e \u003cp\u003eSNPs selection\u003c/p\u003e \u003cp\u003eTo identify eligible SNPs as IVs, the following steps were carried out. Firstly, given the insufficient number of SNPs with p\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e available from the GWAS dataset of CRS, we adopted an alternative threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;6[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e, while the GWAS dataset of IBD, CD and UC were adopted a threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e. Secondly, to avoid the effect of linkage disequilibrium in SNPs, we set the clumping process with a distance of 10,000 kb and r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Thirdly, both the exposure and outcome data were harmonized to guarantee the consistency of alleles, and meanwhile the ambiguous or palindromic variants should be removed. Fourthly, we exclude confounder factors related to the exposure SNPs, including body mass index, obesity, smoking, and autoimmune diseases, via visiting the PhenoScanner database\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Fifthly, we calculated the F statistic for indicating instrument strength of individual SNPs, and SNP was considered a strong instrument strongly associated with exposure when the F statistic was greater than 10\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eOur study was performed using inverse variance weighted (IVW) as the major analyses method, which provides a convincing causal estimate in the absence of horizontal pleiotropy between the exposure and outcome, divided into the fixed-effects and the random-effects models. Besides, weighted median and MR-Egger methods were used for supplementary methods to enhance accuracy and stability\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. In addition, we used Cochran\u0026rsquo;s Q test to assess the heterogeneity, and if heterogeneity(P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) was existed, a random-effects IVW model was applied, otherwise a fixed-effect IVW model. We also MR-Egger regression to assess the horizontal pleiotropy and MR-PRESSO method to check potential outliers.\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. At last, leave-one-out analysis was performed to assess whether the possibility of result was driven by a single SNP\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. All analyses were carried out by TwoSampleMR and MR-PRESSO packages in R software(version 4.3.1).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAfter SNP dataset filtering, we obtained all the detailed information on SNPs for this study, which were shown in Supplementary Tables\u0026nbsp;1\u0026ndash;6.\u003c/p\u003e \u003cp\u003eCausal effects of CRS on IBD\u003c/p\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the IVW fixed-effects model was used due to the absence of heterogeneity. We found CRS was significantly associated with an increased risk of UC(OR\u0026thinsp;=\u0026thinsp;3.44E\u0026thinsp;+\u0026thinsp;08, 95% CI\u0026thinsp;=\u0026thinsp;3.01\u0026ndash;3.94\u0026thinsp;+\u0026thinsp;16, p\u0026thinsp;=\u0026thinsp;0.038). Additionally, we found CRS was positively associated with IBD (OR\u0026thinsp;=\u0026thinsp;1710.96, 95% CI\u0026thinsp;=\u0026thinsp;4.57E-04-6.40E\u0026thinsp;+\u0026thinsp;09, p\u0026thinsp;=\u0026thinsp;0.335), but negatively associated with CD (OR\u0026thinsp;=\u0026thinsp;7.27E-04, 95% CI\u0026thinsp;=\u0026thinsp;8.08E-18-6.54E\u0026thinsp;+\u0026thinsp;10, p\u0026thinsp;=\u0026thinsp;0.659), and these results had no statistical significance. The same effect directions were observed in weighted median and MR-Egger methods, but the results had no statistical significance either. The scatter plots were shown in Supplementary Fig.\u0026nbsp;1\u0026ndash;3.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMR analysis of the causality of CRS on IBD.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSNPs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMethods\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRS\u003c/p\u003e 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colname=\"c4\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.03E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(2.45E-40-2.02E\u0026thinsp;+\u0026thinsp;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.638\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.81E-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(1.18E-18-6.72\u0026thinsp;+\u0026thinsp;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.952\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.44E\u0026thinsp;+\u0026thinsp;08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(3.01\u0026ndash;3.94\u0026thinsp;+\u0026thinsp;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.36E\u0026thinsp;+\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(2.21E-02-8.35E\u0026thinsp;+\u0026thinsp;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.02E\u0026thinsp;+\u0026thinsp;06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(7.04E-05-3.57E\u0026thinsp;+\u0026thinsp;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.226\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eCRS, chronic rhinosinusitis; IBD, inflammatory bowel disease; CD, Crohn\u0026rsquo;s disease; UC, ulcerative colitis; IVW, inverse variance weighted; OR, odds ratio; CI, confidence interval\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCausal effects of IBD on CRS\u003c/p\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the IVW fixed-effects model was used due to the absence of heterogeneity. We found IBD was associated with a decreased risk of CRS(OR\u0026thinsp;=\u0026thinsp;0.999, 95% CI\u0026thinsp;=\u0026thinsp;0.998-1.000, p\u0026thinsp;=\u0026thinsp;0.020). Likewise, we also found CRS was negatively associated with CD and UC, but these results had no statistical significance. The same effect directions were observed in weighted median and MR-Egger methods, but the results had no statistical significance either. The scatter plots were shown in Supplementary Fig.\u0026nbsp;4\u0026ndash;6.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMR analysis of the causality of IBD on CRS.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSNPs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMethods\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.998, 1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.998, 1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.312\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.998, 1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.084\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.998, 1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.281\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.998, 1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.977\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.998, 1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.452\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.999,1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.437\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.998, 1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.487\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e(0.998, 1.000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eIBD, inflammatory bowel disease; CD, Crohn\u0026rsquo;s disease; UC, ulcerative colitis; CRS, chronic rhinosinusitis; IVW, inverse variance weighted; OR, odds ratio; CI, confidence interval\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSensitivity analyses\u003c/p\u003e \u003cp\u003eTables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shown that there were no significant heterogeneity observed across the above studies (all P -values for Cochran\u0026rsquo;s Q test\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and no significant horizontal pleiotropy based on the analysis results of intercept of MR-Egger regression. Additionally, there were no SNP outliers indicated by MR-PRESSO analysis. Moreover, leave-one-out plots were shown in Supplementary Fig.\u0026nbsp;1\u0026ndash;6, we found that a SNP (rs74753441) may affect the result of the causality of CRS on CD, and an opposite result that CRS was positively associated with CD (OR\u0026thinsp;=\u0026thinsp;15.404, 95% CI\u0026thinsp;=\u0026thinsp;5.74E-14-4.140E\u0026thinsp;+\u0026thinsp;15, p\u0026thinsp;=\u0026thinsp;0.659) after removing above SNP, but it had no statistical significance.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitivity analyses of MR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCochran's Q-derived P value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMR-Egger intercept-derived P value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.981\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.641\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.709\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.563\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.841\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.734\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.554\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.631\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCRS, chronic rhinosinusitis; IBD, inflammatory bowel disease; CD, Crohn\u0026rsquo;s disease; UC, ulcerative colitis\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first MR study to investigate the causality between CRS and IBD, and we found CRS was significantly associated with an increased risk of UC, while IBD was associated with a decreased risk of CRS. Several studies have explored the link between CRS and IBD previously. A small single-center retrospective study from UChicago Medicine suggested that the diagnosis and duration of UC may be more associated with development of CRS, while CRS may be considered as an extraintestinal manifestation of IBD due to CRS precedes IBD in some patients\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Besides, Lin et al. found that patients with IBD history, especially UC, had an increased risk of subsequent development of CRS\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. A 10-year-long retrospective cohort study by Lee et al. including 15,175 CRS patients and 30,350 controls to assess the subsequent incidence of IBD, shown that CRS was significantly related to the risk of UC(adjusted HR\u0026thinsp;=\u0026thinsp;1.72, 95% CI\u0026thinsp;=\u0026thinsp;1.26\u0026ndash;2.36) after adjusting for sex, age, residence, income level, and comorbidities, but not CD, and more precisely, the subgroup analysis shown that CRS without nasal polyps was related to an increased incidence of UC(adjusted HR\u0026thinsp;=\u0026thinsp;1.71, 95% CI\u0026thinsp;=\u0026thinsp;1.24\u0026ndash;2.35)\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. However, not all observational studies have found a correlation between CRS and IBD\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Regrettably, causality could not be addressed through the above studies. Rather, our MR study overcame these limitations.\u003c/p\u003e \u003cp\u003eThe epithelial barrier integrity plays a critical role in maintaining homeostasis in the nose and paranasal sinuses\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. There are multiple factors such as geographical, ethnic, environmental exposure, changed sinonasal microbiota, decreased mucociliary clearance, abnormal epithelial barrier and immune response are involved in the development of CRS\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e, which leads to chronic inflammation in several pathways, like activating inflammatory cytokines, releasing exosome, dysregulating Vitamin D3 and so on\u003csup\u003e[\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Additionally, some reports suggested that S. aureus, a bacterium can secrete a variety of virulence factors such as superantigens, hemolysins, enterotoxins and so on, colonizes in the nasal cavity, may also have played a key role in the development of CRS\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Surprisingly, S. aureus superantigens deriving from sinuses may reach the gut via swallowing and impair the intestinal mucosal barrier to induce ulcerative colitis\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. On the other hand, there are not only in the nasal cavity\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, but in the gut existing microbiota dysbiosis in CRS patients, which may be caused by the treatment of CRS, especially antibiotic use\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e, or by the lung-gut crosstalk, a certain pathophysiological correlation between the respiratory and gastrointestinal system\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. These suggest a possible association between CRS and IBD.\u003c/p\u003e \u003cp\u003eIn conclusion, our MR study revealed that CRS was associated with an increased risk of UC, and we suggested that clinicians should pay attention to the intestinal symptoms in CRS patients and a timely screening colonoscopy to detect early lesions. Additionally, our reverse MR analysis revealed that IBD was associated with a decreased risk of CRS, although the effect is mild as the OR is very close to 1, and the specific mechanism is not completely clear, which may be associated with microbiota dysbiosis. It had the following strengths in our study. Firstly, our study drawn a convincing causality between CRS and IBD by implementing MR analysis compared with conventional observational studies. Secondly, our study was limited to individuals of European ancestry for minimizing the population structure bias. Thirdly, there was no pleiotropy observed suggesting that the results were robust. However, there are also limitations. Firstly, the results of this study might not be appropriate to other ancestry besides European. Secondly, the large OR and CI were observed due to the limited sample size possibly. Therefore, in order to verify the accuracy of our results, future studies with larger sample GWAS datasets are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.\u003c/p\u003e\n\u003ch3\u003eAuthor Contributions\u003c/h3\u003e\n\u003cp\u003eZL conceived the study, participated in its design and coordination, and critically revised the manuscript.\u0026nbsp;JH\u0026nbsp;finished data collection and analysis and drafted the manuscript. Both authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eNo funding was provided for this study.\u003c/p\u003e\n\u003ch3\u003eConflict of Interest\u003c/h3\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNoble AJ, Nowak JK, Adams AT, Uhlig HH, Satsangi J (2023) Defining Interactions Between the Genome, Epigenome, and the Environment in Inflammatory Bowel Disease: Progress and Prospects. Gastroenterology 165(1):44\u0026ndash;60\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSabo CM, Simiras C, Ismaiel A, Dumitrascu DL (2023) Diet and Gut Inflammation: The Effect of Diet on Inflammatory Markers in Inflammatory Bowel Disease - A Scoping Review. 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Front Cell Infect Microbiol 11:812920\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChristensen JM, Cheng J, Earls P, Gunton J, Sewell W, Sacks R et al (2017) Vitamin D pathway regulatory genes encoding 1α-hydroxylase and 24-hydroxylase are dysregulated in sinonasal tissue during chronic rhinosinusitis. Int Forum Allergy Rhinol 7(2):169\u0026ndash;176\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChegini Z, Noei M, Hemmati J, Arabestani MR, Shariati A (2023) The destruction of mucosal barriers, epithelial remodeling, and impaired mucociliary clearance: possible pathogenic mechanisms of Pseudomonas aeruginosa and Staphylococcus aureus in chronic rhinosinusitis. Cell Commun Signal 21(1):306\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang PC, Wang CS, An ZY (2005) A murine model of ulcerative colitis: induced with sinusitis-derived superantigen and food allergen. BMC Gastroenterol 5:6\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePsaltis AJ, Mackenzie BW, Cope EK, Ramakrishnan VR (2022) Unraveling the role of the microbiome in chronic rhinosinusitis. J Allergy Clin Immunol 149(5):1513\u0026ndash;1521\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMichalik M, Podbielska-Kubera A, Basińska AM, Szewc M, Gałęcka M, Schwiertz A (2023) Alteration of indicator gut microbiota in patients with chronic sinusitis. Immun Inflamm Dis 11(9):e996\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDu B, Fu Y, Han Y, Sun Q, Xu J, Yang Y et al (2023) The lung-gut crosstalk in respiratory and inflammatory bowel disease. Front Cell Infect Microbiol 13:1218565\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":"chronic rhinosinusitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, Mendelian randomization","lastPublishedDoi":"10.21203/rs.3.rs-4447676/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4447676/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Prior studies have shown that chronic rhinosinusitis(CRS) was associated with inflammatory bowel disease(IBD) consisted of Crohn's disease (CD) and ulcerative colitis (UC). However, the causality needs to be further verified. We performed a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal effect between CRS and IBD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We obtained CRS database from the IEU Open GWAS project and IBD database from FinnGen. Inverse-variance weighted (IVW) method was used as the primary statistical method, while weighted median and MR-Egger methods were used to examine the robustness of our results. Furthermore, Cochran’s Q test, MR-Egger intercept, MR-PRESSO and leave-one-out methods were used to examine pleiotropy and heterogeneity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003eIVW method revealed that CRS was associated with an increased risk of UC(OR=3.44E+08, 95% CI=3.01-3.94+16, p=0.038). Reverse MR analysis revealed that IBD was associated with a decreased risk of CRS(OR=0.999, 95% CI=0.998-1.000, p=0.020).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Our findings revealed that CRS was associated with an increased risk of UC, while IBD was associated with a decreased risk of CRS and the effect is mild. We suggested that clinicians should pay attention to the intestinal symptoms in CRS patients and a timely screening colonoscopy to detect early lesions.\u003c/p\u003e","manuscriptTitle":"The causality between chronic rhinosinusitis and inflammatory bowel disease: a bi-directional two-sample Mendelian randomization analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-03 10:53:47","doi":"10.21203/rs.3.rs-4447676/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":"26cd7a2f-6e05-4a56-b8df-3fbd9d4e974d","owner":[],"postedDate":"June 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-24T11:02:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-03 10:53:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4447676","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4447676","identity":"rs-4447676","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}