Genetic association of allergic diseases, serum IgE levels and osteoarthritis: a Mendelian randomization study

Genetic association of allergic diseases, serum IgE levels and osteoarthritis: a Mendelian randomization study | 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 Article Genetic association of allergic diseases, serum IgE levels and osteoarthritis: a Mendelian randomization study Kai Zhang, Xianghua Xiong, Ning Wu, Hangyu Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4529182/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 Objective The question of whether there is a causal relationship between allergic diseases, immunoglobulin E levels, and osteoarthritis remains unclear. This study aimed to examine the bidirectional causal association between allergic diseases, serum IgE levels, and osteoarthritis using a Mendelian randomization study approach. Methods This study utilized publicly available pooled statistics from large genome-wide association studies to assess the causal associations between allergic diseases, serum IgE levels, and osteoarthritis. The analysis employed inverse variance weighting, MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses were also conducted using MR-Egger regression, Cochran's Q test, and MR-PRESSO test to ensure the reliability of the findings. Results The IVW results indicated that there was no significant causal relationship between allergic asthma and atopic dermatitis with KOA (OR = 1.02, 95% CI:0.96–1.09, P = 0.544; OR = 1.00, 95% CI:0.96–1.04, P = 0.933) and HOA (OR = 0.95, 95% CI:0.89–1.02, P = 0.127; OR = 1.00, 95% CI: 0.94–1.06, P = 0.992). Similarly, KOA and HOA did not have a causal effect on allergic asthma (OR = 1.07, 95% CI: 0.86–1.32, P = 0.553; OR = 1.04, 95% CI: 0.89–1.23, P = 0.610), atopic dermatitis (OR = 1.05, 95% CI: 0.83–1.31, P = 0.692; OR = 0.94, 95% CI: 0.83–1.05, P = 0.284), and serum IgE levels (OR 0.98, 95% CI: 0.74–1.31, P = 0.916; OR 1.15, 95% CI: 0.99–1.34, P = 0.071). However, there was a causal effect of serum IgE levels on KOA, as they were found to increase the incidence of KOA (OR = 1.05, 95% CI: 1.00-1.10, P < 0.05). On the other hand, serum IgE levels did not have a causal effect on HOA (OR = 1.01, 95% CI: 0.94–1.08, P = 0.799). Conclusions From a genetic perspective, a causal relationship between serum IgE levels and the risk of KOA was observed. However, there was no evidence of a bidirectional causality between atopic disease and OA. Furthermore, the use of MR methods did not support the existence of a causal effect of IgE levels on HOA or OA on IgE levels. Health sciences/Medical research Health sciences/Pathogenesis Health sciences/Rheumatology Health sciences/Risk factors allergic diseases serum IgE levels osteoarthritis Mendelian randomization Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Osteoarthritis (OA) is a multifaceted disease that affects various joint tissues, often coexisting with other chronic conditions. Allergic diseases, also known as atopic diseases, encompass immune-inflammatory responses triggered by allergens, such as atopy, asthma, and atopic dermatitis. Histamine and IgE are believed to have significant roles in the development of allergic diseases like asthma, atopic dermatitis, and allergic rhinitis ( 1 ). Research has shown the presence of histamine, histamine receptors, and histamine-producing enzymes in chondrocytes affected by osteoarthritis, suggesting a potential link between these components and the onset and progression of OA ( 2 , 3 ). Furthermore, studies using animal models have indicated that IgE may impact the progression of OA by activating mast cells and hastening cartilage damage ( 4 ). Recent retrospective cohort studies have also demonstrated an increased risk of OA in individuals with allergic asthma and atopic dermatitis ( 5 ). Despite these findings, the exact causal relationship between allergic diseases, serum IgE levels, and OA remains unclear. The current evidence is primarily based on observational studies, making it challenging to directly assess the potential for confounding bias and reverse causation in determining the causal link between allergic diseases, serum IgE levels, and OA. Mendelian randomization (MR) studies use genetic variants as instrumental variables to uncover causal relationships between risk factors and disease outcomes. By leveraging the random assignment of genetic variants at conception, MR analyses can minimize confounders and reverse causation, resulting in stronger causal inferences. Our study aims to investigate the genetic-level causal relationship between allergic diseases, serum IgE levels, and OA through MR methods. Methods Data Sources Summary statistics on allergic diseases, serum IgE levels, and osteoarthritis were extracted from large genome-wide association studies (GWAS). Allergic disease data, including allergic asthma and atopic dermatitis, were sourced from the FinnGen genome database. The dataset for allergic asthma consisted of 4,859 cases and 140,308 control samples, while atopic dermatitis had 7,024 cases and 198,740 control samples. Serum IgE level data were obtained from the INTERVAL study, which analyzed plasma proteins from 3,301 healthy blood donors in England. Osteoarthritis datasets for KOA and HOA were sourced from the IEU GWAS database, with KOA comprising 403,124 samples and 29,999,696 SNPs, and HOA including 393,873 samples and 29,771,219 SNPs. All data were from individuals of European ancestry. A summary of the information is provided in Table 1 . Ethical approval was not required for this study as it involved secondary analysis of publicly available data. Table 1 Genome-wide association analysis data information GWAS ID Exposure or outcome Sample size SNPs (n) Population ebi-a-GCST007090 Knee osteoarthritis 403,124 29,999,696 European ebi-a-GCST007091 Hip osteoarthritis 393,873 29,771,219 European finn-b-ALLERG_ASTHMA Allergic asthma 140,308 16,379,987 European finn-b-L12_ATOPIC Atopic dermatitis 205,764 16,380,443 European prot-a-1456 Immunoglobulin E levels 3,301 10,534,735 European Genetic tool variables We utilized single nucleotide polymorphisms (SNPs) that adhered to three stringent assumptions as instrumental variables (IVs). These assumptions stipulated that: 1) the IVs were strongly linked to the exposure group; 2) the IVs had no association with the outcome; and 3) the IVs were independent of any potential confounders (SNPs with confounding factors were identified and manually excluded using the Phenoscanner tool, with confounders defined as being related to obesity and smoking) (Annex 13). To identify additional instrumental variables, we applied a genome-wide significance threshold with a P-value range of P < 5E-08 to P < 5E-06, a linkage disequilibrium correlation coefficient threshold of r2 < 0.001, and a minimum distance of 10,000 bases between SNPs. Furthermore, we filtered out SNPs that exhibited weak correlation (F-statistic < 10) and had incompatible alleles. The F-value was computed as F = R2(N-2)/(1-R2), where R2 was calculated as R2 = 2×MAF×(1-MAF)×beta2, with N representing the sample size of the exposed group, beta denoting the allelic effect value, and MAF indicating the minor allele frequency of the SNPs. Mendelian randomization analysis In this study, four MR methods were utilized to investigate the causal relationship between allergic diseases, serum IgE levels, and OA (KOA and HOA): inverse variance weighting (IVW), MR-Egger's method, weighted median method, and weighted model. IVW was selected as the primary analytical method due to its robust statistical power and ability to provide more dependable causal estimates. Additionally, the MR-Egger method, weighted median method, and weighted model were employed as supplementary approaches to IVW, each based on distinct assumptions regarding horizontal pleiotropy. All analyses were conducted using the TwoSampleMR (version 0.5.7) package in R (version 4.3.1). Sensitivity analyses To ensure the robustness of our findings, we conducted sensitivity analyses using MR-Egger regression, Cochran's Q test, and MR-PRESSO test. MR-Egger regression was specifically used to test for directed pleiotropy, while Cochran's Q test was used to assess heterogeneity. The MR-PRESSO test was employed to identify and address the impact of outliers. In cases where horizontal pleiotropic outliers were detected, outlier IVs with p < 0.05 were removed, and MR analysis was repeated. A significance threshold of p 10) and met the criteria for genome-wide significance based on P-values, as well as passing the linkage disequilibrium test. Subsequently, SNPs with palindromic sequences and those associated with potential confounders (Annex 14 and Annex 15) were excluded. If the outlier test (MR-PRESSO) identified any outliers with a significance level of p<0.05, the corresponding SNPs were also eliminated. Finally, the remaining SNPs were used as instrumental variables for the MR analysis. Effect of allergic diseases on OA A total of 10 strongly associated SNPs were identified in the Mendelian randomization analysis of allergic asthma on knee osteoarthritis (KOA) and hand osteoarthritis (HOA) (Annex 1 and Annex 2). The IVW results indicated no causal association of allergic asthma with either KOA (OR=1.02, 95% CI: 0.96-1.09, P=0.544) or HOA (OR=0.95, 95% CI: 0.89-1.02, P=0.127)(Fig.2). Furthermore, the results from weighted median, weighted mode, and MR-Egger analyses were also non-significant (refer to Fig.3). The MR-Egger regression, Cochran's Q test, and MR-PRESSO test all supported robust findings (Table 2). In the Mendelian randomization analysis of atopic dermatitis on KOA and HOA, 15 and 13 strongly associated SNPs were identified, respectively (Annex 3 and Annex 4). The IVW results indicated that atopic dermatitis was not causally associated with either KOA (OR=1.00, 95% CI: 0.96-1.04, P=0.933) or HOA (OR=1.00, 95% CI: 0.94-1.06, P=0.992)(Fig.2). Consistent results were obtained from weighted median, weighted mode, and MR-Egger analyses (refer to Fig.3). Sensitivity analysis of atopic dermatitis to HOA revealed heterogeneity based on Cochran's Q test (P<0.05). Further MR-PRESSO test analysis identified two significant outliers ( rs5792371 , rs61839660 ), which upon removal, eliminated the heterogeneity. No horizontal pleiotropy was detected in the MR-Egger regression. Conversely, no heterogeneity or horizontal pleiotropy was observed in the sensitivity analysis of atopic dermatitis to KOA using Cochran's Q test, MR-Egger regression, and MR-PRESSO test (Table 2). Effect of IgE levels on OA In the Mendelian randomization analysis of serum IgE levels on KOA, 11 independent SNPs strongly associated with serum IgE levels were selected as instrumental variables. The F-statistics of these IVs were all greater than 10 (Annex 5). The results from the IVW method indicated that serum IgE levels causally influenced KOA, with an increase in serum IgE levels associated with a higher incidence of KOA (OR=1.05, 95% CI: 1.00-1.10, P<0.05)(Fig.2). However, the results from MR-Egger regression, weighted median, and weighted model did not show significance (refer to Fig.3). Sensitivity analysis, including Cochran's Q test (Q=29.683, P=0.002) revealing heterogeneity, led to the identification of outliers ( rs9277562 ) using the MR-PRESSO test, which were subsequently excluded. After re-running Cochran's Q test, no heterogeneity was observed (Q=8.796, P=0.552). Furthermore, MR-Egger regression indicated no evidence of pleiotropy (Table 2). In the Mendelian randomization analysis of serum IgE levels on HOA, a total of 12 strongly associated SNPs were identified (Annex 6). The results of IVW indicated that serum IgE levels did not show a causal association with HOA (OR=1.01, 95% CI: 0.94-1.08, P=0.799)(Fig.2). Additionally, the results from MR-Egger regression, weighted median, and weighted model did not reach statistical significance (Fig.3). The p-values from Cochran's Q test and MR-Egger regression were 0.186 and 0.696, respectively, suggesting no significant heterogeneity or horizontal pleiotropy (Table 2). Effect of OA on allergic diseases A total of 16 significant and independently associated strong SNPs were identified in an inverse Mendelian randomization analysis of KOA in relation to allergic asthma and atopic dermatitis(Annex 7 and Annex 8). The IVW analysis results indicated that there was no statistically significant association between KOA and either allergic asthma (OR=1.07, 95% CI: 0.86-1.32, P=0.553) or atopic dermatitis (OR=1.05, 95% CI: 0.83-1.31, P=0.692)(Fig.1). This lack of correlation was further supported by the results of MR-Egger regression, weighted median, and weighted models, as depicted in Fig.2 and Fig.4A,B. When examining the relationship between KOA and atopic dermatitis in a sensitivity analysis, heterogeneity was detected through Cochran's Q test (Q=26.139, P=0.037), but no significant outliers (P 0.05 for both tests), as shown in Table 2. In the reverse Mendelian randomization analyses of HOA on allergic asthma and atopic dermatitis, 17 and 16 independent SNPs strongly associated with allergic asthma and atopic dermatitis, respectively, were used as instrumental variables (Annex 10 and Annex 11). The inverse variance-weighted method results indicated that there was no causal association between HOA exposure and either allergic asthma (OR=1.04, 95% CI: 0.89-1.23, P=0.610) or atopic dermatitis (OR=0.94, 95% CI: 0.83-1.05, P=0.284) (refer to Fig. 2 and Fig. 4D,E). Additionally, the Cochran's Q test results revealed heterogeneity in the association between HOA exposure and atopic dermatitis (Q=28.856, P=0.043). After removing two outliers (rs12040949, rs10896015), the test for heterogeneity was repeated, and the results indicated that the heterogeneity disappeared (P=0.459). Moreover, the MR-Egger intercept analysis results suggested the absence of horizontal pleiotropy (P>0.05) (Table 2). Effect of OA on IgE levels Seventeen SNPs strongly associated with KOA and HOA were identified in the inverse Mendelian randomization analysis on IgE levels (Annex 9 and Annex 12). Our findings indicate no causal effect of KOA and HOA on serum IgE levels, with P-values of 0.916 (OR 0.98, 95%CI: 0.74-1.31) and 0.071 (OR 1.15, 95%CI: 0.99-1.34) respectively, as derived from the IVW method(Fig.1). Results from the weighted median, weighted model, and MR-Egger analyses were consistent with those of IVW (refer to Fig.2 and Fig.4C,F). Sensitivity analysis, including Cochran's Q test, MR-PRESSO test, and MR-Egger intercept analysis, did not reveal evidence of heterogeneity or horizontal pleiotropy (all p-values greater than 0.05) (Table 2). Tab.2 Sensitivity analysis of Mendelian randomization results Exposure Outcome MR-Egger Test Cochrane Q Test (IVW) MR-PRESSO Global Test Intercept SE P-value Q Q_df P-value Adjusted P-value* RSSobs P-value Knee osteoarthritis Allergic asthma -0.043 0.026 0.118 13.802 14 0.465 NA 18.662 0.356 Atopic dermatitis -0.040 0.029 0.176 26.139 15 0.037 NA 43.175 0.024 Immunoglobulin E 0.026 0.045 0.568 23.899 16 0.092 NA 27.207 0.088 Hip osteoarthritis Allergic asthma 0.005 0.026 0.863 24.042 15 0.064 NA 27.189 0.095 Atopic dermatitis 0.003 0.019 0.866 14.891 15 0.043 0.459 17.998 0.408 Immunoglobulin E 0.007 0.025 0.781 14.253 16 0.580 NA 15.951 0.596 Allergic asthma Knee osteoarthritis 0.055 0.030 0.110 8.624 8 0.375 NA 15.054 0.221 Hip osteoarthritis -0.001 0.037 0.972 3.195 8 0.922 NA 3.915 0.962 Atopic dermatitis Knee osteoarthritis 0.003 0.007 0.669 18.312 14 0.193 NA 20.840 0.212 Hip osteoarthritis -0.000 0.011 0.975 18.454 12 0.001 0.103 21.224 0.125 Immunoglobulin E Knee osteoarthritis 0.010 0.010 0.360 8.796 10 0.002 0.552 10.980 0.547 Hip osteoarthritis 0.006 0.015 0.696 14.916 11 0.186 NA 17.370 0.205 *Cochrane Q Test-related p-values after removal of anomalous outliers. NA, Not applicable. Discussion Recent MR studies have explored the causal relationship between atopic diseases and OA. One study identified a genetic correlation between asthma and OA, but lacked some instrumental variables and used partially overlapping samples, potentially impacting result reliability ( 6 ). Another study found no causal effect of allergic asthma on OA ( 7 ). However, this study only analyzed the unidirectional relationship between allergic asthma and total OA, leaving the bidirectional causality with other atopic diseases and IgE levels unclear. Further research is needed to comprehensively assess these bidirectional relationships, as previous studies have shown significant correlations between atopic dermatitis and OA prevalence, high IgE levels and KOA, and increased risk of allergic asthma comorbidities in OA patients ( 8 – 10 ). Our findings on allergic diseases and OA differ from most previous studies. A recent large-sample retrospective study adjusted for factors like age, sex, race, and follow-up duration through propensity score matching and concluded that allergic asthma and atopic dermatitis may increase OA risk ( 11 ). However, this study did not consider all potential confounders. In contrast, our Mendelian randomization approach uses genetic factors as exposure, providing a more stable estimate of the association between anaphylaxis and OA. Our results suggest a positive causal link between IgE levels and KOA, consistent with prior studies, but not with HOA. This implies differing immunopathogenesis between hand and knee OA ( 9 , 12 ). The impact of OA on IgE levels remains unclear, with no current reports supporting a bidirectional causal relationship. Further research is necessary to explore this correlation. The current understanding of the relationship between serum IgE levels and OA remains largely theoretical. Recent research suggests that mast cells may contribute to the development of OA through various signaling pathways ( 13 ). Another study indicates that IgE may play a role in the pathogenesis of OA by triggering the release of inflammatory mediators from activated mast cells, potentially influencing the progression of OA ( 4 ). Furthermore, preliminary studies on anti-IgE therapy have shown some efficacy in patients with KOA ( 12 ). These findings indicate a potential link between serum IgE levels and the risk of KOA, particularly at the mechanistic and genetic levels, offering a new avenue for future research and treatment of OA. Several limitations exist in this study. Firstly, the findings are limited to individuals of European descent and may not be generalizable to other ethnic groups. Secondly, we utilized more lenient P-value thresholds (P < 5E-06 and P < 5E-07) as instrumental variables in certain exposure groups, potentially increasing the risk of false-positive outcomes. Thirdly, the small sample size of IgE levels in our research may have constrained our ability to thoroughly examine the association with OA. Lastly, despite efforts to minimize heterogeneity by excluding outliers, some studies still exhibited mild heterogeneity that could have influenced the results. Conclusion The study found a causal relationship between serum IgE levels and the risk of KOA from a genetic standpoint. However, there was no evidence of a bidirectional causal relationship between allergic diseases and OA. Additionally, the causal effect of serum IgE levels on HOA and OA on serum IgE levels was not confirmed through Mendelian randomization methods. These findings offer valuable insights for the management and treatment of these conditions. Declarations Author Contribution Kai Zhang and Xianghua Xiong are mainly responsible for writing the article, We thank Prof. Hangyu Li for his review of this study and suggestions for revisions. Acknowledgements The authors want to acknowledge all the participants and investigators of the GWASs involved in the present study for generously sharing the data. Data Availability The data supporting the results of this study can be obtained from https://gwas.mrcieu.ac.uk and https://www.finngen.fi/en. The availability of this data is not restricted. References LK K. Osteoarthritis and comorbidity: Time for action. Osteoarthr Cartilage. (2023) 31: 423–4. doi: 10.1016/j.joca.2023.01.007 MH S, R V, T J, V V, SR D, PA W, et al. The role of allergen-specific IgE, IgG and IgA in allergic disease. Allergy. (2021) 76: 3627–41. doi: 10.1111/all.14908 LC T, DE W. Histamine, histamine receptors (H1 and H2), and histidine decarboxylase expression by chondrocytes of osteoarthritic cartilage: An immunohistochemical study. Rheumatol Int. (2005) 26: 173–8. doi: 10.1007/s00296-005-0622-x Q W, CM L, H R, LL R, MM T, HH W, et al. IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis. Elife. (2019) 8. doi: 10.7554/eLife.39905 MC B, K S, R L, D L, von Kaeppler EP, A B, et al. Increased risk of osteoarthritis in patients with atopic disease. Ann Rheum Dis. (2023) 82: 866–72. doi: 10.1136/ard-2022-223640 MC B, WH R, Q O. Genetic association between atopic disease and osteoarthritis. Osteoarthr Cartilage. (2024) 32: 220–5. doi: 10.1016/j.joca.2023.11.003 DA L, RM H, JA S, N T, G DS. Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat Med. (2008) 27: 1133–63. doi: 10.1002/sim.3034 J Y, Y Z, X Z, G C, D W, K D, et al. Increased risk of rheumatoid arthritis in patients with asthma: A genetic association study using Two-Sample mendelian randomization analysis. Arthrit Care Res. (2023). doi: 10.1002/acr.25193 J L, A M, A T, JJ W. Association between atopic dermatitis and osteoarthritis among US adults in the 1999–2006 NHANES. Journal of the European Academy of Dermatology and Venereology: JEADV. (2021) 35: e375-7. doi: 10.1111/jdv.17147 S P, NK C. Association between serum immunoglobulin E levels and knee osteoarthritis in Korean adults. Osteoarthr Cartilage. (2020) 28: 462–7. doi: 10.1016/j.joca.2020.02.830 S S, C C, C M, CF K, A S, SMA B, et al. Temporal relationship between osteoarthritis and comorbidities: A combined case control and cohort study in the UK primary care setting. Rheumatology (Oxford, England). (2021) 60: 4327–39. doi: 10.1093/rheumatology/keab067 A A, L F, C B, L A, A G. The effect of anti-IgE therapy in knee osteoarthritis: A pilot observational study. J Biol Reg Homeos Ag. (2017) 31: 1–5. A L, T M, K H, A M, A C. The multifaceted role of mast cells in joint inflammation and arthritis. Osteoarthr Cartilage. (2023) 31: 567–75. doi: 10.1016/j.joca.2023.01.005 Additional Declarations No competing interests reported. Supplementary Files 68.doc 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-4529182","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":318390059,"identity":"a4c7dd12-7f03-43fa-94d2-46a2e1bd81b3","order_by":0,"name":"Kai Zhang","email":"","orcid":"","institution":"Xianyang Hospital, Yan'an University","correspondingAuthor":false,"prefix":"","firstName":"Kai","middleName":"","lastName":"Zhang","suffix":""},{"id":318390061,"identity":"06dab7f6-6556-44b0-9703-69d6d59fb5a7","order_by":1,"name":"Xianghua Xiong","email":"","orcid":"","institution":"The People's Hospital of Chongqing Liangping District","correspondingAuthor":false,"prefix":"","firstName":"Xianghua","middleName":"","lastName":"Xiong","suffix":""},{"id":318390063,"identity":"60bcd3e9-b380-4448-92c7-0f20f48e51bc","order_by":2,"name":"Ning Wu","email":"","orcid":"","institution":"People's Hospital of Ningxia Hui Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Ning","middleName":"","lastName":"Wu","suffix":""},{"id":318390064,"identity":"b5dee2b5-b9bb-4616-a6ab-d952229e70a7","order_by":3,"name":"Hangyu Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYBACPmYeCMP+/vvvv/9USMjxE9LCBtPCcCDBQILnjIWxZAMhLQzIWnjbKhI3ENTCznvwc8Gvw4mNDUA9kvMkGDcwMD98dAOvw/iSpWf2HU5sZgTqMdwmwWzOwGZsnIPfLwbSvD2HE9uYgXoSt0mwWTbwsEkT0GL8G6Slhw2o5+AcCR6DA4S1mEnz/DicOIMHqKexQUKCKC3WvA3pxhskgHoYjkkYSDYT8As//xnj2zx/rGUhWmrq6vvZmx8+xqcFDBjbmpF4zISUg8GfOqKUjYJRMApGwQgFAK89QzMSzEgCAAAAAElFTkSuQmCC","orcid":"","institution":"People's Hospital of Ningxia Hui Autonomous Region","correspondingAuthor":true,"prefix":"","firstName":"Hangyu","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-06-04 15:31:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4529182/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4529182/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59069373,"identity":"ec87767f-147e-4cd9-905e-a5db700809e3","added_by":"auto","created_at":"2024-06-26 04:11:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":303995,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of dominance ratios between osteoarthritis and allergic diseases and serum IgE levels; OR is the dominance ratio and CI is the confidence interval.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4529182/v1/23884fafea940ea13b952182.png"},{"id":59070397,"identity":"58aae032-236a-4373-a364-400232750314","added_by":"auto","created_at":"2024-06-26 04:27:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":308567,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of dominance ratios between allergic diseases, serum IgE levels and osteoarthritis; OR is the dominance ratio and CI is the confidence interval.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4529182/v1/d786a4c791978849c93e2607.png"},{"id":59069374,"identity":"89965d92-51e7-407a-a6ff-7bc2ee017100","added_by":"auto","created_at":"2024-06-26 04:11:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":318260,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of genetic associations between osteoarthritis and allergic diseases, serum IgE levels; A. KOA on allergic asthma, B. KOA on atopic dermatitis, C. KOA on serum IgE levels, D. HOA on allergic asthma, E. HOA on atopic dermatitis, F. HOA on serum IgE levels.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4529182/v1/c3454a35a91758cc16b1e01e.png"},{"id":59069821,"identity":"768c44a4-9232-4637-8d29-7dbbd22f5a19","added_by":"auto","created_at":"2024-06-26 04:19:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":266999,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of genetic associations between allergic diseases, serum IgE levels, and osteoarthritis; A. Allergic asthma on KOA, B. Allergic asthma on HOA, C. Atopic dermatitis on KOA, D. Atopic dermatitis on HOA, E. Serum IgE levels on KOA, F. Serum IgE levels on HOA.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4529182/v1/b71c029b3e9ca7972967ea8b.png"},{"id":80191237,"identity":"a858e4ee-c418-4bad-b3ed-d4d8c13b4181","added_by":"auto","created_at":"2025-04-09 04:16:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1635668,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4529182/v1/f4e6a4d2-c5e8-4273-b895-e8b917c2eabf.pdf"},{"id":59069376,"identity":"e1fae130-50d5-4c82-860f-4de4314b9a70","added_by":"auto","created_at":"2024-06-26 04:11:40","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":564210,"visible":true,"origin":"","legend":"","description":"","filename":"68.doc","url":"https://assets-eu.researchsquare.com/files/rs-4529182/v1/f2a50e1199158c0fcc1acc24.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Genetic association of allergic diseases, serum IgE levels and osteoarthritis: a Mendelian randomization study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOsteoarthritis (OA) is a multifaceted disease that affects various joint tissues, often coexisting with other chronic conditions. Allergic diseases, also known as atopic diseases, encompass immune-inflammatory responses triggered by allergens, such as atopy, asthma, and atopic dermatitis. Histamine and IgE are believed to have significant roles in the development of allergic diseases like asthma, atopic dermatitis, and allergic rhinitis (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Research has shown the presence of histamine, histamine receptors, and histamine-producing enzymes in chondrocytes affected by osteoarthritis, suggesting a potential link between these components and the onset and progression of OA (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Furthermore, studies using animal models have indicated that IgE may impact the progression of OA by activating mast cells and hastening cartilage damage (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Recent retrospective cohort studies have also demonstrated an increased risk of OA in individuals with allergic asthma and atopic dermatitis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Despite these findings, the exact causal relationship between allergic diseases, serum IgE levels, and OA remains unclear. The current evidence is primarily based on observational studies, making it challenging to directly assess the potential for confounding bias and reverse causation in determining the causal link between allergic diseases, serum IgE levels, and OA.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) studies use genetic variants as instrumental variables to uncover causal relationships between risk factors and disease outcomes. By leveraging the random assignment of genetic variants at conception, MR analyses can minimize confounders and reverse causation, resulting in stronger causal inferences. Our study aims to investigate the genetic-level causal relationship between allergic diseases, serum IgE levels, and OA through MR methods.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Sources\u003c/h2\u003e \u003cp\u003eSummary statistics on allergic diseases, serum IgE levels, and osteoarthritis were extracted from large genome-wide association studies (GWAS). Allergic disease data, including allergic asthma and atopic dermatitis, were sourced from the FinnGen genome database. The dataset for allergic asthma consisted of 4,859 cases and 140,308 control samples, while atopic dermatitis had 7,024 cases and 198,740 control samples. Serum IgE level data were obtained from the INTERVAL study, which analyzed plasma proteins from 3,301 healthy blood donors in England. Osteoarthritis datasets for KOA and HOA were sourced from the IEU GWAS database, with KOA comprising 403,124 samples and 29,999,696 SNPs, and HOA including 393,873 samples and 29,771,219 SNPs. All data were from individuals of European ancestry. A summary of the information is provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Ethical approval was not required for this study as it involved secondary analysis of publicly available data.\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\u003eGenome-wide association analysis data information\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGWAS ID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExposure or outcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSNPs (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eebi-a-GCST007090\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKnee osteoarthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e403,124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29,999,696\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eebi-a-GCST007091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHip osteoarthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e393,873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29,771,219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efinn-b-ALLERG_ASTHMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAllergic asthma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e140,308\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16,379,987\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efinn-b-L12_ATOPIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAtopic dermatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e205,764\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16,380,443\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eprot-a-1456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImmunoglobulin E levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3,301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10,534,735\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eGenetic tool variables\u003c/h2\u003e \u003cp\u003eWe utilized single nucleotide polymorphisms (SNPs) that adhered to three stringent assumptions as instrumental variables (IVs). These assumptions stipulated that: 1) the IVs were strongly linked to the exposure group; 2) the IVs had no association with the outcome; and 3) the IVs were independent of any potential confounders (SNPs with confounding factors were identified and manually excluded using the Phenoscanner tool, with confounders defined as being related to obesity and smoking) (Annex 13). To identify additional instrumental variables, we applied a genome-wide significance threshold with a P-value range of P\u0026thinsp;\u0026lt;\u0026thinsp;5E-08 to P\u0026thinsp;\u0026lt;\u0026thinsp;5E-06, a linkage disequilibrium correlation coefficient threshold of r2\u0026thinsp;\u0026lt;\u0026thinsp;0.001, and a minimum distance of 10,000 bases between SNPs. Furthermore, we filtered out SNPs that exhibited weak correlation (F-statistic\u0026thinsp;\u0026lt;\u0026thinsp;10) and had incompatible alleles. The F-value was computed as F\u0026thinsp;=\u0026thinsp;R2(N-2)/(1-R2), where R2 was calculated as R2\u0026thinsp;=\u0026thinsp;2\u0026times;MAF\u0026times;(1-MAF)\u0026times;beta2, with N representing the sample size of the exposed group, beta denoting the allelic effect value, and MAF indicating the minor allele frequency of the SNPs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMendelian randomization analysis\u003c/h2\u003e \u003cp\u003eIn this study, four MR methods were utilized to investigate the causal relationship between allergic diseases, serum IgE levels, and OA (KOA and HOA): inverse variance weighting (IVW), MR-Egger's method, weighted median method, and weighted model. IVW was selected as the primary analytical method due to its robust statistical power and ability to provide more dependable causal estimates. Additionally, the MR-Egger method, weighted median method, and weighted model were employed as supplementary approaches to IVW, each based on distinct assumptions regarding horizontal pleiotropy. All analyses were conducted using the TwoSampleMR (version 0.5.7) package in R (version 4.3.1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analyses\u003c/h2\u003e \u003cp\u003eTo ensure the robustness of our findings, we conducted sensitivity analyses using MR-Egger regression, Cochran's Q test, and MR-PRESSO test. MR-Egger regression was specifically used to test for directed pleiotropy, while Cochran's Q test was used to assess heterogeneity. The MR-PRESSO test was employed to identify and address the impact of outliers. In cases where horizontal pleiotropic outliers were detected, outlier IVs with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were removed, and MR analysis was repeated. A significance threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was applied to all sensitivity analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eInitially, we selected SNPs that were strongly associated (F-statistic \u0026gt; 10) and met the criteria for genome-wide significance based on P-values, as well as passing the linkage disequilibrium test. Subsequently, SNPs with palindromic sequences and those associated with potential confounders (Annex 14 and Annex 15) were excluded. If the outlier test (MR-PRESSO) identified any outliers with a significance level of p\u0026lt;0.05, the corresponding SNPs were also eliminated. Finally, the remaining SNPs were used as instrumental variables for the MR analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffect of allergic diseases on OA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 10 strongly associated SNPs were identified in the Mendelian randomization analysis of allergic asthma on knee osteoarthritis (KOA) and hand osteoarthritis (HOA) (Annex 1 and Annex 2). The IVW results indicated no causal association of allergic asthma with either KOA (OR=1.02, 95% CI: 0.96-1.09, P=0.544) or HOA (OR=0.95, 95% CI: 0.89-1.02, P=0.127)(Fig.2). Furthermore, the results from weighted median, weighted mode, and MR-Egger analyses were also non-significant (refer to Fig.3). The MR-Egger regression, Cochran\u0026apos;s Q test, and MR-PRESSO test all supported robust findings (Table 2).\u003c/p\u003e\n\u003cp\u003eIn the Mendelian randomization analysis of atopic dermatitis on KOA and HOA, 15 and 13 strongly associated SNPs were identified, respectively (Annex 3 and Annex 4). The IVW results indicated that atopic dermatitis was not causally associated with either KOA (OR=1.00, 95% CI: 0.96-1.04, P=0.933) or HOA (OR=1.00, 95% CI: 0.94-1.06, P=0.992)(Fig.2). Consistent results were obtained from weighted median, weighted mode, and MR-Egger analyses (refer to Fig.3). Sensitivity analysis of atopic dermatitis to HOA revealed heterogeneity based on Cochran\u0026apos;s Q test (P\u0026lt;0.05). Further MR-PRESSO test analysis identified two significant outliers (\u003cem\u003ers5792371\u003c/em\u003e, \u003cem\u003ers61839660\u003c/em\u003e), which upon removal, eliminated the heterogeneity. No horizontal pleiotropy was detected in the MR-Egger regression. Conversely, no heterogeneity or horizontal pleiotropy was observed in the sensitivity analysis of atopic dermatitis to KOA using Cochran\u0026apos;s Q test, MR-Egger regression, and MR-PRESSO test (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffect of IgE levels on OA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the Mendelian randomization analysis of serum IgE levels on KOA, 11 independent SNPs strongly associated with serum IgE levels were selected as instrumental variables. The F-statistics of these IVs were all greater than 10 (Annex 5). The results from the IVW method indicated that serum IgE levels causally influenced KOA, with an increase in serum IgE levels associated with a higher incidence of KOA (OR=1.05, 95% CI: 1.00-1.10, P\u0026lt;0.05)(Fig.2). However, the results from MR-Egger regression, weighted median, and weighted model did not show significance (refer to Fig.3). Sensitivity analysis, including Cochran\u0026apos;s Q test (Q=29.683, P=0.002) revealing heterogeneity, led to the identification of outliers (\u003cem\u003ers9277562\u003c/em\u003e) using the MR-PRESSO test, which were subsequently excluded. After re-running Cochran\u0026apos;s Q test, no heterogeneity was observed (Q=8.796, P=0.552). Furthermore, MR-Egger regression indicated no evidence of pleiotropy (Table 2).\u003c/p\u003e\n\u003cp\u003eIn the Mendelian randomization analysis of serum IgE levels on HOA, a total of 12 strongly associated SNPs were identified (Annex 6). The results of IVW indicated that serum IgE levels did not show a causal association with HOA (OR=1.01, 95% CI: 0.94-1.08, P=0.799)(Fig.2). Additionally, the results from MR-Egger regression, weighted median, and weighted model did not reach statistical significance (Fig.3). The p-values from Cochran\u0026apos;s Q test and MR-Egger regression were 0.186 and 0.696, respectively, suggesting no significant heterogeneity or horizontal pleiotropy (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffect of OA on allergic diseases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 16 significant and independently associated strong SNPs were identified in an inverse Mendelian randomization analysis of KOA in relation to allergic asthma and atopic dermatitis(Annex 7 and Annex 8). The IVW analysis results indicated that there was no statistically significant association between KOA and either allergic asthma (OR=1.07, 95% CI: 0.86-1.32, P=0.553) or atopic dermatitis (OR=1.05, 95% CI: 0.83-1.31, P=0.692)(Fig.1). This lack of correlation was further supported by the results of MR-Egger regression, weighted median, and weighted models, as depicted in Fig.2 and Fig.4A,B. When examining the relationship between KOA and atopic dermatitis in a sensitivity analysis, heterogeneity was detected through Cochran\u0026apos;s Q test (Q=26.139, P=0.037), but no significant outliers (P\u0026lt;0.05) were identified in the MR-PRESSO test analysis. Furthermore, the MR-Egger intercept analysis revealed no evidence of polytropy (p-value \u0026gt; 0.05 for both tests), as shown in Table 2.\u003c/p\u003e\n\u003cp\u003eIn the reverse Mendelian randomization analyses of HOA on allergic asthma and atopic dermatitis, 17 and 16 independent SNPs strongly associated with allergic asthma and atopic dermatitis, respectively, were used as instrumental variables (Annex 10 and Annex 11). The inverse variance-weighted method results indicated that there was no causal association between HOA exposure and either allergic asthma (OR=1.04, 95% CI: 0.89-1.23, P=0.610) or atopic dermatitis (OR=0.94, 95% CI: 0.83-1.05, P=0.284) (refer to Fig. 2 and Fig. 4D,E). Additionally, the Cochran\u0026apos;s Q test results revealed heterogeneity in the association between HOA exposure and atopic dermatitis (Q=28.856, P=0.043). After removing two outliers (rs12040949, rs10896015), the test for heterogeneity was repeated, and the results indicated that the heterogeneity disappeared (P=0.459). Moreover, the MR-Egger intercept analysis results suggested the absence of horizontal pleiotropy (P\u0026gt;0.05) (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffect of OA on IgE levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeventeen SNPs strongly associated with KOA and HOA were identified in the inverse Mendelian randomization analysis on IgE levels (Annex 9 and Annex 12). Our findings indicate no causal effect of KOA and HOA on serum IgE levels, with P-values of 0.916 (OR 0.98, 95%CI: 0.74-1.31) and 0.071 (OR 1.15, 95%CI: 0.99-1.34) respectively, as derived from the IVW method(Fig.1). Results from the weighted median, weighted model, and MR-Egger analyses were consistent with those of IVW (refer to Fig.2 and Fig.4C,F). Sensitivity analysis, including Cochran\u0026apos;s Q test, MR-PRESSO test, and MR-Egger intercept analysis, did not reveal evidence of heterogeneity or horizontal pleiotropy (all p-values greater than 0.05) (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTab.2\u0026nbsp;\u003c/strong\u003eSensitivity analysis of Mendelian randomization results\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"110%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.402061855670103%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eExposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eMR-Egger Test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.02061855670103%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eCochrane Q Test (IVW)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" colspan=\"2\"\u003e\n \u003cp\u003eMR-PRESSO Global Test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003eIntercept\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.462686567164179%\" valign=\"top\"\u003e\n \u003cp\u003eSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.955223880597014%\" valign=\"top\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003eQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.462686567164179%\" valign=\"top\"\u003e\n \u003cp\u003eQ_df\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.402985074626866%\" valign=\"top\"\u003e\n \u003cp\u003eAdjusted P-value*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.940298507462687%\" valign=\"top\"\u003e\n \u003cp\u003eRSSobs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.432835820895523%\" valign=\"top\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.978494623655914%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eKnee osteoarthritis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eAllergic asthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e-0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" valign=\"top\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e13.802\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.465\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\" valign=\"top\"\u003e\n \u003cp\u003e18.662\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.67741935483871%\" valign=\"top\"\u003e\n \u003cp\u003e0.356\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.25%\" valign=\"top\"\u003e\n \u003cp\u003eAtopic dermatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e-0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.5%\" valign=\"top\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e26.139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e43.175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eImmunoglobulin E\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" valign=\"top\"\u003e\n \u003cp\u003e0.568\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e23.899\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\" valign=\"top\"\u003e\n \u003cp\u003e27.207\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.67741935483871%\" valign=\"top\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.978494623655914%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eHip osteoarthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eAllergic asthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" valign=\"top\"\u003e\n \u003cp\u003e0.863\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e24.042\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\" valign=\"top\"\u003e\n \u003cp\u003e27.189\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.67741935483871%\" valign=\"top\"\u003e\n \u003cp\u003e0.095\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.25%\" valign=\"top\"\u003e\n \u003cp\u003eAtopic dermatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.5%\" valign=\"top\"\u003e\n \u003cp\u003e0.866\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e14.891\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.459\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e17.998\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.408\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eImmunoglobulin E\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" valign=\"top\"\u003e\n \u003cp\u003e0.781\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e14.253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.580\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\" valign=\"top\"\u003e\n \u003cp\u003e15.951\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.67741935483871%\" valign=\"top\"\u003e\n \u003cp\u003e0.596\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.978494623655914%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAllergic asthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eKnee osteoarthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e0.030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" valign=\"top\"\u003e\n \u003cp\u003e0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e8.624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.375\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\" valign=\"top\"\u003e\n \u003cp\u003e15.054\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.67741935483871%\" valign=\"top\"\u003e\n \u003cp\u003e0.221\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.25%\" valign=\"top\"\u003e\n \u003cp\u003eHip osteoarthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e-0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.5%\" valign=\"top\"\u003e\n \u003cp\u003e0.972\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e3.195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e0.922\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e3.915\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.962\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.978494623655914%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAtopic dermatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eKnee osteoarthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" valign=\"top\"\u003e\n \u003cp\u003e0.669\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e18.312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\" valign=\"top\"\u003e\n \u003cp\u003e20.840\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.67741935483871%\" valign=\"top\"\u003e\n \u003cp\u003e0.212\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.25%\" valign=\"top\"\u003e\n \u003cp\u003eHip osteoarthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e-0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.5%\" valign=\"top\"\u003e\n \u003cp\u003e0.975\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e18.454\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.75%\" valign=\"top\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10%\" valign=\"top\"\u003e\n \u003cp\u003e21.224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.25%\" valign=\"top\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eImmunoglobulin E\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eKnee osteoarthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" valign=\"top\"\u003e\n \u003cp\u003e0.360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e8.796\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003e0.552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\" valign=\"top\"\u003e\n \u003cp\u003e10.980\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.67741935483871%\" valign=\"top\"\u003e\n \u003cp\u003e0.547\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eHip osteoarthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" valign=\"top\"\u003e\n \u003cp\u003e0.696\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e14.916\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.526881720430108%\" valign=\"top\"\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.978494623655914%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\" valign=\"top\"\u003e\n \u003cp\u003e17.370\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.67741935483871%\" valign=\"top\"\u003e\n \u003cp\u003e0.205\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Cochrane Q Test-related p-values after removal of anomalous outliers. NA, Not applicable.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRecent MR studies have explored the causal relationship between atopic diseases and OA. One study identified a genetic correlation between asthma and OA, but lacked some instrumental variables and used partially overlapping samples, potentially impacting result reliability (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Another study found no causal effect of allergic asthma on OA (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). However, this study only analyzed the unidirectional relationship between allergic asthma and total OA, leaving the bidirectional causality with other atopic diseases and IgE levels unclear. Further research is needed to comprehensively assess these bidirectional relationships, as previous studies have shown significant correlations between atopic dermatitis and OA prevalence, high IgE levels and KOA, and increased risk of allergic asthma comorbidities in OA patients (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur findings on allergic diseases and OA differ from most previous studies. A recent large-sample retrospective study adjusted for factors like age, sex, race, and follow-up duration through propensity score matching and concluded that allergic asthma and atopic dermatitis may increase OA risk (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, this study did not consider all potential confounders. In contrast, our Mendelian randomization approach uses genetic factors as exposure, providing a more stable estimate of the association between anaphylaxis and OA. Our results suggest a positive causal link between IgE levels and KOA, consistent with prior studies, but not with HOA. This implies differing immunopathogenesis between hand and knee OA (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The impact of OA on IgE levels remains unclear, with no current reports supporting a bidirectional causal relationship. Further research is necessary to explore this correlation.\u003c/p\u003e \u003cp\u003eThe current understanding of the relationship between serum IgE levels and OA remains largely theoretical. Recent research suggests that mast cells may contribute to the development of OA through various signaling pathways (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Another study indicates that IgE may play a role in the pathogenesis of OA by triggering the release of inflammatory mediators from activated mast cells, potentially influencing the progression of OA (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Furthermore, preliminary studies on anti-IgE therapy have shown some efficacy in patients with KOA (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). These findings indicate a potential link between serum IgE levels and the risk of KOA, particularly at the mechanistic and genetic levels, offering a new avenue for future research and treatment of OA.\u003c/p\u003e \u003cp\u003eSeveral limitations exist in this study. Firstly, the findings are limited to individuals of European descent and may not be generalizable to other ethnic groups. Secondly, we utilized more lenient P-value thresholds (P\u0026thinsp;\u0026lt;\u0026thinsp;5E-06 and P\u0026thinsp;\u0026lt;\u0026thinsp;5E-07) as instrumental variables in certain exposure groups, potentially increasing the risk of false-positive outcomes. Thirdly, the small sample size of IgE levels in our research may have constrained our ability to thoroughly examine the association with OA. Lastly, despite efforts to minimize heterogeneity by excluding outliers, some studies still exhibited mild heterogeneity that could have influenced the results.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe study found a causal relationship between serum IgE levels and the risk of KOA from a genetic standpoint. However, there was no evidence of a bidirectional causal relationship between allergic diseases and OA. Additionally, the causal effect of serum IgE levels on HOA and OA on serum IgE levels was not confirmed through Mendelian randomization methods. These findings offer valuable insights for the management and treatment of these conditions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eKai Zhang and Xianghua Xiong are mainly responsible for writing the article, We thank Prof. Hangyu Li for his review of this study and suggestions for revisions.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors want to acknowledge all the participants and investigators of the GWASs involved in the present study for generously sharing the data.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting the results of this study can be obtained from https://gwas.mrcieu.ac.uk and https://www.finngen.fi/en. The availability of this data is not restricted.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLK K. Osteoarthritis and comorbidity: Time for action. Osteoarthr Cartilage. (2023) 31: 423\u0026ndash;4. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.joca.2023.01.007\u003c/span\u003e\u003cspan address=\"10.1016/j.joca.2023.01.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMH S, R V, T J, V V, SR D, PA W, et al. The role of allergen-specific IgE, IgG and IgA in allergic disease. Allergy. (2021) 76: 3627\u0026ndash;41. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/all.14908\u003c/span\u003e\u003cspan address=\"10.1111/all.14908\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLC T, DE W. Histamine, histamine receptors (H1 and H2), and histidine decarboxylase expression by chondrocytes of osteoarthritic cartilage: An immunohistochemical study. Rheumatol Int. (2005) 26: 173\u0026ndash;8. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00296-005-0622-x\u003c/span\u003e\u003cspan address=\"10.1007/s00296-005-0622-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQ W, CM L, H R, LL R, MM T, HH W, et al. IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis. Elife. (2019) 8. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7554/eLife.39905\u003c/span\u003e\u003cspan address=\"10.7554/eLife.39905\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMC B, K S, R L, D L, von Kaeppler EP, A B, et al. Increased risk of osteoarthritis in patients with atopic disease. Ann Rheum Dis. (2023) 82: 866\u0026ndash;72. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/ard-2022-223640\u003c/span\u003e\u003cspan address=\"10.1136/ard-2022-223640\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMC B, WH R, Q O. Genetic association between atopic disease and osteoarthritis. Osteoarthr Cartilage. (2024) 32: 220\u0026ndash;5. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.joca.2023.11.003\u003c/span\u003e\u003cspan address=\"10.1016/j.joca.2023.11.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDA L, RM H, JA S, N T, G DS. Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat Med. (2008) 27: 1133\u0026ndash;63. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/sim.3034\u003c/span\u003e\u003cspan address=\"10.1002/sim.3034\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ Y, Y Z, X Z, G C, D W, K D, et al. Increased risk of rheumatoid arthritis in patients with asthma: A genetic association study using Two-Sample mendelian randomization analysis. Arthrit Care Res. (2023). doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/acr.25193\u003c/span\u003e\u003cspan address=\"10.1002/acr.25193\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ L, A M, A T, JJ W. Association between atopic dermatitis and osteoarthritis among US adults in the 1999\u0026ndash;2006 NHANES. Journal of the European Academy of Dermatology and Venereology: JEADV. (2021) 35: e375-7. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jdv.17147\u003c/span\u003e\u003cspan address=\"10.1111/jdv.17147\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS P, NK C. Association between serum immunoglobulin E levels and knee osteoarthritis in Korean adults. Osteoarthr Cartilage. (2020) 28: 462\u0026ndash;7. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.joca.2020.02.830\u003c/span\u003e\u003cspan address=\"10.1016/j.joca.2020.02.830\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS S, C C, C M, CF K, A S, SMA B, et al. Temporal relationship between osteoarthritis and comorbidities: A combined case control and cohort study in the UK primary care setting. Rheumatology (Oxford, England). (2021) 60: 4327\u0026ndash;39. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/rheumatology/keab067\u003c/span\u003e\u003cspan address=\"10.1093/rheumatology/keab067\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA A, L F, C B, L A, A G. The effect of anti-IgE therapy in knee osteoarthritis: A pilot observational study. J Biol Reg Homeos Ag. (2017) 31: 1\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA L, T M, K H, A M, A C. The multifaceted role of mast cells in joint inflammation and arthritis. Osteoarthr Cartilage. (2023) 31: 567\u0026ndash;75. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.joca.2023.01.005\u003c/span\u003e\u003cspan address=\"10.1016/j.joca.2023.01.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"allergic diseases, serum IgE levels, osteoarthritis, Mendelian randomization","lastPublishedDoi":"10.21203/rs.3.rs-4529182/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4529182/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe question of whether there is a causal relationship between allergic diseases, immunoglobulin E levels, and osteoarthritis remains unclear. This study aimed to examine the bidirectional causal association between allergic diseases, serum IgE levels, and osteoarthritis using a Mendelian randomization study approach.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study utilized publicly available pooled statistics from large genome-wide association studies to assess the causal associations between allergic diseases, serum IgE levels, and osteoarthritis. The analysis employed inverse variance weighting, MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses were also conducted using MR-Egger regression, Cochran's Q test, and MR-PRESSO test to ensure the reliability of the findings.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe IVW results indicated that there was no significant causal relationship between allergic asthma and atopic dermatitis with KOA (OR\u0026thinsp;=\u0026thinsp;1.02, 95% CI:0.96\u0026ndash;1.09, P\u0026thinsp;=\u0026thinsp;0.544; OR\u0026thinsp;=\u0026thinsp;1.00, 95% CI:0.96\u0026ndash;1.04, P\u0026thinsp;=\u0026thinsp;0.933) and HOA (OR\u0026thinsp;=\u0026thinsp;0.95, 95% CI:0.89\u0026ndash;1.02, P\u0026thinsp;=\u0026thinsp;0.127; OR\u0026thinsp;=\u0026thinsp;1.00, 95% CI: 0.94\u0026ndash;1.06, P\u0026thinsp;=\u0026thinsp;0.992). Similarly, KOA and HOA did not have a causal effect on allergic asthma (OR\u0026thinsp;=\u0026thinsp;1.07, 95% CI: 0.86\u0026ndash;1.32, P\u0026thinsp;=\u0026thinsp;0.553; OR\u0026thinsp;=\u0026thinsp;1.04, 95% CI: 0.89\u0026ndash;1.23, P\u0026thinsp;=\u0026thinsp;0.610), atopic dermatitis (OR\u0026thinsp;=\u0026thinsp;1.05, 95% CI: 0.83\u0026ndash;1.31, P\u0026thinsp;=\u0026thinsp;0.692; OR\u0026thinsp;=\u0026thinsp;0.94, 95% CI: 0.83\u0026ndash;1.05, P\u0026thinsp;=\u0026thinsp;0.284), and serum IgE levels (OR 0.98, 95% CI: 0.74\u0026ndash;1.31, P\u0026thinsp;=\u0026thinsp;0.916; OR 1.15, 95% CI: 0.99\u0026ndash;1.34, P\u0026thinsp;=\u0026thinsp;0.071). However, there was a causal effect of serum IgE levels on KOA, as they were found to increase the incidence of KOA (OR\u0026thinsp;=\u0026thinsp;1.05, 95% CI: 1.00-1.10, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). On the other hand, serum IgE levels did not have a causal effect on HOA (OR\u0026thinsp;=\u0026thinsp;1.01, 95% CI: 0.94\u0026ndash;1.08, P\u0026thinsp;=\u0026thinsp;0.799).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eFrom a genetic perspective, a causal relationship between serum IgE levels and the risk of KOA was observed. However, there was no evidence of a bidirectional causality between atopic disease and OA. Furthermore, the use of MR methods did not support the existence of a causal effect of IgE levels on HOA or OA on IgE levels.\u003c/p\u003e","manuscriptTitle":"Genetic association of allergic diseases, serum IgE levels and osteoarthritis: a Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-26 04:11:35","doi":"10.21203/rs.3.rs-4529182/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":"2d14953c-7df8-41a3-8dc6-85239b502a00","owner":[],"postedDate":"June 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":33665183,"name":"Health sciences/Medical research"},{"id":33665184,"name":"Health sciences/Pathogenesis"},{"id":33665185,"name":"Health sciences/Rheumatology"},{"id":33665186,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-04-09T04:08:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-26 04:11:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4529182","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4529182","identity":"rs-4529182","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}