Causal relationship between rheumatoid arthritis and bronchiectasis: A bidirectional Mendelian randomization study

Causal relationship between rheumatoid arthritis and bronchiectasis: A bidirectional 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 Research Article Causal relationship between rheumatoid arthritis and bronchiectasis: A bidirectional Mendelian randomization study Zehu Chen, Xuegang Li, Honglei Shi, Yiying Huang, Jing Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3818188/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Epidemiological observational studies have elucidated a correlation between rheumatoid arthritis (RA) and bronchiectasis. However, the causal nature of this association remains ambiguous. To clarify this potential causal linkage, we conducted a two-sample Mendelian randomization (MR) analysis to explore the bidirectional causality between RA and bronchiectasis. Methods Summary statistics for RA and bronchiectasis were obtained from the IEU OpenGWAS database We employed various methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode, to explore potential causal links between RA and bronchiectasis. Additionally, a series of sensitivity studies, such as Cochran's Q test, MR Egger intercept test, and leave-one-out analysis, were conducted to assess the MR analysis's accuracy further. Results In the forward MR analysis, the primary analysis indicated that a genetic predisposition to RA correlated with an increased risk of bronchiectasis in European populations (IVW odds ratio (OR): 1.28, 95% confidence interval (CI): 1.20–1.37, p = 1.18E-13). Comparable results were noted in the East Asian subjects (IVW OR: 1.55, 95% CI: 1.30–1.34, p = 8.33E-07). The OR estimates from the other four methods were consistent with those obtained from the IVW method. Sensitivity analysis detected no evidence of horizontal pleiotropy or heterogeneity. Conversely, in the reverse MR analysis, we found no evidence to support a genetic causality between bronchiectasis and RA in either European or East Asian populations. Conclusion This study indicates that genetic predisposition to RA correlates with a heightened risk of bronchiectasis in both European and East Asian populations. These results imply that routine screening for bronchiectasis in RA patients could be beneficial, and effective management of RA may contribute to a reduced risk of bronchiectasis. Future research should aim to clarify the underlying mechanisms linking these two conditions. rheumatoid arthritis bronchiectasis Mendelian randomization genome-wide association study single-nucleotide polymorphisms Figures Figure 1 Figure 2 Figure 3 Background Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by progressive joint damage and extra-articular manifestations, potentially leading to permanent disability and heightened mortality [ 1 ]. A meta-analysis of 67 rheumatoid arthritis cohort studies across 41 countries indicated a pooled prevalence of 0.46% [ 2 ]. The most common extra-articular manifestation of RA is lung involvement, which can affect up to 60% of patients with RA during the disease course [ 3 ]. Bronchiectasis is an established extra-articular manifestation of RA, which presents as irreversible damage to the bronchi along with widening and thickening resulting in exuberant mucus production [ 4 ]. Approximately 30% of RA patients demonstrate bronchiectasis on High-Resolution Computed Tomography, which can be asymptomatic and may precede or follow the development of RA [ 5 – 7 ]. RA-associated bronchiectasis significantly reduces quality of life and increases the risk of mortality [ 4 , 8 ]. Consequently, it is imperative to investigate the relationship and pathogenesis between RA and bronchiectasis. The link between bronchiectasis and RA has been a subject of extensive research over several decades. Numerous studies indicate that RA may contribute to the risk of developing bronchiectasis. For instance, a systematic review and meta-analysis revealed an elevated prevalence of both radiological and symptomatic bronchiectasis among RA patients relative to the general population [ 9 ]. Conversely, evidence also suggests that bronchiectasis could be a risk factor for RA. A prospective study observed that 50% of bronchiectasis patients with positive rheumatoid factor and high anti-cyclic citrullinated peptide levels developed RA within a 12-month period [ 10 ]. These observational studies could be influenced by potential confounders and reverse causation, which makes it difficult to ascertain the causality between bronchiectasis and RA. Mendelian randomization (MR), a statistical approach employing genetic variation as an instrumental variable (IV), evaluates whether the observational association between exposure factors and outcomes aligns with a causal effect [ 11 ]. It avoided confounding and reverse causality because genetic variants were identified at the time of conception [ 12 ]. Consequently, our study took advantage of MR and investigated the bidirectional causal relationship between bronchiectasis and RA. Materials and methods Study design An overview of the bidirectional MR study design is shown in Fig. 1 . First, a two-sample MR analysis was conducted, treating RA as the exposure and bronchiectasis as the outcome. Subsequently, the analysis was inverted to investigate bronchiectasis as the exposure and RA as the outcome. The validity of MR analysis hinges on three critical assumptions [ 13 ] : (1) There is a strong association between the instrumental variables and the exposure; (2) Each IV is not associated with any confounding variables; (3) Each IV is associated with the outcome solely through the exposure, and there are no alternative pathways for the association. GWAS data sources The datasets for this MR study were obtained from the publicly accessible IEU Open GWAS database ( https://gwas.mrcieu.ac.uk/ , accessed on 19 November 2023). Summary statistics for RA were obtained from a genome-wide association study (GWAS) including 417,256 European subjects and another encompassing 178,616 individuals from East Asian populations. Similarly, bronchiectasis data were derived from a GWAS including 443,151 European subjects and an additional study involving 162,044 East Asian individuals. Comprehensive details of all GWAS used in our study are detailed in Table 1 . Table 1 Details of GWAS included in Mendelian randomization analysis Traits GWAS ID Year Ancestor Sample Size Number of SNP RA ebi-a-GCST90018910 2021 European 417,256 24,175,266 Bronchiectasis ebi-a-GCST90018801 2021 European 443,151 24,189,609 RA ebi-a-GCST90018690 2021 East Asian 178,616 12,454,695 Bronchiectasis ebi-a-GCST90018581 2021 East Asian 162,044 12,451,975 RA, rheumatoid arthritis; GWAS, Genome Wide Association Study; SNP, single nucleotide polymorphism; Instrumental variable selection To ensure the validity of our genetic IVs and satisfy the three core MR assumptions, we employed a comprehensive set of quality control techniques. Firstly, single nucleotide polymorphisms (SNPs) associated with the exposure were identified using a genome-wide significance threshold of p < 5E–08. In cases where the number of SNPs meeting this criterion is inadequate, SNPs with a relaxed significance threshold ( p < 5E–06) may be considered as IVs. Secondly, to reduce linkage disequilibrium, the identified exposure SNPs were clumped (r² = 0.001, window = 10 Mb, p -value threshold = 5E-8) utilizing the 1000 Genomes European dataset as a reference. Thirdly, we also excluded SNPs with palindromic intermediate allele frequencies and incompatible alleles [ 14 ]. Fourthly, each SNP's secondary phenotype was assessed using the PhenoScanner database ( http://www.phenoscanner.medschl.cam.ac.uk/ ) with a p -value threshold of p < 1E–05, and SNPs linked to confounders were excluded to mitigate pleiotropic effects. Finally, we ensured that the F statistic of all IVs was greater than the threshold 10 to minimize weak instrument bias. The F statistic was calculated using the formula F = R2(N-K-1)/K(1-R2) [ 15 ]. Statistical analysis This study employed multiple complementary methods to explore the causal relationship between bronchiectasis and RA. These methods included the inverse variance weighted method, the weighted median approach, the MR-Egger regression, the simple mode and weighted mode. The IVW method, used as the primary analysis for causal estimates, was most precise when all instrumental variables are valid [ 16 ]. The weighted median approach offered a consistent estimate of the causal effect when at least half of the SNPs serve as effective IVs [ 17 ]. The MR-Egger regression was used to confirm whether horizontal pleiotropy of IVs exists, and its intercept represents the effect estimate of horizontal pleiotropy [ 18 ]. The simple mode and weighted mode were performed as complementary analyses. Additionally, we performed sensitivity analyses to assess the dependability of our findings. The MR-Egger intercept was used to determine directional horizontal pleiotropy [ 19 ]. Subsequently, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test was applied to detect potential horizontal pleiotropy and correct it by removing outliers [ 20 ]. The Cochrane Q test was used to evaluate heterogeneity between SNPs [ 21 ]. Furthermore, the leave-one-out analysis was used to investigate whether the genetic causal relationship between exposures and outcomes was influenced by a single SNP [ 22 ]. All statistical analyses were performed using the “TwoSampleMR” and “MR-PRESSO” packages in R software (version 4.3.1). Results Forward MR analyses of the effects of RA on bronchiectasis Following a rigorous selection process for eligible IVs and the exclusion of potential pleiotropic SNPs, 24 SNPs for RA in European populations and 31 SNPs for RA in East Asian populations were finally identified as IVs in the MR analysis. The F-statistics of the screened SNPs were all > 10 to avoid bias caused by weak IVs. The information of these genetic variants utilized in the MR analyses is detailed in Supplementary Table 1–2. Figure 2 illustrates that the MR results support a causal link between genetic susceptibility to RA and an increased risk of bronchiectasis. Among individuals of European ancestry, the primary analysis revealed a significant causal association (IVW odds ratio (OR): 1.28, 95% confidence interval (CI): 1.20–1.37, p = 1.18E-13). Similar findings were observed in the East Asian population (IVW OR: 1.55, 95% CI: 1.30–1.34, p = 8.33E-07). This result was broadly consistent with results obtained using other MR methods including the weighted median approach, the MR-Egger regression, the simple mode and weighted mode. In the sensitivity analysis, the Cochran Q test revealed no heterogeneity ( p -value > 0.05), and the MR-Egger regression indicated no evidence of pleiotropy (intercept p -value > 0.05), as detailed in Table 2 . Additionally, the leave-one-out analysis suggested that the causal effect of RA on bronchiectasis was not driven by any single SNP (Supplementary Fig. 1–2). Table 2 Sensitivity analysis of the associations between rheumatoid arthritis and bronchiectasis Exposures Outcomes Ancestor Heterogeneity test (MR-Egger) Heterogeneity test (IVW) Pleiotropy test (MR-Egger) Cochran’s Q P Cochran’s Q P Intercept P RA Bronchiectasis European 20.20 0.57 20.72 0.59 -0.007 0.48 RA Bronchiectasis East Asian 31.77 0.33 31.78 0.38 -0.003 0.95 Bronchiectasis RA European 1.51 0.91 3.76 0.71 -0.0318 0.19 Bronchiectasis RA East Asian 1.38 0.71 4.39 0.36 0.0269 0.18 RA, rheumatoid arthritis; IVW, inverse variance weighted. Reverse MR analyses of the effects of bronchiectasis on RA After using strict criteria to rule out SNPs, 7 SNPs for bronchiectasis in European populations and 5 SNPs for bronchiectasis in Asian populations were identified as IVs in the MR analysis. The F-statistics of the screened SNPs were all > 10 to avoid bias caused by weak IVs. The information of these genetic variants utilized in the MR analyses is detailed in Supplementary Table 3–4. As shown in Fig. 3 , there were no causal effects of bronchiectasis on RA either in European ancestry (IVW OR: 0.93, 95% CI: 0.86–1.02, p = 0.113) or East Asian populations (IVW OR: 0.99, 95% CI: 0.97–1.03, p = 0.74). This absence of causal effects was consistent across various MR methods including the weighted median approach, the MR-Egger regression, the simple mode and weighted mode. The sensitivity analysis did not find heterogeneity ( p -value of Cochran Q > 0.05) and pleiotropy ( p -value for intercept > 0.05) (Table 2 ). Leave-one-out analysis showed that no outlier SNP was detected. (Supplementary Fig. 3–4). Discussion For the first time, we conducted a bidirectional two-sample MR analysis to investigate the causal effect between RA and bronchiectasis. The results revealed a causal association between genetic susceptibility to RA and an increased risk of bronchiectasis. Conversely, no evidence was found to suggest a causal relationship between bronchiectasis and an increased risk of RA. The findings of this study offer significant insights into the potential causal connection between these two conditions. Epidemiological research has consistently shown a link between rheumatoid arthritis and bronchiectasis. For instance, a cross-sectional study indicated that RA might contribute to more severe and extensive bronchiectasis [ 23 ]. Additionally, evidence from a retrospective cohort study suggested that RA disease duration is associated with higher risk of having respiratory symptoms (not specific to bronchiectasis) [ 24 ]. These results are consistent with our forward MR analysis. However, our reverse MR analysis provided contrasting evidence, diverging from observational studies. A recent meta-analysis revealed that bronchiectasis preceded RA in 53 of 69 cases, indicating that bronchiectasis may contribute to the development of RA [ 9 ]. Furthermore, a prospective study observed that 50% of bronchiectasis patients with positive rheumatoid factor and high anti-cyclic citrullinated peptide levels developed RA within a 12-month period [ 10 ]. A potential explanation for the differences between the results of observational studies and our reverse MR analysis might be that the previously observed results were either coincidental or influenced by unidentified confounding factors. Several hypothesis have been put forward to explain the mechanisms underlying the development of bronchiectasis in RA [ 25 ]. Primarily, the onset of bronchiectasis in RA may be linked to RA-related autoantibodies. Aubart et al. demonstrated that elevated levels of anti-cyclic citrullinated peptide antibodies (ACPA) correlated with the occurrence of pulmonary diseases like bronchiectasis in RA patients [ 26 ]. Additionally, Attar et al. reported that patients with RA who were positive for ACPA exhibited an increased risk of bronchiectasis [ 27 ]. Collectively, these studies implied that autoantibodies substantially may contribute to bronchiectasis in RA patients. Secondly, genetic factors may also play a role in the association between RA and bronchiectasis. A family-based association study highlighted that cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in RA patients are crucial indicators of associated bronchiectasis risk [ 28 ]. Further, a prospective study indicated that mutated CFTR proteins in the airways might predispose to both the onset and severity of bronchiectasis in individuals with RA [ 29 ]. Consequently, it is speculated that CFTR gene mutations in RA patients are significant risk markers for concurrent bronchiectasis. Lastly, other theories of bronchiectasis in patients with RA include the possibility that recurrent infection related to chronic immune suppression predisposes patients with RA to bronchiectasis [ 8 ]. For instance, patients with RA and bronchiectasis have frequent lower respiratory tract infections, and these infections were associated with the utilization of biologic disease-modifying antirheumatic drugs [ 30 ]. There are several advantages to this study. Firstly, we used a MR analysis that is not affected by confounders and reverse causation compared with observational studies. Secondly, the bidirectional approach facilitates the exploration of causal relationships in both directions between RA and bronchiectasis. Additionally, the validation of our findings across European and East Asian datasets enhances the credibility of our conclusions. However, there are still limitations. The MR results are primarily based on European and East Asian populations, and the applicability of these findings to other populations requires further investigation. Furthermore, the SNPs used in the analysis may be associated with other traits due to genetic polymorphisms, potentially impacting the accuracy of causal inference. Conclusions In summary, this study utilized a bidirectional two-sample MR approach to assess the causal relationship between RA and bronchiectasis. It established a causal link between genetic predisposition to RA and an elevated risk of bronchiectasis, while not finding a similar association for genetic predisposition to bronchiectasis increasing the risk of RA. These findings indicate that routine screening for bronchiectasis in RA patients, alongside effective management of RA, may contribute to reducing the development risk of bronchiectasis. Currently, the pathogenesis of bronchiectasis in RA patients is not well understood. Future research should therefore be directed towards elucidating the underlying mechanisms connecting these two conditions. Abbreviations RA: Rheumatoid arthritis; MR: Mendelian randomization; SNP: Single-nucleotide polymorphism; GWAS: Genome-wide association; IVW: Inverse-variance-weighted; OR: Odds ratio; CI: confidence interval; MRPRESSO: Mendelian randomization pleiotropy residual sum and outlier; ACPA: anti-cyclic citrullinated peptide antibodies; CFTR: cystic fibrosis transmembrane conductance regulator study Declarations Ethics approval and consent to participate The summary statistics used in the present study are aggregated level of data which do not contain any personal information. The original GWAS have obtained ethical approval from relevant ethics review committees. Consent for publication All authors read and approved the fnal manuscript. And agree to the publication of the manuscript. Availability of data and materials Publicly available datasets can be found here: the Integrative Epidemiology Unit (IEU) GWAS database (https://gwas.mrcieu. ac.uk). Competing interests The authors declare no competing interests. Funding Not applicable. Authors’ contributions JL and YYH designed the study. ZHC and HLS acquired and analyzed the data. XGL and ZHC drafted the article. All authors read and approved the final manuscript. Acknowledgements We appreciate a lot for the investigators who shared the GWAS data. References Finckh A, Gilbert B, Hodkinson B, Bae S-C, Thomas R, Deane KD, et al. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol. 2022;18(10):591-602. Almutairi K, Nossent J, Preen D, Keen H, Inderjeeth C. The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review. Rheumatol Int. 2021;41(5):863-77. Laria A, Lurati AM, Zizzo G, Zaccara E, Mazzocchi D, Re KA, et al. Interstitial Lung Disease in Rheumatoid Arthritis: A Practical Review. Front Med (Lausanne). 2022;9:837133. Martin LW, Prisco LC, Huang W, McDermott G, Shadick NA, Doyle TJ, et al. 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Risk of infections in bronchiectasis during disease-modifying treatment and biologics for rheumatic diseases. BMC Infect Dis. 2011;11:304. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 08 Apr, 2024 Reviews received at journal 03 Apr, 2024 Reviewers agreed at journal 27 Mar, 2024 Reviewers agreed at journal 01 Feb, 2024 Reviews received at journal 29 Jan, 2024 Reviewers agreed at journal 19 Jan, 2024 Reviewers invited by journal 16 Jan, 2024 Editor assigned by journal 29 Dec, 2023 Submission checks completed at journal 29 Dec, 2023 First submitted to journal 28 Dec, 2023 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. 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20:00:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3818188/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3818188/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49134579,"identity":"8cc5ab2c-e523-4951-abbd-f58f17271121","added_by":"auto","created_at":"2024-01-03 16:57:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":726076,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design for our Mendelian randomization.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3818188/v1/850c203f2cbca54ef52134d0.png"},{"id":49134578,"identity":"d1cb18d4-49c0-451b-a4a6-4800eb3d91a3","added_by":"auto","created_at":"2024-01-03 16:57:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":234252,"visible":true,"origin":"","legend":"\u003cp\u003eMendelian randomization for the association of rheumatoid arthritis on bronchiectasis.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3818188/v1/ba38d279b97e168d60611be8.png"},{"id":49134580,"identity":"72fa8e78-7e4f-45a3-b824-5c35a0ec1a10","added_by":"auto","created_at":"2024-01-03 16:57:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":416792,"visible":true,"origin":"","legend":"\u003cp\u003eMendelian randomization for the association of bronchiectasis on rheumatoid arthritis.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3818188/v1/7b5e676ca8acf64d2b174bd2.png"},{"id":49135403,"identity":"e4565c52-373a-4ac9-803a-09387d708266","added_by":"auto","created_at":"2024-01-03 17:05:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1310967,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3818188/v1/48002b96-1f5d-4dfa-9075-f5f91b455be3.pdf"},{"id":49134583,"identity":"ef731a71-7b43-4741-bfc5-3994ecb394ac","added_by":"auto","created_at":"2024-01-03 16:57:49","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28791788,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3818188/v1/d5c2761b7391966e37f2c8f2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Causal relationship between rheumatoid arthritis and bronchiectasis: A bidirectional Mendelian randomization study","fulltext":[{"header":"Background","content":"\u003cp\u003eRheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by progressive joint damage and extra-articular manifestations, potentially leading to permanent disability and heightened mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. A meta-analysis of 67 rheumatoid arthritis cohort studies across 41 countries indicated a pooled prevalence of 0.46% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The most common extra-articular manifestation of RA is lung involvement, which can affect up to 60% of patients with RA during the disease course [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Bronchiectasis is an established extra-articular manifestation of RA, which presents as irreversible damage to the bronchi along with widening and thickening resulting in exuberant mucus production [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Approximately 30% of RA patients demonstrate bronchiectasis on High-Resolution Computed Tomography, which can be asymptomatic and may precede or follow the development of RA [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. RA-associated bronchiectasis significantly reduces quality of life and increases the risk of mortality [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Consequently, it is imperative to investigate the relationship and pathogenesis between RA and bronchiectasis.\u003c/p\u003e \u003cp\u003eThe link between bronchiectasis and RA has been a subject of extensive research over several decades. Numerous studies indicate that RA may contribute to the risk of developing bronchiectasis. For instance, a systematic review and meta-analysis revealed an elevated prevalence of both radiological and symptomatic bronchiectasis among RA patients relative to the general population [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Conversely, evidence also suggests that bronchiectasis could be a risk factor for RA. A prospective study observed that 50% of bronchiectasis patients with positive rheumatoid factor and high anti-cyclic citrullinated peptide levels developed RA within a 12-month period [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese observational studies could be influenced by potential confounders and reverse causation, which makes it difficult to ascertain the causality between bronchiectasis and RA. Mendelian randomization (MR), a statistical approach employing genetic variation as an instrumental variable (IV), evaluates whether the observational association between exposure factors and outcomes aligns with a causal effect [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. It avoided confounding and reverse causality because genetic variants were identified at the time of conception [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Consequently, our study took advantage of MR and investigated the bidirectional causal relationship between bronchiectasis and RA.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eAn overview of the bidirectional MR study design is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. First, a two-sample MR analysis was conducted, treating RA as the exposure and bronchiectasis as the outcome. Subsequently, the analysis was inverted to investigate bronchiectasis as the exposure and RA as the outcome. The validity of MR analysis hinges on three critical assumptions [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] : (1) There is a strong association between the instrumental variables and the exposure; (2) Each IV is not associated with any confounding variables; (3) Each IV is associated with the outcome solely through the exposure, and there are no alternative pathways for the association.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eGWAS data sources\u003c/h2\u003e \u003cp\u003eThe datasets for this MR study were obtained from the publicly accessible IEU Open GWAS database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, accessed on 19 November 2023). Summary statistics for RA were obtained from a genome-wide association study (GWAS) including 417,256 European subjects and another encompassing 178,616 individuals from East Asian populations. Similarly, bronchiectasis data were derived from a GWAS including 443,151 European subjects and an additional study involving 162,044 East Asian individuals. Comprehensive details of all GWAS used in our study are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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\u003eDetails of GWAS included in Mendelian randomization analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTraits\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGWAS ID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAncestor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSample Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNumber of SNP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eebi-a-GCST90018910\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e417,256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e24,175,266\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eebi-a-GCST90018801\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e443,151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e24,189,609\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eebi-a-GCST90018690\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEast Asian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e178,616\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12,454,695\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eebi-a-GCST90018581\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEast Asian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e162,044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12,451,975\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eRA, rheumatoid arthritis; GWAS, Genome Wide Association Study; SNP, single nucleotide polymorphism;\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInstrumental variable selection\u003c/h2\u003e \u003cp\u003eTo ensure the validity of our genetic IVs and satisfy the three core MR assumptions, we employed a comprehensive set of quality control techniques. Firstly, single nucleotide polymorphisms (SNPs) associated with the exposure were identified using a genome-wide significance threshold of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5E\u0026ndash;08. In cases where the number of SNPs meeting this criterion is inadequate, SNPs with a relaxed significance threshold (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5E\u0026ndash;06) may be considered as IVs. Secondly, to reduce linkage disequilibrium, the identified exposure SNPs were clumped (r\u0026sup2; = 0.001, window\u0026thinsp;=\u0026thinsp;10 Mb, \u003cem\u003ep\u003c/em\u003e -value threshold\u0026thinsp;=\u0026thinsp;5E-8) utilizing the 1000 Genomes European dataset as a reference. Thirdly, we also excluded SNPs with palindromic intermediate allele frequencies and incompatible alleles [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Fourthly, each SNP's secondary phenotype was assessed using the PhenoScanner database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.phenoscanner.medschl.cam.ac.uk/\u003c/span\u003e\u003cspan address=\"http://www.phenoscanner.medschl.cam.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) with a \u003cem\u003ep\u003c/em\u003e -value threshold of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;1E\u0026ndash;05, and SNPs linked to confounders were excluded to mitigate pleiotropic effects. Finally, we ensured that the F statistic of all IVs was greater than the threshold 10 to minimize weak instrument bias. The F statistic was calculated using the formula F\u0026thinsp;=\u0026thinsp;R2(N-K-1)/K(1-R2) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThis study employed multiple complementary methods to explore the causal relationship between bronchiectasis and RA. These methods included the inverse variance weighted method, the weighted median approach, the MR-Egger regression, the simple mode and weighted mode. The IVW method, used as the primary analysis for causal estimates, was most precise when all instrumental variables are valid [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The weighted median approach offered a consistent estimate of the causal effect when at least half of the SNPs serve as effective IVs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The MR-Egger regression was used to confirm whether horizontal pleiotropy of IVs exists, and its intercept represents the effect estimate of horizontal pleiotropy [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The simple mode and weighted mode were performed as complementary analyses.\u003c/p\u003e \u003cp\u003eAdditionally, we performed sensitivity analyses to assess the dependability of our findings. The MR-Egger intercept was used to determine directional horizontal pleiotropy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Subsequently, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test was applied to detect potential horizontal pleiotropy and correct it by removing outliers [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The Cochrane Q test was used to evaluate heterogeneity between SNPs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Furthermore, the leave-one-out analysis was used to investigate whether the genetic causal relationship between exposures and outcomes was influenced by a single SNP [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. All statistical analyses were performed using the \u0026ldquo;TwoSampleMR\u0026rdquo; and \u0026ldquo;MR-PRESSO\u0026rdquo; packages in R software (version 4.3.1).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eForward MR analyses of the effects of RA on bronchiectasis\u003c/h2\u003e \u003cp\u003eFollowing a rigorous selection process for eligible IVs and the exclusion of potential pleiotropic SNPs, 24 SNPs for RA in European populations and 31 SNPs for RA in East Asian populations were finally identified as IVs in the MR analysis. The F-statistics of the screened SNPs were all \u0026gt;\u0026thinsp;10 to avoid bias caused by weak IVs. The information of these genetic variants utilized in the MR analyses is detailed in Supplementary Table\u0026nbsp;1\u0026ndash;2.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates that the MR results support a causal link between genetic susceptibility to RA and an increased risk of bronchiectasis. Among individuals of European ancestry, the primary analysis revealed a significant causal association (IVW odds ratio (OR): 1.28, 95% confidence interval (CI): 1.20\u0026ndash;1.37, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.18E-13). Similar findings were observed in the East Asian population (IVW OR: 1.55, 95% CI: 1.30\u0026ndash;1.34, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.33E-07). This result was broadly consistent with results obtained using other MR methods including the weighted median approach, the MR-Egger regression, the simple mode and weighted mode.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the sensitivity analysis, the Cochran Q test revealed no heterogeneity (\u003cem\u003ep\u003c/em\u003e -value\u0026thinsp;\u0026gt;\u0026thinsp;0.05), and the MR-Egger regression indicated no evidence of pleiotropy (intercept \u003cem\u003ep\u003c/em\u003e -value\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Additionally, the leave-one-out analysis suggested that the causal effect of RA on bronchiectasis was not driven by any single SNP (Supplementary Fig.\u0026nbsp;1\u0026ndash;2).\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\u003eSensitivity analysis of the associations between rheumatoid arthritis and bronchiectasis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\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=\"left\" 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=\"char\" char=\".\" 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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eExposures\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAncestor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eHeterogeneity test (MR-Egger)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eHeterogeneity test (IVW)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003ePleiotropy test (MR-Egger)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCochran\u0026rsquo;s Q\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCochran\u0026rsquo;s Q\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIntercept\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\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\u003eRA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEast Asian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e31.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.0318\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEast Asian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0269\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eRA, rheumatoid arthritis; IVW, inverse variance weighted.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eReverse MR analyses of the effects of bronchiectasis on RA\u003c/h2\u003e \u003cp\u003eAfter using strict criteria to rule out SNPs, 7 SNPs for bronchiectasis in European populations and 5 SNPs for bronchiectasis in Asian populations were identified as IVs in the MR analysis. The F-statistics of the screened SNPs were all \u0026gt;\u0026thinsp;10 to avoid bias caused by weak IVs. The information of these genetic variants utilized in the MR analyses is detailed in Supplementary Table\u0026nbsp;3\u0026ndash;4.\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, there were no causal effects of bronchiectasis on RA either in European ancestry (IVW OR: 0.93, 95% CI: 0.86\u0026ndash;1.02, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.113) or East Asian populations (IVW OR: 0.99, 95% CI: 0.97\u0026ndash;1.03, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.74). This absence of causal effects was consistent across various MR methods including the weighted median approach, the MR-Egger regression, the simple mode and weighted mode. The sensitivity analysis did not find heterogeneity (\u003cem\u003ep\u003c/em\u003e -value of Cochran Q\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and pleiotropy (\u003cem\u003ep\u003c/em\u003e -value for intercept\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Leave-one-out analysis showed that no outlier SNP was detected. (Supplementary Fig.\u0026nbsp;3\u0026ndash;4).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eFor the first time, we conducted a bidirectional two-sample MR analysis to investigate the causal effect between RA and bronchiectasis. The results revealed a causal association between genetic susceptibility to RA and an increased risk of bronchiectasis. Conversely, no evidence was found to suggest a causal relationship between bronchiectasis and an increased risk of RA. The findings of this study offer significant insights into the potential causal connection between these two conditions.\u003c/p\u003e \u003cp\u003eEpidemiological research has consistently shown a link between rheumatoid arthritis and bronchiectasis. For instance, a cross-sectional study indicated that RA might contribute to more severe and extensive bronchiectasis [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Additionally, evidence from a retrospective cohort study suggested that RA disease duration is associated with higher risk of having respiratory symptoms (not specific to bronchiectasis) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These results are consistent with our forward MR analysis. However, our reverse MR analysis provided contrasting evidence, diverging from observational studies. A recent meta-analysis revealed that bronchiectasis preceded RA in 53 of 69 cases, indicating that bronchiectasis may contribute to the development of RA [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, a prospective study observed that 50% of bronchiectasis patients with positive rheumatoid factor and high anti-cyclic citrullinated peptide levels developed RA within a 12-month period [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A potential explanation for the differences between the results of observational studies and our reverse MR analysis might be that the previously observed results were either coincidental or influenced by unidentified confounding factors.\u003c/p\u003e \u003cp\u003eSeveral hypothesis have been put forward to explain the mechanisms underlying the development of bronchiectasis in RA [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Primarily, the onset of bronchiectasis in RA may be linked to RA-related autoantibodies. Aubart et al. demonstrated that elevated levels of anti-cyclic citrullinated peptide antibodies (ACPA) correlated with the occurrence of pulmonary diseases like bronchiectasis in RA patients [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Additionally, Attar et al. reported that patients with RA who were positive for ACPA exhibited an increased risk of bronchiectasis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Collectively, these studies implied that autoantibodies substantially may contribute to bronchiectasis in RA patients. Secondly, genetic factors may also play a role in the association between RA and bronchiectasis. A family-based association study highlighted that cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in RA patients are crucial indicators of associated bronchiectasis risk [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Further, a prospective study indicated that mutated CFTR proteins in the airways might predispose to both the onset and severity of bronchiectasis in individuals with RA [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Consequently, it is speculated that CFTR gene mutations in RA patients are significant risk markers for concurrent bronchiectasis. Lastly, other theories of bronchiectasis in patients with RA include the possibility that recurrent infection related to chronic immune suppression predisposes patients with RA to bronchiectasis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. For instance, patients with RA and bronchiectasis have frequent lower respiratory tract infections, and these infections were associated with the utilization of biologic disease-modifying antirheumatic drugs [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are several advantages to this study. Firstly, we used a MR analysis that is not affected by confounders and reverse causation compared with observational studies. Secondly, the bidirectional approach facilitates the exploration of causal relationships in both directions between RA and bronchiectasis. Additionally, the validation of our findings across European and East Asian datasets enhances the credibility of our conclusions. However, there are still limitations. The MR results are primarily based on European and East Asian populations, and the applicability of these findings to other populations requires further investigation. Furthermore, the SNPs used in the analysis may be associated with other traits due to genetic polymorphisms, potentially impacting the accuracy of causal inference.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, this study utilized a bidirectional two-sample MR approach to assess the causal relationship between RA and bronchiectasis. It established a causal link between genetic predisposition to RA and an elevated risk of bronchiectasis, while not finding a similar association for genetic predisposition to bronchiectasis increasing the risk of RA. These findings indicate that routine screening for bronchiectasis in RA patients, alongside effective management of RA, may contribute to reducing the development risk of bronchiectasis. Currently, the pathogenesis of bronchiectasis in RA patients is not well understood. Future research should therefore be directed towards elucidating the underlying mechanisms connecting these two conditions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRA: Rheumatoid arthritis; MR: Mendelian randomization; SNP: Single-nucleotide polymorphism; GWAS: Genome-wide association; IVW: Inverse-variance-weighted; OR: Odds ratio; CI: confidence interval; MRPRESSO: Mendelian randomization pleiotropy residual sum and outlier; ACPA: anti-cyclic citrullinated peptide antibodies; CFTR: cystic fibrosis transmembrane conductance regulator study\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe summary statistics used in the present study are aggregated level of\u0026nbsp;data which do not contain any personal information. The original GWAS\u0026nbsp;have obtained ethical approval from relevant ethics review committees.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the fnal manuscript. And agree to the publication of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePublicly available datasets can be found here: the Integrative Epidemiology Unit (IEU) GWAS database (https://gwas.mrcieu. ac.uk).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJL and YYH designed the study. ZHC\u0026nbsp;and HLS\u0026nbsp;acquired and analyzed\u0026nbsp;the data. XGL\u0026nbsp;and ZHC\u0026nbsp;drafted the article. All authors read\u0026nbsp;and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe appreciate a lot for the investigators who shared the GWAS data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFinckh A, Gilbert B, Hodkinson B, Bae S-C, Thomas R, Deane KD, et al. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol.\u003cem\u003e \u003c/em\u003e2022;18(10):591-602.\u003c/li\u003e\n\u003cli\u003eAlmutairi K, Nossent J, Preen D, Keen H, Inderjeeth C. The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review. Rheumatol Int.\u003cem\u003e \u003c/em\u003e2021;41(5):863-77.\u003c/li\u003e\n\u003cli\u003eLaria A, Lurati AM, Zizzo G, Zaccara E, Mazzocchi D, Re KA, et al. Interstitial Lung Disease in Rheumatoid Arthritis: A Practical Review. 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Int J Epidemiol.\u003cem\u003e \u003c/em\u003e2015;44(2):512-25.\u003c/li\u003e\n\u003cli\u003eVerbanck M, Chen C-Y, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet.\u003cem\u003e \u003c/em\u003e2018;50(5):693-98.\u003c/li\u003e\n\u003cli\u003eHemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife.\u003cem\u003e \u003c/em\u003e2018;7.\u003c/li\u003e\n\u003cli\u003eSu Y, Hu Y, Xu Y, Yang M, Wu F, Peng Y. Genetic causal relationship between age at menarche and benign oesophageal neoplasia identified by a Mendelian randomization study. Front Endocrinol (Lausanne).\u003cem\u003e \u003c/em\u003e2023;14:1113765.\u003c/li\u003e\n\u003cli\u003eMetafratzi ZM, Georgiadis AN, Ioannidou CV, Alamanos Y, Vassiliou MP, Zikou AK, et al. Pulmonary involvement in patients with early rheumatoid arthritis. Scand J Rheumatol.\u003cem\u003e \u003c/em\u003e2007;36(5):338-44.\u003c/li\u003e\n\u003cli\u003eRemy-Jardin M, Remy J, Cortet B, Mauri F, Delcambre B. Lung changes in rheumatoid arthritis: CT findings. Radiology.\u003cem\u003e \u003c/em\u003e1994;193(2):375-82.\u003c/li\u003e\n\u003cli\u003eBakheet SM, Hammami MM, Powe J. Radioiodine uptake in rheumatoid arthritis-associated lung disease mimicking thyroid cancer metastases. Clin Nucl Med.\u003cem\u003e \u003c/em\u003e1998;23(5):319-20.\u003c/li\u003e\n\u003cli\u003eAubart F, Crestani B, Nicaise-Roland P, Tubach F, Bollet C, Dawidowicz K, et al. High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J Rheumatol.\u003cem\u003e \u003c/em\u003e2011;38(6):979-82.\u003c/li\u003e\n\u003cli\u003eReynisdottir G, Karimi R, Joshua V, Olsen H, Hensvold AH, Harju A, et al. Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol.\u003cem\u003e \u003c/em\u003e2014;66(1):31-39.\u003c/li\u003e\n\u003cli\u003ePu\u0026eacute;chal X, G\u0026eacute;nin E, Bienvenu T, Le Jeunne C, Dusser DJ. Poor survival in rheumatoid arthritis associated with bronchiectasis: a family-based cohort study. PLoS One.\u003cem\u003e \u003c/em\u003e2014;9(10):e110066.\u003c/li\u003e\n\u003cli\u003ePu\u0026eacute;chal X, Fajac I, Bienvenu T, Desmazes-Dufeu N, Hubert D, Kaplan JC, et al. Increased frequency of cystic fibrosis deltaF508 mutation in bronchiectasis associated with rheumatoid arthritis. Eur Respir J.\u003cem\u003e \u003c/em\u003e1999;13(6):1281-87.\u003c/li\u003e\n\u003cli\u003eGeri G, Dadoun S, Bui T, Del Castillo Pinol N, Paternotte S, Dougados M, et al. Risk of infections in bronchiectasis during disease-modifying treatment and biologics for rheumatic diseases. BMC Infect Dis.\u003cem\u003e \u003c/em\u003e2011;11:304.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"arthritis-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arrt","sideBox":"Learn more about [Arthritis Research \u0026 Therapy](http://arthritis-research.biomedcentral.com/)","snPcode":"13075","submissionUrl":"https://submission.nature.com/new-submission/13075/3","title":"Arthritis Research \u0026 Therapy","twitterHandle":"@ArthritisRes","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"rheumatoid arthritis, bronchiectasis, Mendelian randomization, genome-wide association study, single-nucleotide polymorphisms","lastPublishedDoi":"10.21203/rs.3.rs-3818188/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3818188/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEpidemiological observational studies have elucidated a correlation between rheumatoid arthritis (RA) and bronchiectasis. However, the causal nature of this association remains ambiguous. To clarify this potential causal linkage, we conducted a two-sample Mendelian randomization (MR) analysis to explore the bidirectional causality between RA and bronchiectasis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSummary statistics for RA and bronchiectasis were obtained from the IEU OpenGWAS database We employed various methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode, to explore potential causal links between RA and bronchiectasis. Additionally, a series of sensitivity studies, such as Cochran's Q test, MR Egger intercept test, and leave-one-out analysis, were conducted to assess the MR analysis's accuracy further.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the forward MR analysis, the primary analysis indicated that a genetic predisposition to RA correlated with an increased risk of bronchiectasis in European populations (IVW odds ratio (OR): 1.28, 95% confidence interval (CI): 1.20\u0026ndash;1.37, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.18E-13). Comparable results were noted in the East Asian subjects (IVW OR: 1.55, 95% CI: 1.30\u0026ndash;1.34, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.33E-07). The OR estimates from the other four methods were consistent with those obtained from the IVW method. Sensitivity analysis detected no evidence of horizontal pleiotropy or heterogeneity. Conversely, in the reverse MR analysis, we found no evidence to support a genetic causality between bronchiectasis and RA in either European or East Asian populations.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study indicates that genetic predisposition to RA correlates with a heightened risk of bronchiectasis in both European and East Asian populations. These results imply that routine screening for bronchiectasis in RA patients could be beneficial, and effective management of RA may contribute to a reduced risk of bronchiectasis. Future research should aim to clarify the underlying mechanisms linking these two conditions.\u003c/p\u003e","manuscriptTitle":"Causal relationship between rheumatoid arthritis and bronchiectasis: A bidirectional Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 16:57:42","doi":"10.21203/rs.3.rs-3818188/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-08T15:06:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-03T09:16:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ad70ffc7-1bdc-4c58-a4fe-414d642c2961","date":"2024-03-27T17:56:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223dfe80-6b1a-4a96-aa16-51cbff21cf7c","date":"2024-02-01T23:28:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-29T21:56:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"74f04a4e-a15d-4ecd-b6ba-d8098218f94d","date":"2024-01-19T06:15:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-16T18:32:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-29T10:28:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-29T07:16:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Arthritis Research \u0026 Therapy","date":"2023-12-28T19:59:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"arthritis-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arrt","sideBox":"Learn more about [Arthritis Research \u0026 Therapy](http://arthritis-research.biomedcentral.com/)","snPcode":"13075","submissionUrl":"https://submission.nature.com/new-submission/13075/3","title":"Arthritis Research \u0026 Therapy","twitterHandle":"@ArthritisRes","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"616df9d0-808e-40e8-9e36-543a131ee87b","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-05-01T00:09:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-03 16:57:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3818188","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3818188","identity":"rs-3818188","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}