Association between Vitamin B2 Intake and Prevalence of Rheumatoid Arthritis in the general United States population: A Cohort Study from the NHANES 1999-2018

Association between Vitamin B2 Intake and Prevalence of Rheumatoid Arthritis in the general United States population: A Cohort Study from the NHANES 1999-2018 | 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 Association between Vitamin B2 Intake and Prevalence of Rheumatoid Arthritis in the general United States population: A Cohort Study from the NHANES 1999-2018 Qingling Guo#, Shuzhen Yuan, Youping Lin, Yishan Yin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7131533/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The relationship between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis (RA) in the general United States population is an area of research which has not yet been extensively explored in the field of nutritional epidemiology, highlighting a significant research gap. Objective The present study aims to explore the potential association between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis in the general United States population. Methods This longitudinal cohort study analysed 8,761 individuals from the United States aged 20 years or older who participated in the National Health and Nutrition Examination Survey from 1999 to 2018. A comprehensive data set pertaining to the prevalence of rheumatoid arthritis (RA), the intake of dietary vitamin B2, and pertinent confounding variables was systematically collected and analysed. The potential association was investigated by means of a Cox regression analysis and spline curve fitting. Results Following the adjustment for confounding factors, a significant inverse relationship was identified between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis in the general United States population. The adjusted hazard ratios (HRs) for the second (Q2) and third (Q3) tertiles of vitamin B2 intake were 0.87 and 0.89, respectively. Non-linear modelling indicated a threshold effect, characterised by a curve that associated dietary intake of vitamin B2 with rheumatoid arthritis risk prevalence (p = 0.021). A critical analysis of the extant literature revealed an intake threshold of 1.7 mg/day, below which each unit increment in vitamin B2 intake was associated with a 34.2% decrease in the prevalence of rheumatoid arthritis risk (HR = 0.658). In contrast, no substantial correlation was identified between intake levels that exceeded this threshold and the prevalence of rheumatoid arthritis risk (HR = 0.977). Conclusion The findings of this study suggest a positive correlation between increased dietary intake of vitamin B2 and a reduced risk of rheumatoid arthritis in the general United States population. The dose-response relationship exhibits a non-linear pattern, featuring a critical inflection point at an intake of approximately 1.7 mg/day. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Rheumatology Health sciences/Risk factors Rheumatoid arthritis (RA ) dietary vitamin B2 intake NHANES association cohort study Figures Figure 1 Figure 2 Figure 3 1. Introduction Rheumatoid arthritis (RA) is a chronic autoimmune and inflammatory disease that imposes a substantial global burden.( 1 – 2 )It is characterized by a high prevalence, significant disability, and considerable economic strain. RA affects millions of individuals worldwide, often leading to joint deformities, impaired mobility, and reduced quality of life. The chronic inflammatory nature of RA not only impacts physical health but also places a significant economic burden on healthcare systems and affected individuals through medical costs and lost productivity.༈3–5༉ RA is fundamentally an autoimmune disorder driven by chronic inflammation. The pathogenesis of RA involves the dysregulation of immune responses, leading to the production of autoantibodies and the infiltration of immune cells into the synovial joints. ( 6 – 8 )This results in persistent inflammation, cartilage destruction, and bone erosion. The chronic nature of RA and its associated inflammation contribute to systemic complications and comorbidities, further exacerbating the disease burden. Vitamin B₂, also known as riboflavin, is an essential micronutrient with several critical physiological functions. It plays a vital role in energy metabolism, particularly through its involvement in mitochondrial function. Riboflavin is a precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)( 9 – 10 ), which are essential cofactors for various enzymatic reactions. These reactions are crucial for the production of adenosine triphosphate (ATP), the primary energy currency of the cell. Additionally, vitamin B₂ is integral to antioxidant defense mechanisms, specifically by maintaining the activity of glutathione reductase, an enzyme that helps recycle glutathione, a key antioxidant in the body. ༈11–13༉Riboflavin also supports cell growth and repair, contributing to overall cellular health.༈14–15༉ The potential link between vitamin B₂ and RA is biologically plausible. ( 16 – 18 )Oxidative stress is a key factor in the pathogenesis of RA, contributing to the activation of inflammatory pathways and the production of pro-inflammatory cytokines. Vitamin B₂, through its antioxidant properties, may help mitigate oxidative stress and reduce inflammation. Furthermore, mitochondrial dysfunction has been implicated in the activation of immune cells and the perpetuation of inflammation in RA. Vitamin B₂, by supporting mitochondrial function, may play a role in regulating immune responses and reducing the risk of RA. Deficiencies in vitamin B₂ have been associated with the dysregulation of inflammatory pathways, such as the activation of nuclear factor-kappa B (NF-κB)( 19 – 21 ), a transcription factor that controls transcription of DNA, cytokine production, and cell survival, thus potentially contributing to the development of RA. Despite the biological plausibility of a link between vitamin B₂ and RA, current epidemiological evidence is limited and inconsistent. Few studies have examined this relationship, and most have been conducted in small or non-representative populations. There is a significant gap in the literature regarding large-scale, nationally representative studies that can provide robust insights into the association between vitamin B₂ intake and RA prevalence in the general population. 2. Materials and methods 2.1. Study design and population The National Health and Nutrition Examination Survey (NHANES)( 22 – 23 ), conducted by the Centers for Disease Control and Prevention (CDC), is a comprehensive health and nutrition status assessment of the United States (US) population. It includes data on vitamin B2 consumption and its association with rheumatic diseases, such as arthritis and rheumatoid arthritis (RA). The present study employed the multimodal assessment techniques of the NHANES, encompassing interviews, physical evaluations and laboratory analyses. The specific methodologies, including the evaluation of vitamin B2 intake, are detailed on the NHANES website. The present study was conducted in accordance with the ethical standards set by the CDC's Institutional Review Board and adhered to the NHANES protocol ( 24 ), ensuring the safeguarding of participants' rights and confidentiality. Prior to participation, all subjects provided written informed consent, thereby ensuring their voluntary engagement and ensuring full comprehension of the study's objectives and procedures. The research utilised data from a pre-approved NHANES, which had been reviewed by an institutional review board. The board determined that our study fulfilled all ethical standards and granted an exemption from further review, due to the use of de-identified data from a preexisting, approved survey. The prospective cohort study utilised the NHANES data from 1999 to 2018. Stringent exclusion criteria were applied in order to ensure a precise sample size. Individuals with incomplete records of vitamin B2 intake, or an unverified diagnosis of RA, were excluded from the study. This ensured the precision and dependability of the study population. The methodology of participant selection, including the inclusion and exclusion criteria, is depicted in Fig. 1 and presented as an accompanying flowchart. 2.2. Definition of independent and dependent variables In the present study, the dietary intake of vitamin E was measured using a 24-hour recall method that has been validated for accuracy. This method was conducted during NHANES dietary interviews at the Mobile Examination Center (MEC). The participants reported their intake of vitamin E during the course of these interviews. This information was then quantified using a comprehensive food composition database in order to standardise the subsequent nutrient assessment. The diagnosis of rheumatoid arthritis (RA) was determined through the implementation of a two-stage self-report questionnaire ( 25 – 26 ). Initially, the participants were asked whether a healthcare provider had diagnosed them with arthritis, with emphasis on clarity and precision in the questions posed. The responses given were limited to "yes" or "no", with a positive response leading to a subsequent inquiry. Participants who responded in the affirmative were requested to identify the specific type of arthritis diagnosed by a healthcare provider from an exhaustive list that included all major forms, with additional options for "refused" and "do not know" to account for any lack of information. 2.3. Covariates The present study meticulously evaluated various covariates with a view to enhancing analytical precision, in alignment with the extant scholarly consensus ( 27 – 28 ). The demographic variables encompassed age (categorised as < 60 years and ≥ 60 years) and sex. The classification of ethnicity as non-Hispanic white, non-Hispanic black, Mexican American, or other was employed. Marital status was categorised as follows: married, living with a partner, or living alone. Education levels were stratified as follows: <9 years, between 9 and 12 years, and ≥ 12 years. The division of economic status into three categories was determined by the poverty income ratio (PIR), with classification as follows: low (PIR ≤ 1.3), medium (1.3 3.5). This classification system is outlined in a recent report by the US government ( 29 ).Prior to the MEC interviews, the participants provided a 24-hour dietary recall detailing their caloric intake, including proteins, carbohydrates, and fats. Anthropometric measurements, including height, weight, waist circumference, and body mass index (BMI), were also obtained during the interview. The smoking status of participants was categorised as follows: 'never smokers', 'current smokers' and 'former smokers'. These categories were defined in accordance with the established definitions ( 30 ), with the categorisation of 'current smokers' and 'former smokers' being based on lifetime cigarette consumption. The quantity of alcohol consumed was determined through the administration of self-reported annual intake questionnaires, with a maximum threshold of twelve drinks.Self-reported medical histories of conditions such as hypertension and diabetes were collected using specially designed questionnaires. The multivariable models were adjusted for demographic variables, BMI, lifestyle elements, and comorbidities. The missing data were addressed using multiple imputation, ensuring that no more than 20% of the data points were unfilled. 2.4. Statistical Analyses A descriptive analysis was conducted on all participants. Depending on the data type, continuous data were analysed using either the mean and standard deviation (SD) or the median and interquartile range (IQR). Categorical variables were expressed as proportions (%). The χ² test was employed to compare categorical variables. For the purpose of conducting comparisons involving normally distributed data, the one-way analysis of variance (ANOVA) test was employed, whereas for data exhibiting skewed distributions, the Kruskal–Wallis test was utilised. The relationship between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis was examined using logistic regression models. Model 1 was a rudimentary model. Model 2 took into account demographic data, including age, gender, race/ethnicity, education, marital status and family income, according to the PIR. The Model 3 incorporated both BMI and waist circumference. The fourth model was developed as an extension of the third model, incorporating lifestyle factors such as alcohol and smoking habits, in addition to chronic conditions including hypertension and diabetes. Model 5 enhanced the analysis by incorporating nutritional components, encompassing total caloric and macronutrient intake. Subgroup analyses elucidated the variability in the impact of vitamin B2 on RA, highlighting both the statistical and clinical significance. The application of the radar cross-section (RCS) model was substantiated by fit indices, affirming its suitability for the data under consideration. The analyses were conducted using R (version 4.3.1) and Free Statistics software (version 1.9.2) ( 31 – 32 ). The utilisation of a p-value of less than 0.05 as the criterion for statistical significance is elucidated, with adjustments for multiple comparisons employed to regulate the type I error rate. 3. Results 3.1. Study population characteristics The present study utilised ten cycles of NHANES data from 1999 to 2018. The initial identification process yielded 101,316 potential participants. Of these, 55,081 adults aged 20 years or older completed the interview and underwent MEC examination. Participants lacking RA were excluded from the study, resulting in the removal of 39,994 individuals. Following the exclusion of participants with missing data on vitamin B2 intake (n = 6326), the final analysis was conducted on a total of 8761 participants. The present study's sample comprised 2626 patients with RA (mean age: 61.1 ± 14.0 years; men: 41.3%). The baseline characteristics of the study population, stratified by vitamin E intake, are shown in Table 1 . The analysis revealed that participants diagnosed with rheumatoid arthritis (RA) exhibited a higher probability of having lower intakes of vitamin B2, being younger, and possessing lower levels of education, as well as having a lower PIR (P < 0.01). Table 1 Baseline characteristics of the study participants. Variables Total (n = 8761) No RA(n = 6135) RA(n = 2626) p Gender, n (%) 0.008 Male 3436 (39.2) 2351 (38.3) 1085 (41.3) Female 5325 (60.8) 3784 (61.7) 1541 (58.7) Age, Mean ± SD 62.2 ± 14.1 62.7 ± 14.1 61.1 ± 14.0 < 0.001 Race, n (%) < 0.001 Non-Hispanic white 4949 (56.5) 3850 (62.8) 1099 (41.9) Non-Hispanic black 1762 (20.1) 990 (16.1) 772 (29.4) Mexican American 956 (10.9) 535 (8.7) 421 ( 16 ) Others 1094 (12.5) 760 (12.4) 334 (12.7) PIR, n (%) < 0.001 3.5 2586 (29.5) 2002 (32.6) 584 (22.2) Education, n (%) < 0.001 12 4250 (48.5) 3238 (52.8) 1012 (38.5) Marriage, n (%) < 0.001 Married or living with a partner 5011 (57.2) 3599 (58.7) 1412 (53.8) Living alone 3750 (42.8) 2536 (41.3) 1214 (46.2) BMI, Mean ± SD 30.7 ± 7.5 30.8 ± 7.6 30.6 ± 7.5 0.485 Waist.circumference , Mean ± SD 104.2 ± 16.6 104.4 ± 16.5 103.8 ± 16.6 0.132 Hypertension, n (%) 0.509 No 4321 (49.3) 3040 (49.6) 1281 (48.8) Yes 4440 (50.7) 3095 (50.4) 1345 (51.2) Diabetes, n (%) < 0.001 No 6876 (78.5) 4892 (79.7) 1984 (75.6) Yes 1885 (21.5) 1243 (20.3) 642 (24.4) Drinking, n (%) < 0.001 No 2685 (30.6) 1782 ( 29 ) 903 (34.4) Yes 6076 (69.4) 4353 (71) 1723 (65.6) Smoking, n (%) < 0.001 No 7035 (80.3) 5031 (82) 2004 (76.3) Yes 1726 (19.7) 1104 ( 18 ) 622 (23.7) Total energy intake , Mean ± SD 1874.2 ± 790.7 1885.9 ± 774.2 1846.7 ± 827.5 0.034 Protein intake , Mean ± SD 73.1 ± 33.4 73.5 ± 32.5 72.0 ± 35.3 0.043 Carbohydrate intakes , Mean ± SD 228.6 ± 101.8 229.6 ± 100.8 226.2 ± 103.8 0.147 Fat intakes , Mean ± SD 72.3 ± 37.2 73.0 ± 36.4 70.8 ± 38.9 0.015 Vitamin B2 intake , Mean ± SD 2.0 ± 1.0 2.0 ± 1.1 1.9 ± 1.0 < 0.001 Note : Data presented are Mean ± SD,Median (IQR),or n (%). Abbreviations:RA: Rheumatoid Arthritis;PIR: Poverty Income Ratio༛BMI: Body Mass Index。 3.2. Association between dietary vitamin B2 intake and RA A thorough investigation into the intake of vitamin B2, categorised into tertiles, revealed a notable inverse correlation between vitamin E intake and mortality, with this correlation being sustained after adjustments were made to account for potential confounders. In the event of participants with the lowest vitamin B2 intake (Q1: 2.179 mg/day), the adjusted HRs for mortality were found to be 0.As demonstrated in Table 2 , the respective values were determined to be 87 (95% CI: 0.77–0.99, p = 0.036) and 0.89 (95% CI: 0.76–1.03, p = 0.124), respectively.Consequently, the relationship between vitamin B2 intake and RA revealed a nonlinear curve (p = 0.In the RCS analysis (see Fig. 2 ), it was found that participants with a vitamin B2 intake below 1.7 mg/day had an OR for mortality of 0.658 (95% CI: 0.505–0.857, p = 0.0019) (see Table 3 ). This indicates that for each 1 mg increment in daily dietary vitamin B2 intake, the risk of RA reduced by 34.2%. No significant association was observed between dietary intake of vitamin B2 and prevalence of RA at a daily intake of 1.7 mg or higher (see Table 3 ).This result suggests that beyond a daily intake of 1.7 mg, the risk of prevalence of RA does not decrease further with additional vitamin B2 consumption. Table 2 Association between Vitamin B2 intake and Rheumatoid Arthritis (RA) in the NHANES Enrolled Population. Variable OR(95%CI) Model 1 p-Value Model 2 p-Value Model 3 p-Value Model 4 p-Value Model 5 p-Value Vitamin B2 intake(mg/day) Q1(<1.476) 1(Ref) 1(Ref) 1(Ref) 1(Ref) 1(Ref) Q2(1.476–2.179) 0.71 (0.64 ~ 0.8) 2.179) 0.68 (0.6 ~ 0.76) < 0.001 0.86 (0.76 ~ 0.98) 0.019 0.86 (0.76 ~ 0.97) 0.014 0.86 (0.76 ~ 0.98) 0.019 0.89 (0.76 ~ 1.03) 0.124 P for trend < 0.001 0.017 0.012 0.016 0.11 Notes : Model 1 was crude model. Model 2 was adjusted for Model 1 plus age, sex, race, PIR, education level and marriage status. Model 3 was adjusted for Model 2 plus body mass index and waist.circumference. Model 4 was adjusted for Model 3 plus hypertension, diabetes,smoking status,and drinking status. Model 5 was adjusted for Model 4 plus Total energy intake, Protein intake, Carbohydrate intakes and Fat intakes. Abbreviations: OR, hazard ratio; 95% CI, 95% confidence interval. Table 3 Threshold effect analysis of the relationship of vitamin B2 intake with Rheumatoid Arthritis (RA). Threshold of vitamin B2 intake (mg/day) OR (95%CI) P-value <1.7 0.658 (0.505, 0.857) 0.0019 ≥ 1.7 0.977 (0.885,1.077) 0.6347 Likelihood Ratio test 0.001 Notes: Adjusted for sociodemographic factors including age, sex, marital status, race/ethnicity, education level, Payment-to-Income Ratio (PIR), body mass index, smoking status, drinking status, hypertension, diabetes, energy intake, protein intake, carbohydrate intake, and fat intake. Only 99% of the data are displayed. Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval. 3.3. Stratified Analyses Stratified analyses were conducted within various subgroups in order to evaluate the potential effect modifications of the association between intake of vitamin B2 and the prevalence of rheumatoid arthritis. Subsequent to the stratification of subjects according to criteria including sex, age, BMI, history of hypertension and diabetes, no significant interactions were identified (see Fig. 3 ). 4. Discussion In this large-scale, nationally representative cohort study of the United States population, we identified a significant inverse association between dietary vitamin B₂intake and the prevalence of rheumatoid arthritis (RA). Specifically, higher dietary vitamin B₂intake was associated with a reduced risk of RA, with a notable threshold effect observed at an intake level of approximately 1.7 mg/day. Below this threshold, each unit increase in vitamin B₂intake was associated with a substantial reduction in RA risk. This finding highlights the potential importance of adequate vitamin B₂ intake in modulating RA risk within the general population. Our findings add to the limited body of research exploring the relationship between vitamin B₂ and RA. Previous studies have suggested potential links between vitamin B₂ and other autoimmune or inflammatory diseases( 33 – 34 ), often highlighting the nutrient's role in reducing oxidative stress and supporting mitochondrial function, both of which are implicated in the pathogenesis of such conditions. However, evidence specifically linking vitamin B₂ to RA has been sparse and inconclusive. Our study provides robust, nationally representative data supporting an inverse association, which contrasts with the lack of clear findings in smaller, non-representative studies. The consistency of our results across different demographic subgroups further strengthens the plausibility of this association. The biological functions of vitamin B₂, particularly its role in antioxidant defense and mitochondrial support, provide a plausible mechanism underlying our findings. Vitamin B₂ is essential for maintaining the activity of glutathione reductase, a key enzyme in the glutathione antioxidant system. Impaired function of this system can lead to increased oxidative stress, which is a well-documented contributor to inflammation and autoimmune activation in RA.( 35 – 36 ) Additionally, mitochondrial dysfunction has been implicated in the abnormal activation of immune cells and the perpetuation of a pro-inflammatory state in RA. ( 37 – 39 )By supporting mitochondrial function, adequate vitamin B₂ intake may help maintain immune homeostasis and reduce the risk of RA development. ( 40 – 41 )Our findings align with these mechanistic considerations, suggesting that vitamin B₂ may play a protective role against RA through these pathways. However, our results may differ from previous smaller studies due to several factors. Methodological differences, such as the use of more comprehensive dietary assessment methods and adjustment for a wider range of confounding variables in our study, may account for discrepancies. Additionally, the diverse and nationally representative nature of our sample, compared to more homogeneous populations in prior studies, could explain variations in findings. The use of a large, longitudinal dataset like NHANES also allows for more robust statistical analyses and the detection of subtle associations that may not be evident in smaller studies. This study provides important epidemiological evidence for the potential role of vitamin B₂ in the etiology or management of RA. Future research should aim to address the limitations of our study. Prospective cohort studies are needed to establish the temporal sequence and causality between vitamin B₂ intake and RA risk. Randomized controlled trials (RCTs) should be conducted to evaluate the preventive effects of vitamin B₂ supplementation in high-risk populations or the impact on disease activity and symptoms in individuals with established RA. Future studies should also incorporate more precise measures of exposure, such as long-term biomarkers of vitamin B₂ status, and more definitive outcome measures, such as clinically confirmed RA diagnoses and disease activity scores. Additionally, further investigations into the specific molecular mechanisms through which vitamin B₂ may influence RA are warranted. 5. Conclusion In summary, the present study posits the hypothesis that an elevated intake of vitamin B2 in the diet may be causally associated with the prevalence of rheumatoid arthritis (RA) in the general United States population. The dose-response curve, which has an inflection point at approximately 1.7 mg/day, suggests an ideal level of vitamin B2 intake. The present study demonstrates a significant inverse correlation between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis (RA) in the general United States population. Whilst the present findings do appear to suggest a potential protective role for vitamin B2, further research is required in order to confirm this relationship and to explore the underlying mechanisms. Abbreviations RA Rheumatoid Arthritis PIR Poverty Income Ratio༛BMI : Body Mass Index。 Declarations Acknowledgements The authors thank the NHANES staff, investigators, and participants. Thanks to the Free Statistics team for providing technical assistance and valuable tools for data analysis and visualization. Author contributions Qingling Guo and Shuzhen Yuan performed data collection, analysis and drafted the manuscript. Youping Lin and Yishan Yin participated in data analysis.Qingling Guo conceived the study and revised the manu script. All authors approved the submitted version. D isclosure statement No potential conflict of interest was reported by the author(s). Ethics approval and consent to participate Not applicable. Funding Funding support hasn’t been received for this study. Data availability statement The authors confirm that data supporting the findings of this study are available within the article References GBD 2021 Rheumatoid Arthritis Collaborators. Global, regional, and national burden of rheumatoid arthritis, 1990–2020, and projections to 2050: results from the Global Burden of Disease Study 2021. Lancet Rheumatol. 6 (3), e158–e170. 10.1016/S2665-9913(23)00211-4 (2024). [Malemba, J. J. & Mbuyi Muamba, J. M. The burden of rheumatoid arthritis in low-resource settings: a systematic review. Clin. Rheumatol. 40 (10), 4341–4350. 10.1007/s10067-021-05865-7 (2021). Kobelt, G. & Jönsson, B. 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Nat. Rev. Rheumatol. 15 (6), 331–342. 10.1038/s41584-019-0221-y (2019). Biniecka, M. et al. Mitochondrial Dysfunction in Synovial T Cells Promotes Pro-Inflammatory State in Rheumatoid Arthritis. Ann. Rheum. Dis. 81 (5), 639–647. 10.1136/annrheumdis-2021-221447 (2022). Weinberg, S. E. et al. Mitochondrial Dysfunction Impairs Macrophage Efferocytosis and Promotes Inflammatory Cytokine Production in RA Synovium. Arthritis Rheumatol. 73 (12), 2236–2247. 10.1002/art.41955 (2021). Li, Y. et al. Impaired Mitochondrial Biogenesis in RA Neutrophils Links to Enhanced NETosis and Inflammation. Cell. Death Dis. 14 (2), 102. 10.1038/s41419-023-05647-w (2023). Zhou, S. S. et al. Riboflavin Deficiency Induces Mitochondrial Dysfunction and Activates NLRP3 Inflammasome in CD4 + T Cells: Implications for Autoimmunity. Redox Biol. 46 , 102105. 10.1016/j.redox.2021.102105 (2021). Masullo, M. et al. Mitochondrial Protection by Riboflavin in Autoimmune Inflammation: Restoration of Complex I Activity and Attenuation of ROS Production. Antioxid. (Basel) . 10 (9), 1387. 10.3390/antiox10091387 (2021). Additional Declarations No competing interests reported. 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-7131533","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":495984806,"identity":"48a8d1bc-6e8b-412f-8106-44304b0c6c79","order_by":0,"name":"Qingling Guo#","email":"","orcid":"","institution":"Binhaiwan Central Hospital of Dongguan ， Dongguan","correspondingAuthor":false,"prefix":"","firstName":"Qingling","middleName":"","lastName":"Guo#","suffix":""},{"id":495984807,"identity":"d832ddb0-f07a-4a64-a571-d73a9e0f10cb","order_by":1,"name":"Shuzhen Yuan","email":"","orcid":"","institution":"Southern Medical University, Dongguan People's Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Shuzhen","middleName":"","lastName":"Yuan","suffix":""},{"id":495984808,"identity":"45f06976-4d6b-4299-b8e5-2407d9849ba9","order_by":2,"name":"Youping Lin","email":"","orcid":"","institution":"Binhaiwan Central Hospital of Dongguan","correspondingAuthor":false,"prefix":"","firstName":"Youping","middleName":"","lastName":"Lin","suffix":""},{"id":495984809,"identity":"ad057e88-9604-4582-ba12-685ec5d3b8d5","order_by":3,"name":"Yishan Yin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIie3QsQrCMBCA4SuF6nCQTU4UfIUUQToIvoAP0S5ODo6dRBA61V1x8BX6CJFAXCquBZeKL5Cxo9ZVsXFzyD/n4+4CYLP9YewghQhjQtZaC6ErA0JCRWWZB/1uqqLjLjUgHPKhf0viMS+mQ9n2TIizGlGYE0KBWgLCgHVEA3FhRvUtzn6TyUUA/m4ffie+AvWa4vbPmdwihPzaQHjuJBQlhB7NS4meCSlcl9cEaQ5mhArPKevFCBV/fjI138IOF32s4uVkclrfta7GA9ZrIG9Tf3tus9lsts89AIIwSrvK+bikAAAAAElFTkSuQmCC","orcid":"","institution":"The Armed Police Forces Hospital of Shandong","correspondingAuthor":true,"prefix":"","firstName":"Yishan","middleName":"","lastName":"Yin","suffix":""}],"badges":[],"createdAt":"2025-07-15 14:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7131533/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7131533/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88424279,"identity":"0eefcaf8-012f-41a9-a0ea-a7fdc7a41a4b","added_by":"auto","created_at":"2025-08-06 09:45:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39075,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of the patient selection process.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7131533/v1/059cb6647feb5042812fbe42.png"},{"id":88424281,"identity":"79858e3f-f215-4489-bb24-2015227617f1","added_by":"auto","created_at":"2025-08-06 09:45:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":49913,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA ssociation of vitamin B2 intake with prevalence of rheumatoid arthritis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7131533/v1/195639d367b90b1ad79e6950.png"},{"id":88425430,"identity":"d629541e-9a5c-4d3c-b9e3-d6aab0e0444c","added_by":"auto","created_at":"2025-08-06 09:53:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":77182,"visible":true,"origin":"","legend":"\u003cp\u003etratified analyses of the association between vitamin B2 intake with prevalence of rheumatoid arthritis according to baseline characteristics.\u003c/p\u003e\n\u003cp\u003eAbbreviations: OR, odds ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7131533/v1/e10b7916da80d4997aeb841b.png"},{"id":89635856,"identity":"18fbe19e-c942-40dd-91d7-b50c55d05dcd","added_by":"auto","created_at":"2025-08-22 07:17:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2317425,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7131533/v1/501de649-02de-4713-985e-f2e3a9c5f747.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between Vitamin B2 Intake and Prevalence of Rheumatoid Arthritis in the general United States population: A Cohort Study from the NHANES 1999-2018","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eRheumatoid arthritis (RA) is a chronic autoimmune and inflammatory disease that imposes a substantial global burden.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)It is characterized by a high prevalence, significant disability, and considerable economic strain. RA affects millions of individuals worldwide, often leading to joint deformities, impaired mobility, and reduced quality of life. The chronic inflammatory nature of RA not only impacts physical health but also places a significant economic burden on healthcare systems and affected individuals through medical costs and lost productivity.༈3\u0026ndash;5༉\u003c/p\u003e\u003cp\u003eRA is fundamentally an autoimmune disorder driven by chronic inflammation. The pathogenesis of RA involves the dysregulation of immune responses, leading to the production of autoantibodies and the infiltration of immune cells into the synovial joints. (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)This results in persistent inflammation, cartilage destruction, and bone erosion. The chronic nature of RA and its associated inflammation contribute to systemic complications and comorbidities, further exacerbating the disease burden.\u003c/p\u003e\u003cp\u003eVitamin B₂, also known as riboflavin, is an essential micronutrient with several critical physiological functions. It plays a vital role in energy metabolism, particularly through its involvement in mitochondrial function. Riboflavin is a precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), which are essential cofactors for various enzymatic reactions. These reactions are crucial for the production of adenosine triphosphate (ATP), the primary energy currency of the cell. Additionally, vitamin B₂ is integral to antioxidant defense mechanisms, specifically by maintaining the activity of glutathione reductase, an enzyme that helps recycle glutathione, a key antioxidant in the body. ༈11\u0026ndash;13༉Riboflavin also supports cell growth and repair, contributing to overall cellular health.༈14\u0026ndash;15༉\u003c/p\u003e\u003cp\u003eThe potential link between vitamin B₂ and RA is biologically plausible. (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)Oxidative stress is a key factor in the pathogenesis of RA, contributing to the activation of inflammatory pathways and the production of pro-inflammatory cytokines. Vitamin B₂, through its antioxidant properties, may help mitigate oxidative stress and reduce inflammation. Furthermore, mitochondrial dysfunction has been implicated in the activation of immune cells and the perpetuation of inflammation in RA. Vitamin B₂, by supporting mitochondrial function, may play a role in regulating immune responses and reducing the risk of RA. Deficiencies in vitamin B₂ have been associated with the dysregulation of inflammatory pathways, such as the activation of nuclear factor-kappa B (NF-κB)(\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), a transcription factor that controls transcription of DNA, cytokine production, and cell survival, thus potentially contributing to the development of RA.\u003c/p\u003e\u003cp\u003eDespite the biological plausibility of a link between vitamin B₂ and RA, current epidemiological evidence is limited and inconsistent. Few studies have examined this relationship, and most have been conducted in small or non-representative populations. There is a significant gap in the literature regarding large-scale, nationally representative studies that can provide robust insights into the association between vitamin B₂ intake and RA prevalence in the general population.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Study design and population\u003c/h2\u003e\u003cp\u003eThe National Health and Nutrition Examination Survey (NHANES)(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), conducted by the Centers for Disease Control and Prevention (CDC), is a comprehensive health and nutrition status assessment of the United States (US) population. It includes data on vitamin B2 consumption and its association with rheumatic diseases, such as arthritis and rheumatoid arthritis (RA). The present study employed the multimodal assessment techniques of the NHANES, encompassing interviews, physical evaluations and laboratory analyses. The specific methodologies, including the evaluation of vitamin B2 intake, are detailed on the NHANES website. The present study was conducted in accordance with the ethical standards set by the CDC's Institutional Review Board and adhered to the NHANES protocol (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), ensuring the safeguarding of participants' rights and confidentiality. Prior to participation, all subjects provided written informed consent, thereby ensuring their voluntary engagement and ensuring full comprehension of the study's objectives and procedures. The research utilised data from a pre-approved NHANES, which had been reviewed by an institutional review board. The board determined that our study fulfilled all ethical standards and granted an exemption from further review, due to the use of de-identified data from a preexisting, approved survey.\u003c/p\u003e\u003cp\u003eThe prospective cohort study utilised the NHANES data from 1999 to 2018. Stringent exclusion criteria were applied in order to ensure a precise sample size. Individuals with incomplete records of vitamin B2 intake, or an unverified diagnosis of RA, were excluded from the study. This ensured the precision and dependability of the study population. The methodology of participant selection, including the inclusion and exclusion criteria, is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and presented as an accompanying flowchart.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Definition of independent and dependent variables\u003c/h2\u003e\u003cp\u003eIn the present study, the dietary intake of vitamin E was measured using a 24-hour recall method that has been validated for accuracy. This method was conducted during NHANES dietary interviews at the Mobile Examination Center (MEC). The participants reported their intake of vitamin E during the course of these interviews. This information was then quantified using a comprehensive food composition database in order to standardise the subsequent nutrient assessment.\u003c/p\u003e\u003cp\u003eThe diagnosis of rheumatoid arthritis (RA) was determined through the implementation of a two-stage self-report questionnaire (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Initially, the participants were asked whether a healthcare provider had diagnosed them with arthritis, with emphasis on clarity and precision in the questions posed. The responses given were limited to \"yes\" or \"no\", with a positive response leading to a subsequent inquiry. Participants who responded in the affirmative were requested to identify the specific type of arthritis diagnosed by a healthcare provider from an exhaustive list that included all major forms, with additional options for \"refused\" and \"do not know\" to account for any lack of information.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Covariates\u003c/h2\u003e\u003cp\u003eThe present study meticulously evaluated various covariates with a view to enhancing analytical precision, in alignment with the extant scholarly consensus (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The demographic variables encompassed age (categorised as \u0026lt;\u0026thinsp;60 years and \u0026ge;\u0026thinsp;60 years) and sex. The classification of ethnicity as non-Hispanic white, non-Hispanic black, Mexican American, or other was employed. Marital status was categorised as follows: married, living with a partner, or living alone. Education levels were stratified as follows: \u0026lt;9 years, between 9 and 12 years, and \u0026ge;\u0026thinsp;12 years. The division of economic status into three categories was determined by the poverty income ratio (PIR), with classification as follows: low (PIR\u0026thinsp;\u0026le;\u0026thinsp;1.3), medium (1.3\u0026thinsp;\u0026lt;\u0026thinsp;PIR\u0026thinsp;\u0026le;\u0026thinsp;3.5), and high income (PIR\u0026thinsp;\u0026gt;\u0026thinsp;3.5). This classification system is outlined in a recent report by the US government (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).Prior to the MEC interviews, the participants provided a 24-hour dietary recall detailing their caloric intake, including proteins, carbohydrates, and fats. Anthropometric measurements, including height, weight, waist circumference, and body mass index (BMI), were also obtained during the interview. The smoking status of participants was categorised as follows: 'never smokers', 'current smokers' and 'former smokers'. These categories were defined in accordance with the established definitions (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), with the categorisation of 'current smokers' and 'former smokers' being based on lifetime cigarette consumption. The quantity of alcohol consumed was determined through the administration of self-reported annual intake questionnaires, with a maximum threshold of twelve drinks.Self-reported medical histories of conditions such as hypertension and diabetes were collected using specially designed questionnaires. The multivariable models were adjusted for demographic variables, BMI, lifestyle elements, and comorbidities. The missing data were addressed using multiple imputation, ensuring that no more than 20% of the data points were unfilled.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Statistical Analyses\u003c/h2\u003e\u003cp\u003eA descriptive analysis was conducted on all participants. Depending on the data type, continuous data were analysed using either the mean and standard deviation (SD) or the median and interquartile range (IQR). Categorical variables were expressed as proportions (%). The χ\u0026sup2; test was employed to compare categorical variables. For the purpose of conducting comparisons involving normally distributed data, the one-way analysis of variance (ANOVA) test was employed, whereas for data exhibiting skewed distributions, the Kruskal\u0026ndash;Wallis test was utilised. The relationship between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis was examined using logistic regression models. Model 1 was a rudimentary model. Model 2 took into account demographic data, including age, gender, race/ethnicity, education, marital status and family income, according to the PIR. The Model 3 incorporated both BMI and waist circumference. The fourth model was developed as an extension of the third model, incorporating lifestyle factors such as alcohol and smoking habits, in addition to chronic conditions including hypertension and diabetes. Model 5 enhanced the analysis by incorporating nutritional components, encompassing total caloric and macronutrient intake. Subgroup analyses elucidated the variability in the impact of vitamin B2 on RA, highlighting both the statistical and clinical significance. The application of the radar cross-section (RCS) model was substantiated by fit indices, affirming its suitability for the data under consideration. The analyses were conducted using R (version 4.3.1) and Free Statistics software (version 1.9.2) (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). The utilisation of a p-value of less than 0.05 as the criterion for statistical significance is elucidated, with adjustments for multiple comparisons employed to regulate the type I error rate.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Study population characteristics\u003c/h2\u003e\u003cp\u003eThe present study utilised ten cycles of NHANES data from 1999 to 2018. The initial identification process yielded 101,316 potential participants. Of these, 55,081 adults aged 20 years or older completed the interview and underwent MEC examination. Participants lacking RA were excluded from the study, resulting in the removal of 39,994 individuals. Following the exclusion of participants with missing data on vitamin B2 intake (n\u0026thinsp;=\u0026thinsp;6326), the final analysis was conducted on a total of 8761 participants. The present study's sample comprised 2626 patients with RA (mean age: 61.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0 years; men: 41.3%). The baseline characteristics of the study population, stratified by vitamin E intake, are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The analysis revealed that participants diagnosed with rheumatoid arthritis (RA) exhibited a higher probability of having lower intakes of vitamin B2, being younger, and possessing lower levels of education, as well as having a lower PIR (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\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\u003eBaseline characteristics of the study participants.\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=\"char\" char=\".\" 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=\"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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;8761)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo RA(n\u0026thinsp;=\u0026thinsp;6135)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRA(n\u0026thinsp;=\u0026thinsp;2626)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender, n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3436 (39.2)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2351 (38.3)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1085 (41.3)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e5325 (60.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e3784 (61.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1541 (58.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e62.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e62.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e61.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRace, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNon-Hispanic white\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e4949 (56.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e3850 (62.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1099 (41.9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNon-Hispanic black\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1762 (20.1)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e990 (16.1)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e772 (29.4)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMexican American\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e956 (10.9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e535 (8.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e421\u003c/b\u003e (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOthers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1094 (12.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e760 (12.4)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e334 (12.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePIR, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;1.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e2750 (31.4)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e1692 (27.6)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1058 (40.3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1.3-3,5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e3425 (39.1)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e2441 (39.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e984 (37.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e\u0026gt;3.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e2586 (29.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e2002 (32.6)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e584 (22.2)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEducation, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1036 (11.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e566 (9.2)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e470 (17.9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e9\u0026ndash;12\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e3475 (39.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e2331\u003c/b\u003e (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1144 (43.6)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e\u0026gt;12\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e4250 (48.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e3238 (52.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1012 (38.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMarriage, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMarried or living\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ewith a partner\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e5011 (57.2)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e3599 (58.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1412 (53.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLiving alone\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e3750 (42.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e2536 (41.3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1214 (46.2)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e30.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e30.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e30.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.485\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWaist.circumference\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e104.2\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e104.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e103.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.132\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHypertension, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.509\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e4321 (49.3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e3040 (49.6)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1281 (48.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e4440 (50.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e3095 (50.4)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1345 (51.2)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDiabetes, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e6876 (78.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4892 (79.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1984 (75.6)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1885 (21.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e1243 (20.3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e642 (24.4)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDrinking, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e2685 (30.6)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e1782\u003c/b\u003e (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e903 (34.4)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e6076 (69.4)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4353 (71)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1723 (65.6)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmoking, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e7035 (80.3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e5031 (82)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e2004 (76.3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1726 (19.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e1104\u003c/b\u003e (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e622 (23.7)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTotal energy intake\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1874.2\u0026thinsp;\u0026plusmn;\u0026thinsp;790.7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e1885.9\u0026thinsp;\u0026plusmn;\u0026thinsp;774.2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1846.7\u0026thinsp;\u0026plusmn;\u0026thinsp;827.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.034\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eProtein intake\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e73.1\u0026thinsp;\u0026plusmn;\u0026thinsp;33.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e73.5\u0026thinsp;\u0026plusmn;\u0026thinsp;32.5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e72.0\u0026thinsp;\u0026plusmn;\u0026thinsp;35.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.043\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCarbohydrate intakes\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e228.6\u0026thinsp;\u0026plusmn;\u0026thinsp;101.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e229.6\u0026thinsp;\u0026plusmn;\u0026thinsp;100.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e226.2\u0026thinsp;\u0026plusmn;\u0026thinsp;103.8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.147\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFat intakes\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e72.3\u0026thinsp;\u0026plusmn;\u0026thinsp;37.2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e73.0\u0026thinsp;\u0026plusmn;\u0026thinsp;36.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e70.8\u0026thinsp;\u0026plusmn;\u0026thinsp;38.9\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eVitamin B2 intake\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eNote : Data presented are Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD,Median (IQR),or n (%).\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eAbbreviations:RA: Rheumatoid Arthritis;PIR: Poverty Income Ratio༛BMI: Body Mass Index。\u003c/b\u003e\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\u003e3.2. Association between dietary vitamin B2 intake and RA\u003c/h2\u003e\u003cp\u003eA thorough investigation into the intake of vitamin B2, categorised into tertiles, revealed a notable inverse correlation between vitamin E intake and mortality, with this correlation being sustained after adjustments were made to account for potential confounders. In the event of participants with the lowest vitamin B2 intake (Q1: \u0026lt; 1.476 mg/day) being compared with those in quartiles Q2 (1.476\u0026ndash;2.179 mg/day) and Q3 (\u0026gt;\u0026thinsp;2.179 mg/day), the adjusted HRs for mortality were found to be 0.As demonstrated in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the respective values were determined to be 87 (95% CI: 0.77\u0026ndash;0.99, p\u0026thinsp;=\u0026thinsp;0.036) and 0.89 (95% CI: 0.76\u0026ndash;1.03, p\u0026thinsp;=\u0026thinsp;0.124), respectively.Consequently, the relationship between vitamin B2 intake and RA revealed a nonlinear curve (p\u0026thinsp;=\u0026thinsp;0.In the RCS analysis (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), it was found that participants with a vitamin B2 intake below 1.7 mg/day had an OR for mortality of 0.658 (95% CI: 0.505\u0026ndash;0.857, p\u0026thinsp;=\u0026thinsp;0.0019) (see Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This indicates that for each 1 mg increment in daily dietary vitamin B2 intake, the risk of RA reduced by 34.2%. No significant association was observed between dietary intake of vitamin B2 and prevalence of RA at a daily intake of 1.7 mg or higher (see Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).This result suggests that beyond a daily intake of 1.7 mg, the risk of prevalence of RA does not decrease further with additional vitamin B2 consumption.\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\u003e Association between Vitamin B2 intake and Rheumatoid Arthritis (RA) in the NHANES Enrolled Population.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"11\"\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=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"8\" nameend=\"c9\" namest=\"c2\"\u003e\u003cp\u003eOR(95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eModel 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eModel 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eModel 3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eModel 4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eModel 5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVitamin B2\u003c/p\u003e\u003cp\u003eintake(mg/day)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eQ1(\u0026lt;1.476)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1(Ref)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1(Ref)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e1(Ref)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e1(Ref)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e1(Ref)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eQ2(1.476\u0026ndash;2.179)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.71 (0.64\u0026thinsp;~\u0026thinsp;0.8)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.86 (0.76\u0026thinsp;~\u0026thinsp;0.97)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.86 (0.76\u0026thinsp;~\u0026thinsp;0.96)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e0.86 (0.77\u0026thinsp;~\u0026thinsp;0.97)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e0.87 (0.77\u0026thinsp;~\u0026thinsp;0.99)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.036\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eQ3(\u0026gt;2.179)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0.68 (0.6\u0026thinsp;~\u0026thinsp;0.76)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.86 (0.76\u0026thinsp;~\u0026thinsp;0.98)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.019\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.86 (0.76\u0026thinsp;~\u0026thinsp;0.97)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e0.86 (0.76\u0026thinsp;~\u0026thinsp;0.98)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e0.019\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e0.89 (0.76\u0026thinsp;~\u0026thinsp;1.03)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.124\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eP for trend\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e\u003cb\u003e0.11\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cb\u003eNotes\u003c/b\u003e:\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cb\u003eModel 1 was crude model.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cb\u003eModel 2 was adjusted for Model 1 plus age, sex, race, PIR, education level and marriage status.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cb\u003eModel 3 was adjusted for Model 2 plus body mass index and waist.circumference.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cb\u003eModel 4 was adjusted for Model 3 plus hypertension, diabetes,smoking status,and drinking status.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cb\u003eModel 5 was adjusted for Model 4 plus Total energy intake, Protein intake, Carbohydrate intakes and Fat intakes.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cb\u003eAbbreviations: OR, hazard ratio; 95% CI, 95% confidence interval.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u0026ensp;Threshold effect analysis of the relationship of vitamin B2 intake with Rheumatoid Arthritis (RA).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThreshold of vitamin B2 intake (mg/day)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOR (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;1.7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.658 (0.505, 0.857)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.0019\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;1.7\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.977 (0.885,1.077)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.6347\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLikelihood Ratio test\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cb\u003eNotes: Adjusted for sociodemographic factors including age, sex, marital status, race/ethnicity, education level, Payment-to-Income Ratio (PIR), body mass index, smoking status, drinking status, hypertension, diabetes, energy intake, protein intake, carbohydrate intake, and fat intake. Only 99% of the data are displayed. Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.3. Stratified Analyses\u003c/h2\u003e\u003cp\u003eStratified analyses were conducted within various subgroups in order to evaluate the potential effect modifications of the association between intake of vitamin B2 and the prevalence of rheumatoid arthritis. Subsequent to the stratification of subjects according to criteria including sex, age, BMI, history of hypertension and diabetes, no significant interactions were identified (see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this large-scale, nationally representative cohort study of the United States population, we identified a significant inverse association between dietary vitamin B₂intake and the prevalence of rheumatoid arthritis (RA). Specifically, higher dietary vitamin B₂intake was associated with a reduced risk of RA, with a notable threshold effect observed at an intake level of approximately 1.7 mg/day. Below this threshold, each unit increase in vitamin B₂intake was associated with a substantial reduction in RA risk. This finding highlights the potential importance of adequate vitamin B₂ intake in modulating RA risk within the general population.\u003c/p\u003e\u003cp\u003eOur findings add to the limited body of research exploring the relationship between vitamin B₂ and RA. Previous studies have suggested potential links between vitamin B₂ and other autoimmune or inflammatory diseases(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), often highlighting the nutrient's role in reducing oxidative stress and supporting mitochondrial function, both of which are implicated in the pathogenesis of such conditions. However, evidence specifically linking vitamin B₂ to RA has been sparse and inconclusive. Our study provides robust, nationally representative data supporting an inverse association, which contrasts with the lack of clear findings in smaller, non-representative studies. The consistency of our results across different demographic subgroups further strengthens the plausibility of this association.\u003c/p\u003e\u003cp\u003eThe biological functions of vitamin B₂, particularly its role in antioxidant defense and mitochondrial support, provide a plausible mechanism underlying our findings. Vitamin B₂ is essential for maintaining the activity of glutathione reductase, a key enzyme in the glutathione antioxidant system. Impaired function of this system can lead to increased oxidative stress, which is a well-documented contributor to inflammation and autoimmune activation in RA.(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) Additionally, mitochondrial dysfunction has been implicated in the abnormal activation of immune cells and the perpetuation of a pro-inflammatory state in RA. (\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e)By supporting mitochondrial function, adequate vitamin B₂ intake may help maintain immune homeostasis and reduce the risk of RA development. (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e)Our findings align with these mechanistic considerations, suggesting that vitamin B₂ may play a protective role against RA through these pathways.\u003c/p\u003e\u003cp\u003eHowever, our results may differ from previous smaller studies due to several factors. Methodological differences, such as the use of more comprehensive dietary assessment methods and adjustment for a wider range of confounding variables in our study, may account for discrepancies. Additionally, the diverse and nationally representative nature of our sample, compared to more homogeneous populations in prior studies, could explain variations in findings. The use of a large, longitudinal dataset like NHANES also allows for more robust statistical analyses and the detection of subtle associations that may not be evident in smaller studies.\u003c/p\u003e\u003cp\u003eThis study provides important epidemiological evidence for the potential role of vitamin B₂ in the etiology or management of RA. Future research should aim to address the limitations of our study. Prospective cohort studies are needed to establish the temporal sequence and causality between vitamin B₂ intake and RA risk. Randomized controlled trials (RCTs) should be conducted to evaluate the preventive effects of vitamin B₂ supplementation in high-risk populations or the impact on disease activity and symptoms in individuals with established RA. Future studies should also incorporate more precise measures of exposure, such as long-term biomarkers of vitamin B₂ status, and more definitive outcome measures, such as clinically confirmed RA diagnoses and disease activity scores. Additionally, further investigations into the specific molecular mechanisms through which vitamin B₂ may influence RA are warranted.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn summary, the present study posits the hypothesis that an elevated intake of vitamin B2 in the diet may be causally associated with the prevalence of rheumatoid arthritis (RA) in the general United States population. The dose-response curve, which has an inflection point at approximately 1.7 mg/day, suggests an ideal level of vitamin B2 intake. The present study demonstrates a significant inverse correlation between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis (RA) in the general United States population. Whilst the present findings do appear to suggest a potential protective role for vitamin B2, further research is required in order to confirm this relationship and to explore the underlying mechanisms.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eRA\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e\u003cb\u003eRheumatoid Arthritis\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003ePIR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e\u003cb\u003ePoverty Income Ratio༛BMI\u003c/b\u003e:\u003cb\u003eBody Mass Index。\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the NHANES staff, investigators, and participants. Thanks to the Free Statistics team for providing technical assistance and valuable tools for data analysis and visualization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQingling Guo and Shuzhen Yuan performed data collection, analysis and drafted the manuscript. Youping Lin and Yishan Yin participated in data analysis.Qingling Guo conceived the study and revised the manu script. All authors approved the submitted version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e\u003cstrong\u003eisclosure statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflict of interest was reported by the author(s).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding support hasn\u0026rsquo;t been received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that data supporting the findings of this study are available within the article\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD 2021 Rheumatoid Arthritis Collaborators. 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(Basel)\u003c/em\u003e. \u003cb\u003e10\u003c/b\u003e (9), 1387. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/antiox10091387\u003c/span\u003e\u003cspan address=\"10.3390/antiox10091387\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\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":"Rheumatoid arthritis (RA ), dietary vitamin B2 intake, NHANES, association, cohort study","lastPublishedDoi":"10.21203/rs.3.rs-7131533/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7131533/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe relationship between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis (RA) in the general United States population is an area of research which has not yet been extensively explored in the field of nutritional epidemiology, highlighting a significant research gap.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eThe present study aims to explore the potential association between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis in the general United States population.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis longitudinal cohort study analysed 8,761 individuals from the United States aged 20 years or older who participated in the National Health and Nutrition Examination Survey from 1999 to 2018. A comprehensive data set pertaining to the prevalence of rheumatoid arthritis (RA), the intake of dietary vitamin B2, and pertinent confounding variables was systematically collected and analysed. The potential association was investigated by means of a Cox regression analysis and spline curve fitting.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFollowing the adjustment for confounding factors, a significant inverse relationship was identified between dietary intake of vitamin B2 and the prevalence of rheumatoid arthritis in the general United States population. The adjusted hazard ratios (HRs) for the second (Q2) and third (Q3) tertiles of vitamin B2 intake were 0.87 and 0.89, respectively. Non-linear modelling indicated a threshold effect, characterised by a curve that associated dietary intake of vitamin B2 with rheumatoid arthritis risk prevalence (p\u0026thinsp;=\u0026thinsp;0.021). A critical analysis of the extant literature revealed an intake threshold of 1.7 mg/day, below which each unit increment in vitamin B2 intake was associated with a 34.2% decrease in the prevalence of rheumatoid arthritis risk (HR\u0026thinsp;=\u0026thinsp;0.658). In contrast, no substantial correlation was identified between intake levels that exceeded this threshold and the prevalence of rheumatoid arthritis risk (HR\u0026thinsp;=\u0026thinsp;0.977).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe findings of this study suggest a positive correlation between increased dietary intake of vitamin B2 and a reduced risk of rheumatoid arthritis in the general United States population. The dose-response relationship exhibits a non-linear pattern, featuring a critical inflection point at an intake of approximately 1.7 mg/day.\u003c/p\u003e","manuscriptTitle":"Association between Vitamin B2 Intake and Prevalence of Rheumatoid Arthritis in the general United States population: A Cohort Study from the NHANES 1999-2018","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-06 09:45:52","doi":"10.21203/rs.3.rs-7131533/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":"461a1fbb-688f-4fbe-aab9-8f586902c415","owner":[],"postedDate":"August 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":52678876,"name":"Health sciences/Diseases"},{"id":52678877,"name":"Health sciences/Health care"},{"id":52678878,"name":"Health sciences/Medical research"},{"id":52678879,"name":"Health sciences/Rheumatology"},{"id":52678880,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-08-22T07:09:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-06 09:45:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7131533","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7131533","identity":"rs-7131533","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}