Association between dietary zinc intake and herpes simplex virus seropositivity in US adults: A cross-sectional study

Association between dietary zinc intake and herpes simplex virus seropositivity in US adults: A cross-sectional study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association between dietary zinc intake and herpes simplex virus seropositivity in US adults: A cross-sectional study Chunhua Liu, Yingguo Liu, Jingjing Liu, Zhaoyong Lv, Yanan Qin, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7180170/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: Zinc is an essential trace element crucial for immune function maintenance. However, the relationship between dietary zinc intake and herpes simplex virus (HSV) infection has not been elucidated. This study determined the association between dietary zinc intake and HSV seropositivity, providing new insights into HSV prevention and treatment. Methods: This cross-sectional observational study used data from the United States National Health and Nutrition Examination Survey, conducted between 2007 and 2016. This study cohort comprised adults who provided comprehensive 24-h dietary recall data. Multivariate logistic regression, stratified analysis with interaction, restricted cubic splines (RCS), and threshold effect analyses were used to explore the potential association between dietary zinc intake and HSV seropositivity. Results: In total, 10,689 participants aged 20–49 years were enrolled. Of which, 9,290 (69.9%) were positive for HSV serology (HSV group, including HSV-1 and HSV-2 infections), with 55.5% being female and an average age of 35.9 years. In the fully adjusted model, a significant inverse association was observed between dietary zinc intake and HSV seropositivity (quartile variable, Q4 vs Q1, Odd’s ratio: 0.80, 95% confidence intervals: [0.7–0.91], p = 0.003). Consequently, the association between dietary zinc intake and HSV seropositivity exhibited an L-shaped curve (p <0.001) in the RCS，with an estimated threshold of 16.87 mg/day. Conclusion: This study suggests that a higher intake of dietary zinc may be linked to a lower prevalence of HSV seropositivity. Notably, among adults in the US, an L-shaped relationship was observed between dietary zinc intake and HSV seropositivity, with an estimated threshold of 16.87mg/day. zinc herpes simplex virus association National Health and Nutrition Examination Survey risk assessment Figures Figure 1 Figure 2 Figure 3 Key points Overall, 9,290 (69.9%) were positive for HSV serology, with 55.5% being female and an average age of 35.9 years. In the fully adjusted model, a significant inverse association was observed between dietary zinc intake and HSV seropositivity. 1. Introduction Viral infections are a major cause of mortality in humans and animals worldwide. 1 The herpes simplex virus (HSV) is an enveloped virus that infects more than half the world's population. 2 There are two types of HSV: HSV-1 and HSV-2. 3 HSV-1 is frequently associated with several diseases including herpetic stomatitis, recurrent herpes labialis, erythema multiforme, cranial neuropathies, and oral squamous cell carcinoma. 4 , 5 HSV-2 causes genital herpes and increases susceptibility to human immunodeficiency virus (HIV) infections, 6 which causes lesions at or near the point of entry into the body and establish a latent infection in the sensory ganglia. This latency often increases HSV pathogenicity. Early identification of HSV risk provides an opportunity to delay or prevent disease onset. Zinc is a crucial trace element for human growth, development, and the maintenance of immune functions. [7] Its immunomodulatory properties extend to both innate and adaptive immunity, wherein it participates in lymphocyte differentiation, cytokine production, and phagocytic activity. [8–10] Zn status serves as a critical determinant of antiviral immunity, with Zn-deficient populations demonstrating heightened susceptibility to viral infections including HIV and hepatitis C virus. [11, 12] Moreover, emerging evidence has revealed the direct inhibitory effects of zinc on HSV replication through mechanisms involving viral DNA polymerase interference and capsid destabilization. [13–15] Although the interplay between serum Zn status and viral pathogenesis has been extensively investigated, the specific relationship between dietary Zn intake and HSV seropositivity remains unexplored. Further research is required to understand the relationship between dietary Zn intake and HSV seropositivity. Data from the National Health and Nutrition Examination Survey (NHANES) were utilized in this study. 2. Materials and Methods 2.1 Data Source and Study population This cross-sectional study used NHANES data ( http://www.cdc.gov/nchs/nhanes.htm ) from 2007 to 2016, collected by the Centers for Disease Control and Prevention. NHANES aims to evaluate the health and nutritional status of non-institutionalized Americans using a stratified multistage probability survey method. It collects demographic and health information through home visits, screenings, and laboratory tests conducted at a Mobile Examination Center. The Ethics Review Committee of the National Center for Health Statistics approved this study, and all participants provided written informed consent. Notably, secondary analysis did not require additional Institutional Review Board approval. Our study included individuals ≥ 20-years-old who completed the interview process. Those lacking serum Zn levels and HSV test results were excluded from the analysis. 2.2 Indices and methods 2.2.1 General data collection The data included age, sex, marital status, poverty income ratio, body mass index (BMI), smoking, alcohol consumption, diabetes, hypertension, cardiovascular disease (including congestive heart failure, angina, and heart attack), and serum markers (albumin, total cholesterol, and creatinine). Age and BMI were continuous variables, whereas sex was a categorical variable. Marital status was categorized into four types: unmarried, married, has a regular sexual partner, and others (e.g., widowed, divorced, or separated). Socioeconomic status was measured using the PIR scale and divided into three groups with cutoff points of 1.30 and 3.50. Smoking status was classified into three groups: never smoked ( 100 cigarettes, but quit smoking), and current smoker (> 100 cigarettes and still smoking). Drinking history was categorized as severe or moderate. 2.2.2 Serum Zn test Total Zn intake was calculated as the sum of dietary Zn intake and Zn supplementation.This study evaluated the dietary Zn intake of various foods and beverages. Dietary intake was assessed through in-person interviews conducted at a NHANES mobile examination clinics. The participants completed two separate 24-h dietary recalls. The first recall was conducted face-to-face at a Mobile Examination Center by skilled interviewers, and the second was conducted via telephone or mail within 3–10 d. To avoid recall errors, only the first 24 h data were used. Zn intake data, measured in mg, were analyzed as both continuous and categorical variables (Q1–Q4), with the Zn intake distribution divided into four quartiles: Q1 ( 14.83mg/24h), representing low-to-high intake levels. 2.2.3 HSV antibody measurement HSV-1 and HSV-2 infections were detected using strain-specific glycoproteins. This analysis was conducted on individuals aged 20–49 years who were tested for antibodies against HSV-1 and HSV-2 immunoglobulin G. Positive results for either HSV-1 or HSV-2 were used as diagnostic criteria for the respective infections, whereas negative results for both antibodies indicated that the individual was not infected with HSV. 2.3 Statistical analysis Data were analyzed using the statistical software packages R 3.3.2 ( http://wwwR-project.org , The RFoundation) and Free Statistics software version 2.1. Continuous variables are presented as mean ± standard deviation, and categorical variables are presented as frequencies. The basic characteristic differences among HSV subgroups for continuous and categorical variableswere tested by the one-way analysis of variance and chi-squared,respectively. Patients were divided into four groups based on dietary zinc levels (CA < 8 mg/dL,four quartiles:(< 6.99mg/24h, 6.99 ≤ Zn<10.26mg/24h, 10.26 ≤ Zn<14.83mg/24h, ≥ 14.83mg/24h). Multivariate analysis was performed to investigate the relationship between Zn intake and HSV prevalence. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between Zn intake and HSV infection. Multiple covariates were considered for the logistic regression analysis and divided into three models. The results were not adjusted in model I. To investigate independent associations, variables including age, gender, marital status, and poverty-income ratio were adjusted for subgroups in Model II. Finally, age, gender, marital status, poverty-income ratio, body mass index, congestive heart failure, angina, heart attack, smoking, alcohol consumption, diabetes, hypertension, albumin, total cholesterol, and creatinine were adjusted in model III. Smooth curve fitting was adopted to assess the nonlinear relationship between Zn intake and HSV. The regression models contain a quadratic term to test for nonlinearity, with the regression results presented as ORs with 95% CI. The inflection point was determined using a two-segment logic model and recursive algorithm. Less than 5% of the missing data were processed using the listwise deletion method. By a two-tailed testing, a p-value of < 0.05 was declared significant. 3. Results 3.1 Patient inclusion process and outcomes Of the 29,201 participants, 15,868 were excluded from the study due to incomplete HSV-1 and HSV-2 data, another 841 patients were excluded due to missing dietary data, and 1,802 individuals were excluded owing to their missing covariate information (Fig. 1 ). 3.2 Baseline characteristics Overall, 10,689 patients were included in this analysis, of which, 7,321 (69.9%) cases were HSV seropositive (HSV group, HSV-1 and HSV-2 seropositive). The baseline characteristics of the groups have been stratified according to HSV (Table 1 ), with a mean age of 36.1 years, and 53.4% female ration. Compared to the HSV seronegative group, those in the HSV seropositive group tend to be older, higher sex partner, lower serum albumin and creatinine levels, high cholesterol level, higher BMI, and are more likely to have CVDs. Furthermore, smoking and alcohol history were more common in the infection groups (p < 0.05). The mean Zn level was 11.7 mg/day (8.2 mg/day), which was significantly lower than that of the control. Table 1 The baseline characteristics and demographic characteristics of participants Variables Total (n = 10689) Non-HSV(n = 3368) HSV(n = 7321) p Age,Mean ± SD 34.6 ± 8.7 31.5 ± 8.5 36.1 ± 8.4 < 0.001 Sex,n(%) < 0.001 Male 5340 (50.0) 1932 (57.4) 3408 (46.6) Female 5349 (50.0) 1436 (42.6) 3913 (53.4) Marry,n(%) < 0.001 Married 4984 (46.6) 1490 (44.2) 3494 (47.7) Never married 3111 (29.1) 1302 (38.7) 1809 (24.7) Living with partner 1353 (12.7) 350 (10.4) 1003 (13.7) Other 1241 (11.6) 226 (6.7) 1015 (13.9) Poverty-income ratio, n(%) 3.50 3123 (29.2) 1328 (39.4) 1795 (24.5) Smoke,n(%) < 0.001 never 6439 (60.2) 2231 (66.2) 4208 (57.5) former 1573 (14.7) 460 (13.7) 1113 (15.2) now 2677 (25.0) 677 (20.1) 2000 (27.3) Alcohol user, n(%) < 0.001 never 1308 (12.2) 357 (10.6) 951 (13) former 1123 (10.5) 267 (7.9) 856 (11.7) mild 3084 (28.9) 1143 (33.9) 1941 (26.5) moderate 1995 (18.7) 675 (20) 1320 (18) heavy 3179 (29.7) 926 (27.5) 2253 (30.8) BMI, Mean ± SD 29.0 ± 7.3 27.9 ± 7.1 29.5 ± 7.3 < 0.001 Angina, n(%) 0.027 no 10621 (99.4) 3355 (99.6) 7266 (99.2) yes 68 ( 0.6) 13 (0.4) 55 (0.8) Heart attack, n(%) < 0.001 no 10594 (99.1) 3355 (99.6) 7239 (98.9) yes 95 ( 0.9) 13 (0.4) 82 (1.1) Congestive heart failure, n(%) < 0.001 No 10613 (99.3) 3359 (99.7) 7254 (99.1) yes 76 ( 0.7) 9 (0.3) 67 (0.9) Hypertension,n(%) < 0.001 no 8396 (78.5) 2806 (83.3) 5590 (76.4) yes,n(%) 2293 (21.5) 562 (16.7) 1731 (23.6) DM < 0.001 no 9880 (92.4) 3202 (95.1) 6678 (91.2) yes 809 ( 7.6) 166 (4.9) 643 (8.8) ALB,Mean ± SD 43.3 ± 3.3 44.1 ± 3.3 42.9 ± 3.3 < 0.001 CHOL,Mean ± SD 4.9 ± 1.0 4.8 ± 1.0 5.0 ± 1.0 < 0.001 CRE,,Mean ± SD 74.2 ± 23.7 76.2 ± 22.4 73.3 ± 24.2 < 0.001 ZINC,Mean ± SD 12.0 ± 8.1 12.5 ± 7.6 11.7 ± 8.2 < 0.001 3.3 Multifactor logistic regression analysis Upon examining zinc dietary intake categoized into quartiles in multivariable logistic regression analyses, a notable inverse correlation emerged between zinc consumption and HSV seropositivity, after adjusting for all potential covariates. In comparison to individuals with the lowest zinc intake (Q1 14.83mg/24h) exhibited adjusted ORs for HSV seropositivity of 0.82 (95% CI: 0.72–0.93), 0.83 (95% CI: 0.73–0.95), and 0.80 (95% CI:0.70–0.91), respectively (Table 2 ).The results are shown in the forest plot (Fig. 3 ). Table 2 Logistic regression analyses of the association of zinc intake with HSV seropositivity. Model Zinc Quartile (OR 95% CI) OR 95%CI P value Q114.83) Model 1 a 0.88(0.83–0.93) < 0.001 1 (Ref) 0.77 (0.68–0.87) 0.72(0.64–0.81) 0.66(0.58–0.74) Model2 b 0.95 (0.89-1) 0.053 1 (Ref) 0.81(0.72–0.93) 0.82(0.72–0.93) 0.79(0.69–0.90) Model 3 c 0.94 (0.89-1) 0.042 1 (Ref) 0.82(0.72–0.93) 0.83(0.73–0.95) 0.8(0.7–0.91) a Model 1: No adjustment. b Model 2: Adjusted for age, gender, marital status, poverty-income ratio. c Model 3: Adjustment for all covariates [age, gender, marital status,poverty-income ratio, body mass index, cardiovascular disease (congestive.heart.heartfailure, angina and heart attack), smoking, alcohol, diabetes, hypertension and serum indicators (albumin, total cholesterol and creatinine)]. 3.3 Dose-response relationships When the dietary Zn level was treated as a continuous variable, the relationship between Zn intake and HSV seropositivity showed an L-shaped curve (nonlinear, p = 0.002) in the restricted cubic spline (RCS; Fig. 2 ). By combining graphical analysis with clinical significance, the optimal inflection point for Zn intake was identified at 16.87 mg/day. Increasing Zn intake by 10 mg/day reduced the risk of HSV seropositivity by 17.9% (OR, 95% CI: 0.821 [0.741–0.944]; p = 0.0058). However, when the Zn intake was ≥ 16.87 mg/day, this association was not observed (OR, 95% CI: 1.233 [0.993–1.533]; p = 0.0583; Table 3 ). Table 3 Threshold analysis of the relationship between zinc intake and HSV seropositivity. a Zinc intake(mg/day) OR (95%CI) P value zinc<1.687 0.821 (0.714–0.944) 0.0058 Zinc ≥ 1.687 1.233 (0.993–1.533) 0.0583 Likelihood Ratio test - 0.001 a Zinc :Zinc intake was entered as a continuous variable per 10 mg/24 h decrease. Adjustment was made for all covariates, including age, gender, marital status, poverty-income ratio, body mass index, cardiovascular disease (congestive heart failure, angina, and heart attack), smoking, alcohol use, diabetes, hypertension, and serum indicators (albumin, total cholesterol, and creatinine). This means that the risk of HSV infection no longer decreases with increasing dietary Zn intake. 4. Discussion As an essential trace element in the human body, Zn is instrumental in maintaining normal physiological functions. 16 Recently, an increasing number of studies have focused on the relationship between Zn and human health, especially the potential link between Zn intake and viral infections. 17 Additional, HSV has attracted considerable attention regarding the relationship between infection and Zn intake. In this study, using RCS analysis, we revealed a unique nonlinear relationship between dietary Zn intake and HSV seropositivity, showing an L-shaped curve. This suggests that the effect of Zn on HSV infection is not a simple linear dose-response, but rather the presence of a specific optimal inflection point. When Zn intake is below 16.87 mg/day, the risk of HSV infection was significantly reduced as Zn intake increased; however, once Zn intake exceeded this inflection point, increasing Zn intake no longer continued to reduce the risk of HSV infection. This L-shaped curve is characterized by a steep risk decline when Zn intake is below the inflection point, while the risk decline is off or even declines. To the best of our knowledge, this study is the first to explore the correlation between dietary Zn intake and HSV seropositivity using a cross-sectional approach. Previous studies have focused on the relationship between serum Zn levels and HSV, however, no association was observed. Previous studies have found that dietary antioxidants reduce viral infections. Barchitta and Maugeri conducted a cross-sectional study, 18 investigating the association between dietary antioxidant intake and risk of high-risk HPV (hrHPV) infection in 251 Italian women with normal cervical cytology. They determined that Zn, manganese, and vitamins A and C intake was significantly lower in women who tested positive for hrHPV than in uninfected women. In addition, we found a negative association between dietary zinc intake and the hrHPV-positive status. A related study by Zhang et al. 19 found a significant correlation between dietary zinc intake and Helicobacter pylori seroprevalence in individuals aged > 20 years. The results showed that higher Zn intake was associated with lower H. pylori seroprevalence, and the two showed an “L” shaped relationship, indicating that even a slight increase in dietary Zn intake has a protective effect. In addition, a cross-sectional study 20 that investigated the relationship between vitamin D intake and HSV infection rates, found that lower serum 25(OH)D levels were associated with an increased risk of HSV-1 and HSV-2 infection and that high dietary Zn intake reduced the risk of HSV infection, when dietary Zn intake was below 16.87 mg/day. Although the exact mechanism for the negative association between dietary Zn intake and HSV seroprevalence has not been fully elucidated, our findings are supported by available evidence. One possible mechanism underlying the relationship between dietary zinc and HSV seroprevalence may involve Toll-like receptors (TLRs). As key components of the innate immune system, TLRs function as pattern recognition receptors to defend against bacterial invasion. When viruses bind to TLRs, they trigger the production of inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. Numerous studies have investigated the relationship between TLRs and HSV-1-related diseases. 21 , 22 A recent study using the Zn ion carrier pyridine demonstrated reduced NF-κB activation and HSV replication, as it interfered with the protein ubiquitination pathway. 23 Furthermore, Zn is involved in the regulation of gene expression in immune cells. as it affects the activity of transcription factors and methylation DNA status, thereby regulating the expression of immune cell-related genes. 24 , 25 Additionally, Zn is a cofactor for various enzymes and proteins involved in metabolic reactions and biosynthetic processes within immune cells. When Zn intake is insufficient, the function of immune cells may be suppressed, resulting in decreased defense of the immune system against HSV, thus increasing the risk of HSV infection. With the increasing Zn intake, the function of immune cells gradually recovers, defense ability of the immune system increases, and risk of HSV infection decreases accordingly. 26 – 28 A complex nonlinear dose-effect relationship between Zn intake and risk of HSV infection. When intake is below the optimal inflection point, Zn significantly reduces the risk of HSV infection by enhancing immune cell activity (e.g., promoting lymphocyte proliferation and natural killer cell function); however, beyond this threshold, increasing Zn intake does not further increase immune defense efficacy and infection risk. This nonlinear pattern suggests that the recommended standard of Zn intake should overcome the limitations of traditional linear models and adopt nonlinear modeling to accurately locate the best intake interval. Previous studies have suggested that improving the nutritional status of Zn through multiple pathways reduces the risk of HSV infection. Hall and King 29 noted that a Zn-fortified food strategy significantly improved dietary Zn content through industrial addition. Praharaj et al. 30 proposed that Zn biofortification technology upgrades nutrition by maintaining original eating habits. Furthermore, nanozinc technology has shown great potential for innovation. Singh et al. 31 confirmed that it could significantly improve the Zn content of agricultural products by improving the bioavailability of soil Zn and absorption efficiency of crops. Khan et al. 32 emphasized that immune dysfunction caused by Zn deficiency is an important mechanism of HSV susceptibility and that optimization of Zn nutrition is of great public health value. Notably, Duan et al. 33 warned in their review that although appropriate Zn intake is crucial to prevent infection, excessive supplementation may cause health risks such as copper metabolism imbalance and oxidative stress, highlighting the need for precise nutritional intervention. In the future, multi-omics studies and clinical trials are needed to further clarify the mechanism of the interaction between Zn and HSV infection to provide a scientific basis for the development of personalized and life-cycle Zn nutrition intervention programs. From a practical clinical perspective, this study provides a theoretical foundation for formulating nutritional strategies to prevent HSV infection by precisely identifying optimal Zn intake thresholds. In clinical practice, targeted Zn supplementation strategies for high-risk groups with poor Zn nutrition, such as the geriatric, children, pregnant women, and immunocompromised patients, are expected to reduce the rate of HSV infection and improve public health conditions. This study highlights the application value of nonlinear modeling in nutritional research and provides strong support for the establishment of scientifically sound and reasonable nutrient intake recommendations. Although moderate Zn intake plays a positive role in preventing HSV infections, excessive Zn supplementation may pose health risks. Therefore, when implementing Zn nutritional interventions, it is essential to consider individual differences and nutritional status, develop personalized supplementation plans, and avoid blind supplementation and overconsumption. However, this was a retrospective, cross-sectional study with certain limitations. First, retrospective studies cannot establish causality; they can only reveal the correlations between variables. Therefore, although this study found an association between Zn intake and HSV infection risk, it could not determine whether Zn intake is an independent risk factor or a protective factor against HSV infection. Second, confounding variables may have influenced this study. For instance, factors such as age, sex, marital status, household income, BMI, smoking, alcohol consumption, diabetes, and hypertension may be related to both Zn intake and risk of HSV infection, thus interfering with the study results. Although a stratified analysis was conducted to assess the potential impact of these factors, no significant interactions were found. From a public health perspective, maintaining adequate Zn intake may help prevent HSV infections. Public health policies should focus on Zn nutrition by using nutritional interventions to increase Zn intake and reduce the risk of HSV infection. However, a higher Zn intake is not always better, and multiple health factors should be considered when setting recommended standards. In summary, our study demonstrated that there is a nonlinear relationship between Zn intake and the risk of HSV infection.The lowest HSV seropositivity rate was observed at Zn intake level 16.87 mg/day. However, additional prospective cohort studies are necessary to confirm the relationship between zinc intake levels and HSV seropositivity in American adults. Declarations Author contributions Chunhua Liu proposed study concepts,performed data analysis and rand wrote the manuscript. Mengpeng Li performed data analysis and evised the manuscript.Jingjing Liu and Zhaoyong Lv retrieve and performed data analysis.Yingguo Liu and Yanan Qin edited the manuscript and inter preted the results. All authors read and approved the final manuscript. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be interpreted as a potential conflict of interest. Acknowledgments We thank Dr. Liu Jie (People's Liberation Army General Hospital, Beijing, China) for his assistance in this revision. 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Zinc biofortification in food crops could alleviate the zinc malnutrition in human health[J]. Molecules. 2021,26(12):3509. Khan ST, Malik A, Alwarthan A, Shaik MR. The enormity of the zinc deficiency problem and available solutions; an overview[J].Arabian Journal of Chemistry. 2022,15(3):103668. Singh A, Rajput VD, Pandey D, Sharma R, Ghazaryan K, Minkina T. Nano zinc-enabled strategies in crops for combatting zinc malnutrition in human health[J].Frontiers in Bioscience-Landmark. 2023 ,28(8):158. Duan M, Li T, Liu B, Yin S, Zang J, Lv C, Zhao G, Zhang T. Zinc nutrition and dietary zinc supplements[J]. Critical Reviews in Food Science and Nutrition. 2023 ,63(9):1277-92. 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. 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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-7180170","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":497068058,"identity":"89b386d4-473f-4731-a70d-46c78356f9df","order_by":0,"name":"Chunhua Liu","email":"","orcid":"","institution":"Liaocheng People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chunhua","middleName":"","lastName":"Liu","suffix":""},{"id":497068060,"identity":"e8e78260-c8f1-4a9d-94d8-b27aaf131ba1","order_by":1,"name":"Yingguo Liu","email":"","orcid":"","institution":"Liaocheng Infectious Diseases Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yingguo","middleName":"","lastName":"Liu","suffix":""},{"id":497068061,"identity":"be13bf25-af70-4b99-aa41-eec57239b983","order_by":2,"name":"Jingjing Liu","email":"","orcid":"","institution":"Liaocheng People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jingjing","middleName":"","lastName":"Liu","suffix":""},{"id":497068063,"identity":"14e85000-d999-4af9-b472-df2fe1406d05","order_by":3,"name":"Zhaoyong Lv","email":"","orcid":"","institution":"Liaocheng People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhaoyong","middleName":"","lastName":"Lv","suffix":""},{"id":497068067,"identity":"51b9a428-786c-485f-8a9a-760921620ec1","order_by":4,"name":"Yanan Qin","email":"","orcid":"","institution":"Liaocheng People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yanan","middleName":"","lastName":"Qin","suffix":""},{"id":497068071,"identity":"55b5cb8d-f57e-4db0-ba3d-2704a3067e0a","order_by":5,"name":"Mengpeng Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYBACPmYGBmYGAxs5NvbGxocfiNHCBtZSkGbMz3O42ViCKC0MIC0fDifOnJHeJsBDlBZ27rTHBQaHEzfcfNjGIMFgJ6fbQNBhvNuNZxikG2+4ndj2oIAh2djsAGEt26R5DKxlgVraDSQYDiRuI1ILM+OGmwfbJHhI0OKsOHMGIylaZhiAAjkRGMgGRPiFn//sNumCP6CoPP7w4YcKOzmCWtCAAWnKR8EoGAWjYBTgAACWtTtG6eJougAAAABJRU5ErkJggg==","orcid":"","institution":"Liaocheng City People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Mengpeng","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-07-21 18:23:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7180170/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7180170/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88918994,"identity":"b3ce3d8d-5a31-4f39-8562-eb07f80237a2","added_by":"auto","created_at":"2025-08-12 16:53:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":98765,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patients included into the analysis\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7180170/v1/8e0aa7af67452effba1bd49e.png"},{"id":88918985,"identity":"b7dc9e46-a8c9-4cd8-9715-d72db3149a53","added_by":"auto","created_at":"2025-08-12 16:53:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":240585,"visible":true,"origin":"","legend":"\u003cp\u003eDose-Response Relationship Between Dietary Zinc Intake and HSV Seropositivity Odds Ratio. Solid lines represent the predicted values, while dashed lines indicate the 95% confidence intervals. Adjusted for age, gender, marital status, poverty-income ratio, body mass index, cardiovascular disease (congestive heart failure, angina, and heart attack), smoking, alcohol consumption, diabetes, hypertension, and serum indicators (albumin, total cholesterol, and creatinine). Only 99% of the data is shown.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7180170/v1/b8f6cc63bc744e6aca1360ee.png"},{"id":88918989,"identity":"b734fbb8-170f-4289-8506-35a84287a7a8","added_by":"auto","created_at":"2025-08-12 16:53:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":215058,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of the association between dietary zinc intake and HSV seropositivity, adjusted for sociological data(age, gender, marital status, poverty-income ratio, body mass index), smoking, alcohol use, diabetes, hypertension, cardiovascular disease (congestive heart failure, angina, and heart attack) and serum indicators (albumin, total cholesterol, and creatinine).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7180170/v1/44a2fb0cd8b933b337748cb1.png"},{"id":94163892,"identity":"ee7b0c47-b163-45ec-94ec-962bb6901001","added_by":"auto","created_at":"2025-10-23 05:47:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1248946,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7180170/v1/d62acfe9-8952-48f5-849f-26f2d08d955e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between dietary zinc intake and herpes simplex virus seropositivity in US adults: A cross-sectional study","fulltext":[{"header":"Key points","content":"\u003cp\u003eOverall,\u0026nbsp;9,290 (69.9%) were positive for HSV serology, with 55.5% being female and an average age of 35.9 years. In the fully adjusted model, a significant inverse association was observed between dietary zinc intake and HSV seropositivity.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eViral infections are a major cause of mortality in humans and animals worldwide.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The herpes simplex virus (HSV) is an enveloped virus that infects more than half the world's population.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e There are two types of HSV: HSV-1 and HSV-2.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e HSV-1 is frequently associated with several diseases including herpetic stomatitis, recurrent herpes labialis, erythema multiforme, cranial neuropathies, and oral squamous cell carcinoma.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e HSV-2 causes genital herpes and increases susceptibility to human immunodeficiency virus (HIV) infections,\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e which causes lesions at or near the point of entry into the body and establish a latent infection in the sensory ganglia. This latency often increases HSV pathogenicity. Early identification of HSV risk provides an opportunity to delay or prevent disease onset.\u003c/p\u003e\u003cp\u003eZinc is a crucial trace element for human growth, development, and the maintenance of immune functions.\u003csup\u003e[7]\u003c/sup\u003e Its immunomodulatory properties extend to both innate and adaptive immunity, wherein it participates in lymphocyte differentiation, cytokine production, and phagocytic activity.\u003csup\u003e[8\u0026ndash;10]\u003c/sup\u003e Zn status serves as a critical determinant of antiviral immunity, with Zn-deficient populations demonstrating heightened susceptibility to viral infections including HIV and hepatitis C virus.\u003csup\u003e[11, 12]\u003c/sup\u003e Moreover, emerging evidence has revealed the direct inhibitory effects of zinc on HSV replication through mechanisms involving viral DNA polymerase interference and capsid destabilization.\u003csup\u003e[13\u0026ndash;15]\u003c/sup\u003e Although the interplay between serum Zn status and viral pathogenesis has been extensively investigated, the specific relationship between dietary Zn intake and HSV seropositivity remains unexplored.\u003c/p\u003e\u003cp\u003eFurther research is required to understand the relationship between dietary Zn intake and HSV seropositivity. Data from the National Health and Nutrition Examination Survey (NHANES) were utilized in this study.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data Source and Study population\u003c/h2\u003e\u003cp\u003eThis cross-sectional study used NHANES data (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.cdc.gov/nchs/nhanes.htm\u003c/span\u003e\u003cspan address=\"http://www.cdc.gov/nchs/nhanes.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) from 2007 to 2016, collected by the Centers for Disease Control and Prevention. NHANES aims to evaluate the health and nutritional status of non-institutionalized Americans using a stratified multistage probability survey method. It collects demographic and health information through home visits, screenings, and laboratory tests conducted at a Mobile Examination Center. The Ethics Review Committee of the National Center for Health Statistics approved this study, and all participants provided written informed consent. Notably, secondary analysis did not require additional Institutional Review Board approval. Our study included individuals\u0026thinsp;\u0026ge;\u0026thinsp;20-years-old who completed the interview process. Those lacking serum Zn levels and HSV test results were excluded from the analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Indices and methods\u003c/h2\u003e\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\u003ch2\u003e2.2.1 General data collection\u003c/h2\u003e\u003cp\u003eThe data included age, sex, marital status, poverty income ratio, body mass index (BMI), smoking, alcohol consumption, diabetes, hypertension, cardiovascular disease (including congestive heart failure, angina, and heart attack), and serum markers (albumin, total cholesterol, and creatinine). Age and BMI were continuous variables, whereas sex was a categorical variable. Marital status was categorized into four types: unmarried, married, has a regular sexual partner, and others (e.g., widowed, divorced, or separated). Socioeconomic status was measured using the PIR scale and divided into three groups with cutoff points of 1.30 and 3.50. Smoking status was classified into three groups: never smoked (\u0026lt;\u0026thinsp;100 cigarettes), ever smoked (\u0026gt;\u0026thinsp;100 cigarettes, but quit smoking), and current smoker (\u0026gt;\u0026thinsp;100 cigarettes and still smoking). Drinking history was categorized as severe or moderate.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e2.2.2 Serum Zn test\u003c/h2\u003e\u003cp\u003eTotal Zn intake was calculated as the sum of dietary Zn intake and Zn supplementation.This study evaluated the dietary Zn intake of various foods and beverages. Dietary intake was assessed through in-person interviews conducted at a NHANES mobile examination clinics. The participants completed two separate 24-h dietary recalls. The first recall was conducted face-to-face at a Mobile Examination Center by skilled interviewers, and the second was conducted via telephone or mail within 3\u0026ndash;10 d. To avoid recall errors, only the first 24 h data were used. Zn intake data, measured in mg, were analyzed as both continuous and categorical variables (Q1\u0026ndash;Q4), with the Zn intake distribution divided into four quartiles: Q1 (\u0026lt;\u0026thinsp;6.99mg/24h), Q2 (6.99\u0026ndash;10.26mg/24h), Q3 (10.26\u0026ndash;14.83mg/24h), and Q4 (\u0026gt;\u0026thinsp;14.83mg/24h), representing low-to-high intake levels.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.2.3 HSV antibody measurement\u003c/h2\u003e\u003cp\u003eHSV-1 and HSV-2 infections were detected using strain-specific glycoproteins. This analysis was conducted on individuals aged 20\u0026ndash;49 years who were tested for antibodies against HSV-1 and HSV-2 immunoglobulin G. Positive results for either HSV-1 or HSV-2 were used as diagnostic criteria for the respective infections, whereas negative results for both antibodies indicated that the individual was not infected with HSV.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e\u003cp\u003eData were analyzed using the statistical software packages R 3.3.2 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://wwwR-project.org\u003c/span\u003e\u003cspan address=\"http://wwwR-project.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, The RFoundation) and Free Statistics software version 2.1. Continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and categorical variables are presented as frequencies. The basic characteristic differences among HSV subgroups for continuous and categorical variableswere tested by the one-way analysis of variance and chi-squared,respectively. Patients were divided into four groups based on dietary zinc levels\u003c/p\u003e\u003cp\u003e(CA\u0026thinsp;\u0026lt;\u0026thinsp;8 mg/dL,four quartiles:(\u0026lt;\u0026thinsp;6.99mg/24h, 6.99\u0026thinsp;\u0026le;\u0026thinsp;Zn\u0026lt;10.26mg/24h, 10.26\u0026thinsp;\u0026le;\u0026thinsp;Zn\u0026lt;14.83mg/24h, \u0026ge;\u0026thinsp;14.83mg/24h). Multivariate analysis was performed to investigate the relationship between Zn intake and HSV prevalence. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between Zn intake and HSV infection. Multiple covariates were considered for the logistic regression analysis and divided into three models. The results were not adjusted in model I. To investigate independent associations, variables including age, gender, marital status, and poverty-income ratio were adjusted for subgroups in Model II. Finally, age, gender, marital status, poverty-income ratio, body mass index, congestive heart failure, angina, heart attack, smoking, alcohol consumption, diabetes, hypertension, albumin, total cholesterol, and creatinine were adjusted in model III. Smooth curve fitting was adopted to assess the nonlinear relationship between Zn intake and HSV. The regression models contain a quadratic term to test for nonlinearity, with the regression results presented as ORs with 95% CI. The inflection point was determined using a two-segment logic model and recursive algorithm. Less than 5% of the missing data were processed using the listwise deletion method. By a two-tailed testing, a p-value of \u0026lt;\u0026thinsp;0.05 was declared significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Patient inclusion process and outcomes\u003c/h2\u003e\u003cp\u003eOf the 29,201 participants, 15,868 were excluded from the study due to incomplete HSV-1 and HSV-2 data, another 841 patients were excluded due to missing dietary data, and 1,802 individuals were excluded owing to their missing covariate information (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Baseline characteristics\u003c/h2\u003e\u003cp\u003eOverall, 10,689 patients were included in this analysis, of which, 7,321 (69.9%) cases were HSV seropositive (HSV group, HSV-1 and HSV-2 seropositive). The baseline characteristics of the groups have been stratified according to HSV (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), with a mean age of 36.1 years, and 53.4% female ration. Compared to the HSV seronegative group, those in the HSV seropositive group tend to be older, higher sex partner, lower serum albumin and creatinine levels, high cholesterol level, higher BMI, and are more likely to have CVDs. Furthermore, smoking and alcohol history were more common in the infection groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The mean Zn level was 11.7 mg/day (8.2 mg/day), which was significantly lower than that of the control.\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\u003eThe baseline characteristics and demographic characteristics of 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=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"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;10689)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNon-HSV(n\u0026thinsp;=\u0026thinsp;3368)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHSV(n\u0026thinsp;=\u0026thinsp;7321)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge,Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e36.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex,n(%)\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5340 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1932 (57.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3408 (46.6)\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\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5349 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1436 (42.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3913 (53.4)\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\u003eMarry,n(%)\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMarried\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4984 (46.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1490 (44.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3494 (47.7)\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\u003eNever married\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3111 (29.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1302 (38.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1809 (24.7)\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\u003eLiving with partner\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1353 (12.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e350 (10.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1003 (13.7)\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\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1241 (11.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e226 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1015 (13.9)\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\u003ePoverty-income ratio, n(%)\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;1.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3728 (34.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e884 (26.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2844 (38.8)\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\u003e1.31\u0026ndash;3.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3838 (35.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1156 (34.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2682 (36.6)\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\u0026gt;\u0026thinsp;3.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3123 (29.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1328 (39.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1795 (24.5)\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\u003eSmoke,n(%)\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enever\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6439 (60.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2231 (66.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4208 (57.5)\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\u003eformer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1573 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e460 (13.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1113 (15.2)\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\u003enow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2677 (25.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e677 (20.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2000 (27.3)\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\u003eAlcohol user, n(%)\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enever\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1308 (12.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e357 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e951 (13)\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\u003eformer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1123 (10.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e267 (7.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e856 (11.7)\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\u003emild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3084 (28.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1143 (33.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1941 (26.5)\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\u003emoderate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1995 (18.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e675 (20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1320 (18)\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\u003eheavy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3179 (29.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e926 (27.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2253 (30.8)\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\u003eBMI, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAngina, n(%)\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\u003e0.027\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eno\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10621 (99.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3355 (99.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7266 (99.2)\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\u003eyes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68 ( 0.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e55 (0.8)\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\u003eHeart attack, n(%)\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eno\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10594 (99.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3355 (99.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7239 (98.9)\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\u003eyes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e95 ( 0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82 (1.1)\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\u003eCongestive heart failure, n(%)\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10613 (99.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3359 (99.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7254 (99.1)\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\u003eyes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e76 ( 0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e67 (0.9)\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\u003eHypertension,n(%)\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eno\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8396 (78.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2806 (83.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5590 (76.4)\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\u003eyes,n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2293 (21.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e562 (16.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1731 (23.6)\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\u003eDM\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\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eno\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9880 (92.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3202 (95.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6678 (91.2)\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\u003eyes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e809 ( 7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e166 (4.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e643 (8.8)\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\u003eALB,Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCHOL,Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRE,,Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e74.2\u0026thinsp;\u0026plusmn;\u0026thinsp;23.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e76.2\u0026thinsp;\u0026plusmn;\u0026thinsp;22.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e73.3\u0026thinsp;\u0026plusmn;\u0026thinsp;24.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZINC,Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Multifactor logistic regression analysis\u003c/h2\u003e\u003cp\u003eUpon examining zinc dietary intake categoized into quartiles in multivariable logistic regression analyses, a notable inverse correlation emerged between zinc consumption and HSV seropositivity, after adjusting for all potential covariates. In comparison to individuals with the lowest zinc intake (Q1\u0026thinsp;\u0026lt;\u0026thinsp;6.99mg/24h),participants in Q2 (6.99\u0026ndash;10.26mg/24h), Q3 (10.26-14.83mg/24h), and Q4 (\u0026gt;\u0026thinsp;14.83mg/24h) exhibited adjusted ORs for HSV seropositivity of 0.82 (95% CI: 0.72\u0026ndash;0.93), 0.83 (95% CI: 0.73\u0026ndash;0.95), and 0.80 (95% CI:0.70\u0026ndash;0.91), respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).The results are shown in the forest plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\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\u003eLogistic regression analyses of the association of zinc intake with HSV seropositivity.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eModel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eZinc\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c7\" namest=\"c4\"\u003e\u003cp\u003eQuartile (OR 95% CI)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\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\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eQ1\u0026lt;6.99\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eQ2(6.99\u0026ndash;10.26)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eQ3(10.26\u0026ndash;14.83)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eQ4(\u0026gt;14.83)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel 1\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.88(0.83\u0026ndash;0.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (Ref)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.77 (0.68\u0026ndash;0.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.72(0.64\u0026ndash;0.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.66(0.58\u0026ndash;0.74)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel2 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.95 (0.89-1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.053\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (Ref)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.81(0.72\u0026ndash;0.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.82(0.72\u0026ndash;0.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.79(0.69\u0026ndash;0.90)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel 3\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.94 (0.89-1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (Ref)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.82(0.72\u0026ndash;0.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.83(0.73\u0026ndash;0.95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.8(0.7\u0026ndash;0.91)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ea\u003c/sup\u003eModel 1: No adjustment.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003eb\u003c/sup\u003eModel 2: Adjusted for age, gender, marital status, poverty-income ratio.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ec\u003c/sup\u003eModel 3: Adjustment for all covariates [age, gender, marital status,poverty-income ratio, body mass index, cardiovascular disease (congestive.heart.heartfailure, angina and heart attack), smoking, alcohol, diabetes, hypertension and serum indicators (albumin, total cholesterol and creatinine)].\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Dose-response relationships\u003c/h2\u003e\u003cp\u003eWhen the dietary Zn level was treated as a continuous variable, the relationship between Zn intake and HSV seropositivity showed an L-shaped curve (nonlinear, p\u0026thinsp;=\u0026thinsp;0.002) in the restricted cubic spline (RCS; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). By combining graphical analysis with clinical significance, the optimal inflection point for Zn intake was identified at 16.87 mg/day. Increasing Zn intake by 10 mg/day reduced the risk of HSV seropositivity by 17.9% (OR, 95% CI: 0.821 [0.741\u0026ndash;0.944]; p\u0026thinsp;=\u0026thinsp;0.0058). However, when the Zn intake was \u0026ge;\u0026thinsp;16.87 mg/day, this association was not observed (OR, 95% CI: 1.233 [0.993\u0026ndash;1.533]; p\u0026thinsp;=\u0026thinsp;0.0583; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\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\u003eThreshold analysis of the relationship between zinc intake and HSV seropositivity.\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eZinc 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\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ezinc\u0026lt;1.687\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.821 (0.714\u0026ndash;0.944)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.0058\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZinc\u0026thinsp;\u0026ge;\u0026thinsp;1.687\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.233 (0.993\u0026ndash;1.533)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.0583\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLikelihood Ratio test\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ea\u003c/sup\u003eZinc :Zinc intake was entered as a continuous variable per 10 mg/24 h decrease.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eAdjustment was made for all covariates, including age, gender, marital status, poverty-income ratio, body mass index, cardiovascular disease (congestive heart failure, angina, and heart attack), smoking, alcohol use, diabetes, hypertension, and serum indicators (albumin, total cholesterol, and creatinine).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThis means that the risk of HSV infection no longer decreases with increasing dietary Zn intake.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eAs an essential trace element in the human body, Zn is instrumental in maintaining normal physiological functions.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Recently, an increasing number of studies have focused on the relationship between Zn and human health, especially the potential link between Zn intake and viral infections.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Additional, HSV has attracted considerable attention regarding the relationship between infection and Zn intake. In this study, using RCS analysis, we revealed a unique nonlinear relationship between dietary Zn intake and HSV seropositivity, showing an L-shaped curve. This suggests that the effect of Zn on HSV infection is not a simple linear dose-response, but rather the presence of a specific optimal inflection point. When Zn intake is below 16.87 mg/day, the risk of HSV infection was significantly reduced as Zn intake increased; however, once Zn intake exceeded this inflection point, increasing Zn intake no longer continued to reduce the risk of HSV infection. This L-shaped curve is characterized by a steep risk decline when Zn intake is below the inflection point, while the risk decline is off or even declines.\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, this study is the first to explore the correlation between dietary Zn intake and HSV seropositivity using a cross-sectional approach. Previous studies have focused on the relationship between serum Zn levels and HSV, however, no association was observed. Previous studies have found that dietary antioxidants reduce viral infections. Barchitta and Maugeri conducted a cross-sectional study,\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e investigating the association between dietary antioxidant intake and risk of high-risk HPV (hrHPV) infection in 251 Italian women with normal cervical cytology. They determined that Zn, manganese, and vitamins A and C intake was significantly lower in women who tested positive for hrHPV than in uninfected women. In addition, we found a negative association between dietary zinc intake and the hrHPV-positive status. A related study by Zhang et al.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e found a significant correlation between dietary zinc intake and \u003cem\u003eHelicobacter pylori\u003c/em\u003e seroprevalence in individuals aged\u0026thinsp;\u0026gt;\u0026thinsp;20 years. The results showed that higher Zn intake was associated with lower \u003cem\u003eH. pylori\u003c/em\u003e seroprevalence, and the two showed an \u0026ldquo;L\u0026rdquo; shaped relationship, indicating that even a slight increase in dietary Zn intake has a protective effect. In addition, a cross-sectional study\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e that investigated the relationship between vitamin D intake and HSV infection rates, found that lower serum 25(OH)D levels were associated with an increased risk of HSV-1 and HSV-2 infection and that high dietary Zn intake reduced the risk of HSV infection, when dietary Zn intake was below 16.87 mg/day.\u003c/p\u003e\u003cp\u003eAlthough the exact mechanism for the negative association between dietary Zn intake and HSV seroprevalence has not been fully elucidated, our findings are supported by available evidence. One possible mechanism underlying the relationship between dietary zinc and HSV seroprevalence may involve Toll-like receptors (TLRs). As key components of the innate immune system, TLRs function as pattern recognition receptors to defend against bacterial invasion. When viruses bind to TLRs, they trigger the production of inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. Numerous studies have investigated the relationship between TLRs and HSV-1-related diseases.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e A recent study using the Zn ion carrier pyridine demonstrated reduced NF-κB activation and HSV replication, as it interfered with the protein ubiquitination pathway.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Furthermore, Zn is involved in the regulation of gene expression in immune cells. as it affects the activity of transcription factors and methylation DNA status, thereby regulating the expression of immune cell-related genes.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAdditionally, Zn is a cofactor for various enzymes and proteins involved in metabolic reactions and biosynthetic processes within immune cells. When Zn intake is insufficient, the function of immune cells may be suppressed, resulting in decreased defense of the immune system against HSV, thus increasing the risk of HSV infection. With the increasing Zn intake, the function of immune cells gradually recovers, defense ability of the immune system increases, and risk of HSV infection decreases accordingly.\u003csup\u003e\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e A complex nonlinear dose-effect relationship between Zn intake and risk of HSV infection. When intake is below the optimal inflection point, Zn significantly reduces the risk of HSV infection by enhancing immune cell activity (e.g., promoting lymphocyte proliferation and natural killer cell function); however, beyond this threshold, increasing Zn intake does not further increase immune defense efficacy and infection risk. This nonlinear pattern suggests that the recommended standard of Zn intake should overcome the limitations of traditional linear models and adopt nonlinear modeling to accurately locate the best intake interval. Previous studies have suggested that improving the nutritional status of Zn through multiple pathways reduces the risk of HSV infection. Hall and King\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e noted that a Zn-fortified food strategy significantly improved dietary Zn content through industrial addition. Praharaj et al.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e proposed that Zn biofortification technology upgrades nutrition by maintaining original eating habits. Furthermore, nanozinc technology has shown great potential for innovation. Singh et al.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e confirmed that it could significantly improve the Zn content of agricultural products by improving the bioavailability of soil Zn and absorption efficiency of crops. Khan et al.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e emphasized that immune dysfunction caused by Zn deficiency is an important mechanism of HSV susceptibility and that optimization of Zn nutrition is of great public health value. Notably, Duan et al.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e warned in their review that although appropriate Zn intake is crucial to prevent infection, excessive supplementation may cause health risks such as copper metabolism imbalance and oxidative stress, highlighting the need for precise nutritional intervention. In the future, multi-omics studies and clinical trials are needed to further clarify the mechanism of the interaction between Zn and HSV infection to provide a scientific basis for the development of personalized and life-cycle Zn nutrition intervention programs.\u003c/p\u003e\u003cp\u003eFrom a practical clinical perspective, this study provides a theoretical foundation for formulating nutritional strategies to prevent HSV infection by precisely identifying optimal Zn intake thresholds. In clinical practice, targeted Zn supplementation strategies for high-risk groups with poor Zn nutrition, such as the geriatric, children, pregnant women, and immunocompromised patients, are expected to reduce the rate of HSV infection and improve public health conditions. This study highlights the application value of nonlinear modeling in nutritional research and provides strong support for the establishment of scientifically sound and reasonable nutrient intake recommendations. Although moderate Zn intake plays a positive role in preventing HSV infections, excessive Zn supplementation may pose health risks. Therefore, when implementing Zn nutritional interventions, it is essential to consider individual differences and nutritional status, develop personalized supplementation plans, and avoid blind supplementation and overconsumption.\u003c/p\u003e\u003cp\u003eHowever, this was a retrospective, cross-sectional study with certain limitations. First, retrospective studies cannot establish causality; they can only reveal the correlations between variables. Therefore, although this study found an association between Zn intake and HSV infection risk, it could not determine whether Zn intake is an independent risk factor or a protective factor against HSV infection. Second, confounding variables may have influenced this study. For instance, factors such as age, sex, marital status, household income, BMI, smoking, alcohol consumption, diabetes, and hypertension may be related to both Zn intake and risk of HSV infection, thus interfering with the study results. Although a stratified analysis was conducted to assess the potential impact of these factors, no significant interactions were found. From a public health perspective, maintaining adequate Zn intake may help prevent HSV infections. Public health policies should focus on Zn nutrition by using nutritional interventions to increase Zn intake and reduce the risk of HSV infection. However, a higher Zn intake is not always better, and multiple health factors should be considered when setting recommended standards.\u003c/p\u003e\u003cp\u003eIn summary, our study demonstrated that there is a nonlinear relationship between Zn intake and the risk of HSV infection.The lowest HSV seropositivity rate was observed at Zn intake level 16.87 mg/day. However, additional prospective cohort studies are necessary to confirm the relationship between zinc intake levels and HSV seropositivity in American adults.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor contributions\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChunhua Liu proposed study concepts,performed data analysis and rand wrote the manuscript. Mengpeng Li performed data analysis and evised the manuscript.Jingjing Liu and Zhaoyong Lv retrieve and performed data analysis.Yingguo Liu and Yanan Qin edited the manuscript and inter preted the results. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eConflict of Interest\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be interpreted as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe thank Dr. Liu Jie (People\u0026apos;s Liberation Army General Hospital, Beijing, China) for his assistance in this revision.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Natural Science Foundation of Shandong Province (Grant number: ZR2024ME266) and the Shandong Provincial Science and Technology Office.\u003c/p\u003e\n\u003cp\u003eEthics declaration: not applicable（Data from the NHANES database did not require additional Institutional Review Board approval for secondary analysis）\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003evan Doorn, H. 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Molecules. 2021,26(12):3509.\u003c/li\u003e\n\u003cli\u003eKhan ST, Malik A, Alwarthan A, Shaik MR. The enormity of the zinc deficiency problem and available solutions; an overview[J].Arabian Journal of Chemistry. 2022,15(3):103668.\u003c/li\u003e\n\u003cli\u003eSingh A, Rajput VD, Pandey D, Sharma R, Ghazaryan K, Minkina T. Nano zinc-enabled strategies in crops for combatting zinc malnutrition in human health[J].Frontiers in Bioscience-Landmark. 2023 ,28(8):158.\u003c/li\u003e\n\u003cli\u003eDuan M, Li T, Liu B, Yin S, Zang J, Lv C, Zhao G, Zhang T. Zinc nutrition and dietary zinc supplements[J]. Critical Reviews in Food Science and Nutrition. 2023 ,63(9):1277-92.\u003c/li\u003e\n\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":"zinc, herpes simplex virus, association, National Health and Nutrition Examination Survey, risk assessment","lastPublishedDoi":"10.21203/rs.3.rs-7180170/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7180170/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eZinc is an essential trace element crucial for immune function maintenance. However, the relationship between dietary zinc intake and herpes simplex virus (HSV) infection has not been elucidated. This study determined the association between dietary zinc intake and HSV seropositivity, providing new insights into HSV prevention and treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis cross-sectional observational study used data from the United States National Health and Nutrition Examination Survey, conducted between 2007 and 2016. This study cohort comprised adults who provided comprehensive 24-h dietary recall data. Multivariate logistic regression, stratified analysis with interaction, restricted cubic splines (RCS), and threshold effect analyses were used to explore the potential association between dietary zinc intake and HSV seropositivity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e In total, 10,689 participants aged 20–49 years were enrolled. Of which, 9,290 (69.9%) were positive for HSV serology (HSV group, including HSV-1 and HSV-2 infections), with 55.5% being female and an average age of 35.9 years. In the fully adjusted model, a significant inverse association was observed between dietary zinc intake and HSV seropositivity (quartile variable, Q4 vs Q1, Odd’s ratio: 0.80, 95% confidence intervals: [0.7–0.91], p = 0.003). Consequently, the association between dietary zinc intake and HSV seropositivity exhibited an L-shaped curve (p \u0026lt;0.001) in the RCS，with an estimated threshold of 16.87 mg/day.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThis study suggests that a higher intake of dietary zinc may be linked to a lower prevalence of HSV seropositivity. Notably, among adults in the US, an L-shaped relationship was observed between dietary zinc intake and HSV seropositivity, with an estimated threshold of 16.87mg/day.\u003c/p\u003e","manuscriptTitle":"Association between dietary zinc intake and herpes simplex virus seropositivity in US adults: A cross-sectional study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-12 16:53:11","doi":"10.21203/rs.3.rs-7180170/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":"ebe1146a-c3e3-4867-8cd3-ac1f07df6ab6","owner":[],"postedDate":"August 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-23T05:38:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-12 16:53:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7180170","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7180170","identity":"rs-7180170","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}