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Sex-specific relationship between serum 25-hydroxyvitamin D concentrations and antinuclear antibodies in U.S. adults, NHANES 2001–2004

BMC Immunology volume 25, Article number: 81 (2024) Cite this article

Abstract

Background

The relationship of serum 25-hydroxyvitamin D concentrations and ANA positivity according to sex stratification is unclear. The propose of this study was to reveal the sex-specific relationship of serum 25-hydroxyvitamin D concentrations and ANA positivity in American people.

Methods

The study was conducted in 2757 subjects from the National Health and Nutrition Examination Survey (NHANES) 2001–2004. The logistic regression models were used to assess the correlation between the risk of ANA positivity and serum 25-hydroxyvitamin D concentrations. Generalized additive models and smooth fitting curves were used to evaluate the non-linear relationship of the risk of ANA positivity and serum 25-hydroxyvitamin D levels.

Results

Following multivariable adjustment, we observed a negative correlation between serum 25-hydroxyvitamin D concentrations and the risk of ANA positivity in male participants, particularly in men non-white individuals and those exposed to second-hand smoke. However, there was no significant relationship observed in the female participants. Additionally, the relationship between serum 25-hydroxyvitamin D concentrations and the risk of ANA positivity followed an L-shaped pattern, with an inflection point at 18 ng/mL. When serum 25-hydroxyvitamin D levels fell below this inflection point, decrease of 1 unit in serum 25-hydroxyvitamin D concentrations was linked to an 8% increase in the adjusted OR of ANA positivity (OR 0.92; 95% CI 0.87, 0.97; p 0.0026).

Conclusions

In American men, nonlinear relationships were observed between serum 25-hydroxyvitamin D concentrations and the risk of ANA positivity.

Peer Review reports

Introduction

Autoimmune diseases (AIDs) constitute a class of disorders with unknown etiology, and characterized by an excessive immune response, resulting in the destruction or dysfunction of body’s own organs and tissues [1] At present, the prevalence of AIDs is increasing year by year [2], in worldwide, the overall incidence of AIDs increases 19.1% per year [2], about 5% population are affected by AIDs [3], which leading to serious economic and societal burdens [4, 5]. It is well known that women are more susceptible to AIDs than men. In patients with AIDs such as in systemic lupus erythematosus (SLE) and Sjogren’s syndrome (SS), the ratio of female to male is nearly 10:1 [6].

ANAs are clinical biomarkers of certain AIDs, such as systemic lupus erythematosus (SLE) [7], rheumatoid arthritis (RA) [8], Sjogren’s syndrome (SS) [9]. It is of great importance in the diagnosis and differential diagnosis, clinical classification and activity monitoring of AIDs. Unlike usual biomarkers, ANAs can present many years before the AIDs diagnosis [10, 11]. Therefore, it is critical to identify the modifiable factor to reduce the rate of ANA positivity, thus reducing the prevalence of AIDs.

25-hydroxyvitamin D is a steroid hormone with remarkable immunomodulatory properties [12]. Serum 25-hydroxyvitamin D deficiency is linked to the etiology of several AIDs, including SLE [13, 14], RA [15, 16], IBD [17], multiple sclerosis (MS) [18], and SS [19, 20]. In patients with IBD, the serum 25-hydroxyvitamin D levels are related with ANA inversely [17]. A cross-sectional analysis revealed a negative correlation between 25-hydroxyvitamin D concentrations and ANA positivity among the elderly [21]. Additionally, Lemke et al. revealed that large doses of vitamin D supplementation can treat AIDs [22], which in turn demonstrates the importance of vitamin D in AIDs. However, the optimal serum 25-hydroxyvitamin D concentration is still unclear, it is vital to identify the optimal 25-hydroxyvitamin D concentration to reduce the risk of ANA positivity.

Therefore, our main purpose was to reveal the correlation between serum 25-hydroxyvitamin D concentrations and ANA positivity by sex stratification among American population. Moreover, the secondary objective was to identify the optimal 25-hydroxyvitamin D concentration to minimize the risk of ANA positivity.

Methods

Study population

The National Health and Nutrition Examination Survey (NHANES), conducted by the National Center for Health Statistics (NCHS), is a cross-sectional study aimed at assessing the health and nutritional status of non-institutionalized citizens in the U.S. For the present study, data from two cycles (2001–2002 and 2003–2004) were combined, resulting in a total of 21,161 individuals. Of these, 18,210 individuals who did not participate in ANA measurement, 7 individuals who did not have serum 25-hydroxyvitamin D concentrations, 149 individuals were pregnant and 30 subjects were breastfeeding a child during the examination and 8 individuals missing serum cotinine data were excluded. This resulted in a final sample size of 2757 individuals for the analysis. The inclusion and exclusion criteria are provided in Fig. 1. The Ethics Review Board of the National Center for Health Statistics approved all NHANES protocols. Written consent informs were obtained from all participants. The data is free and can be accessed online at https://www.cdc.gov/nchs/nhanes/.

Fig. 1
figure 1

Flow chart of study participants

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Serum ANA and 25-hydroxyvitamin D measurement

Serum samples were diluted 1:80, and ANA was measured using an indirect immunofluorescence assay with NOVA Lite HEp-2 ANA slides, DAPI kit (INOVA Diagnostics, San Diego, CA, USA), and fluorescein isothiocyanate conjugated secondary antibody (goat anti-human IgG). Images were captured and digitally stored by the NOVA View automated fluorescence microscope system (INOVA Diagnostics). According to a standard reference gallery, immunofluorescence staining intensities were ranked from 0 to 4, with values of 3–4 indicating ANA seropositivity [23], and ANA seropositive samples were further assessed by serial dilution to concentrations of 1:160, 1:320, 1:640, and 1:1280. All samples were processed using identical methods in the same laboratory. Two experienced evaluators independently assessed the readings, and they agreed on over 95% of the grades. Any differences were resolved by consensus or by a third blinded rater.

Serum 25-hydroxyvitamin D levels were measured using a Diasorin radioimmunoassay kit (Stillwater, MN). The serum 25-hydroxyvitamin D levels were classified as severe deficiency (< 10 ng/mL), deficiency (10-19.9 ng/mL), insufficiency (20-29.9 ng/mL), and sufficiency (≥ 30 ng/mL) based on the Endocrine Society Clinical Practice guidelines [21, 24].

Covariates

Based on previous studies [25,26,27], we selected the following variables as covariates: age, gender (male, female), race (Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic Black, Other Race), birth place (US, another country), citizenship status (US citizen, other), household number (1–3, 4–5, 6+), and smoking status was divided into three categories according to serum cotinine levels: none (< 0.05ng/mL), second-hand (0.05-14.99ng/mL), or active (≥ 15ng/mL). Medical history of RA was obtained by asking participants, “Doctor ever said you had arthritis?” and “Which type of arthritis?” Medical history of kidney disease was collected by asking, “Ever told you had weak/failing kidneys?” Additionally, the history of cholesterol-lowering medication use was determined by asking, “Now taking prescribed medicine?”

Statistical analysis

All analyses were conducted using R and Empower Stats 2.0 software, and a p-value < 0.05 was considered statistically significant. Continuous variables were presented as means with standard deviations, while categorical variables were presented as numbers with percentages. Logistic regression models were used to evaluate the relationship of serum 25-hydroxyvitamin D concentrations and ANA positivity. Smoothed curve fitting was employed to identify any non-linear trends between serum 25-hydroxyvitamin D concentrations and ANA positivity risk. The models were adjusted for age, race, birth place, citizenship status, household number, cotinine, RA, taking prescribed medicine and kidneys disease.

Results

Characteristics of study participants

Characteristics of study participants are summarized in Table 1 according to gender and serum 25(OH)D concentrations. A total of 2757 subjects were included in the study, including 1414 (51.29%) men and 1343 (48.71%) women (average age, 43.99 ± 21.88 years). In male population, the higher 25(OH)D levels people is likely to be Non-Hispanic White, not have kidney disease and lower prevalence of ANA positivity. In female population, subjects who had higher 25(OH)D concentrations tended to be Non-Hispanic White and not RA. In addition, serum 25(OH)D levels is associated with ANA positivity only in men subjects. We also evaluated the relationship of 25(OH)D concentrations with ANA titer and patterns by sex. ANA patterns include nuclear patterns, cytoplasm patterns and mitotic patterns. Among them, nuclear patterns are common and accounted for the highest proportion of ANA positivity. Speckles and homogenous are the most common nuclear patterns and have the highest clinical value. The results shown that the serum 25(OH)D level is linked with ANA patterns but not ANA titer. However, the positivity of DFS-70 is not related with serum 25 (OH) D concentrations, which is in contrast to the conclusions of previous studies [28].

Table 1 Characteristics of participants according to sex and serum 25(OH)D concentrations
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Serum 25-hydroxyvitamin D concentrations links with ANA positivity to a limited extent in men

As shown in Table 2, serum 25-hydroxyvitamin D concentration had a relationship with ANA positivity in males, but not females. Higher levels of serum 25-hydroxyvitamin D were inversely linked to ANA positivity after adjusting age, race, birth place, citizenship status, household number, cotinine, RA, taking prescribed medicine, kidneys disease (Model III). Compared to the lowest serum 25-hydroxyvitamin D concentration (< 10ng/mL), the adjusted odd ratios (ORs) and 95% confidence intervals (CIs) were 0.32 (0.18, 0.58), 0.30 (0.16, 0.55) and 0.23 (0.11, 0.47) for serum 25-hydroxyvitamin D levels 10-19.9, 20-29.9, ≥ 30 ng/mL, respectively.

Table 2 Relationship between serum 25-hydroxyvitamin D levels and ANA status in different models by sex
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Nonlinear correlation between 25-hydroxyvitamin D concentration and the risk of ANA positivity in men

Since serum 25-hydroxyvitamin D levels are linked to ANA positivity in men, we further investigated the nonlinear association of 25-hydroxyvitamin D concentration and ANA positivity risk in the male participants. The smoothed curve fitting results revealed a non-linear correlation between serum 25-hydroxyvitamin D levels and ANA positivity risk (Fig. 2). Two-piecewise model found an inflection point at 18 ng/mL, p for log-likelihood ratio < 0.05 (Table 3). When serum 25-hydroxyvitamin D concentrations < 18ng/mL, a decrease of 1 unit in serum 25-hydroxyvitamin D concentrations was linked to an 8% increase in the adjusted OR of ANA positivity (OR 0.92; 95% CI 0.87, 0.97; p 0.0026). When serum 25-hydroxyvitamin D concentrations ≥ 18ng/mL, no correlation was found between 25-hydroxyvitamin D concentrations and ANA positivity risk (OR 0.99; 95% CI 0.96, 1.02; p 0.5529).

Fig. 2
figure 2

Smooth fitting curve reflecting the association of serum vitamin D concentrations and the risk of ANA positivity (all) in the men. Adjusted for age, race, birth place, citizenship status, education, household number, smoking status and BMI

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Table 3 Threshold effect analysis of serum 25 (OH) D levels and the risk of ANA positivity using Piece-wise Linear regression
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Stratified analyses

The protective benefit of higher serum 25-hydroxyvitamin D levels (≥ 18 ng/mL) compared to lower levels (< 18 ng/mL) on the risk of ANA positivity was observed consistently across various subgroups, including those stratified by age, race and smoking status (Fig. 3). Apart from smoking status (p-interaction = 0.0436), no remarkable interaction was found between 25 (OH) D concentrations and the stratified variables. Moreover, in male population, an obvious inverse correlation between 25 (OH) D levels and ANA positivity was observed in non-white individuals and those exposed to second-hand smoke.

Fig. 3
figure 3

Forest plots of stratified analyses of serum vitamin D and the risk of ANA positivity in male population. Adjusted for age, race, birth place, citizenship status, household number, cotinine, RA, taking prescribed medicine, kidneys disease except the subgroup variable

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Discussion

This study is the first to investigate the correlation between serum 25-hydroxyvitamin D concentrations and ANA positivity according to sex stratification. Our results reveal that 25-hydroxyvitamin D concentrations are linked to ANA positivity in males but not in females. In the male population, we observed an L-shaped relationship between serum 25-hydroxyvitamin D concentrations and ANA positivity risk. Within a certain range, serum 25-hydroxyvitamin D concentrations were negatively linked to ANA positivity risk. In addition, the serum 25(OH)D level is associated with ANA patterns but not ANA titer. These findings could help inform reasonable dietary and clinical recommendations to reduce the prevalence of ANA positivity.

ANA is an important serological indicator of AIDs, such as SLE [7], RA [8], SS [9]. It has important clinical significance for the diagnosis and differential diagnosis, clinical classification and activity monitoring of AIDs. Besides, ANA seropositivity is also existed in chronic infectious diseases, tumors and healthy people [29,30,31,32]. It is well known that ANA positivity and AIDs prevalence are difference in men and women. Previous research has reported that in the American population, the prevalence of AIDs is approximately 5–8%, with women accounting for 78% of cases [33]. The sex disparity in AIDs may be attributed to the differences in immune systems between males and females. Males tend to exhibit immune suppression, while females tend to have increased immune reactivity. This difference in immune response makes women more susceptible to developing AIDs [34]. The higher immune reactivity observed in women is due, in part, to estrogens, which provide greater resistance to infections but also increase the risk of developing AIDs [35]. Furthermore, autosomal sex-biased genes, X chromosome dosage, and environment factors may also contribute to this sex bias [6, 36]. Therefore, taking gender into account when investigating AIDs is crucial. Interestingly, serum 25-hydroxyvitamin D level may also differ between genders. Some researchers believe that men have higher serum 25-hydroxyvitamin D levels [37], while others have opposite opinions [38]. However, some studies have indicated that 25-hydroxyvitamin D concentrations are not sex-dependent, but it is useful to develop disease prevention strategies based on sex-specific determinants of 25-hydroxyvitamin D concentrations [39].

To explore the correlation of serum 25-hydroxyvitamin D concentrations and ANA positivity in both males and females, we adjusted for various confounding variables that are known to be related with ANA positivity, including age, race, birth place, citizenship status, household number, cotinine, RA, taking prescribed medicine, kidneys disease [25,26,27, 40]. Our results indicated that serum 25-hydroxyvitamin D concentrations were linked with ANA positivity in men, but not in women. We speculate that this gender difference may be due to the interplay between sex hormones and 25-hydroxyvitamin D [41]. Sundkvist et al. discovered that 25-hydroxyvitamin D concentrations were significantly lower in male patients with autoimmune type 1 diabetes compared to female patients, indicating that the role of 25-hydroxyvitamin D in disease pathogenesis may be gender-specific [42]. However, a Dutch study suggested that higher 25-hydroxyvitamin D concentrations are protective against multiple sclerosis in women [43], which is inconsistent with our conclusion. This discrepancy may be due to different populations, different experimental methods and different sample size. Furthermore, the correlation between 25-hydroxyvitamin D concentrations and sex hormones is still a topic of controversy. Michos et al. suggested a negative relationship between 25-hydroxyvitamin D and free testosterone concentrations in both males and females, but a positive correlation with estradiol levels only in females, while total testosterone levels were not linked to 25-hydroxyvitamin D concentrations [44]. However, a positive relationship was observed between 25-hydroxyvitamin D and total testosterone in Malaysian men [45]. Therefore, further investigation is necessary to reveal the relationships between 25-hydroxyvitamin D concentrations, sex hormones, and autoimmunity.

25-hydroxyvitamin D is critical in preventing AIDs, with higher levels of 25-hydroxyvitamin D having immunosuppressive effects [46,47,48,49]. However, determining the optimal concentration of serum 25-hydroxyvitamin D is a subject of controversy [50]. Our research found that men with lower serum 25-hydroxyvitamin D concentrations exhibited a greater propensity towards ANA positivity than those with higher levels, which was similar with prior reports [21]. We also observed an L-shaped relationship between serum 25-hydroxyvitamin D concentrations and ANA positivity risk in the male population, whereby the risk decreased with increasing 25-hydroxyvitamin D levels until serum concentrations reached 18 ng/mL. After 5.3 years of randomized follow-up, Costenbader et al. suggested that daily supplementation with 2000 IU of 25-hydroxyvitamin D reduced AIDs by 22% in women ≥ 55 years old and men ≥ 50 years old, further highlighting the value of 25-hydroxyvitamin D in AIDs [51, 52]. Furthermore, in male population, stratified analyses indicated an obvious negative correlation was observed between 25-hydroxyvitamin D status and ANA positivity in non-white individuals and those exposed to second-hand smoke. Additionally, African Americans are more likely to have severe 25-hydroxyvitamin D deficiency (15–20 times higher than European Americans) [53], and our data indicates that 25-hydroxyvitamin D deficiency is more harmful in non-white populations. Similar to prior studies [25, 54], second-hand smoke may be risk factors of AIDs and associated with ANA positivity.

In this study, we utilized a nationally representative U.S. sample with a relatively large sample size, which allowed us to draw generalizable conclusions. We also enhanced the validity of our findings by adjusting for several potential confounding factors. Additionally, the NHANES database provided a reliable method for detecting serum 25-hydroxyvitamin D levels and ANA positivity, which ensure the reliability of analysis. However, there are some limitations to our research. Firstly, the mere ANA positivity does not represent AID, approximately 13% of healthy individuals are ANA positive [30, 55], and clinical information of ANA positivity cannot obtain expect RA because this was not asked in the NHANES surveys. Secondly, there are limitations within the NHANES database. For instance, the NHANES 2001–2004 cycles lack data on vitamin D supplements, and information on medications affecting vitamin D metabolism is unavailable, except for cholesterol-lowering agents. This may introduce potential deviations in vitamin D levels. Besides, we cannot fully rule out other factors influencing ANA positivity, such as over-the-counter agents and dietary supplements. Thirdly, the cross-sectional nature of the study limits our ability to establish causality between the exposure and outcome. In addition, like other observational studies, our analysis may be affected by unknown or residual confounding variables that may impact the correlation between 25-hydroxyvitamin D levels and ANA positivity.

Conclusions

Following multivariable adjustments, we observed a significant and nonlinear correlation between decreased serum 25-hydroxyvitamin D levels and an increased risk of ANA positivity in U.S. people. Further analysis shown an L-shaped relationship between serum 25-hydroxyvitamin D levels and ANA positivity risk, with a plateau at 18 ng/mL. This suggests that the threshold of 18 ng/mL may represent an intervention target for reducing ANA positivity risk. These findings emphasize the potential benefits of monitoring and assessing 25-hydroxyvitamin D levels in preventing ANA positivity.

Data availability

The original contributions presented in the study are included in the article material. Further inquiries can be directed to the corresponding authors.

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Acknowledgements

The authors thank the staff and the participants of the NHANES study for their valuable contributions.

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Author notes

  1. Zhen Gui, Shuying Li and Hanqing Yu contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, 72# Guangzhou Road, Nanjing, 210008, China

    Zhen Gui, Hanqing Yu, Lin Chang & Yong Chang

  2. Department of Health Management Center, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210000, China

    Shuying Li

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  1. Zhen Gui
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  4. Lin Chang
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Contributions

Z.G and S.L contributed to data collection and analysis, writing, and language polishing. YC contributed to the application of data analysis software. The first three authors contributed equally to the manuscript. HY and LC contributed to the supervision and review. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lin Chang or Yong Chang.

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The Ethics Review Board of the National Center for Health Statistics approved all NHANES protocols. Written consent informs were obtained from all participants.

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The authors declare no competing interests.

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Gui, Z., Li, S., Yu, H. et al. Sex-specific relationship between serum 25-hydroxyvitamin D concentrations and antinuclear antibodies in U.S. adults, NHANES 2001–2004. BMC Immunol 25, 81 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12865-024-00672-6

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12865-024-00672-6

Keywords

BMC Immunology

ISSN: 1471-2172

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