Relationship between vitamin D and IgE: a cross-sectional analysis

Introduction

Vitamin D is a crucial, fat-soluble vitamin with a key role in bone metabolism as well as important immunomodulatory functions (1). Increasing evidence suggests that vitamin D may influence the pathogenesis of allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis (2-10). Immunoglobulin E (IgE) serves as an important biomarker of allergic responses, and elevated IgE levels are generally associated with heightened allergic reactivity (11). Several studies have proposed that vitamin D deficiency may correlate with an elevated IgE level, which could exacerbate allergic conditions (3,7,12). However, previous studies on the relationship between vitamin D and IgE levels have yielded inconsistent results, with several studies reporting a negative association between vitamin D and IgE, suggesting that vitamin D deficiency may lead to elevated IgE (2,4,7,8), while others have found no significant link between the levels of these factors (5,6,9). The discrepancies in these study results may be due to variations in population characteristics, such as age, sex, and allergic disease status, as well as differences in study design, such as the consideration of seasonal variation. Moreover, most prior studies have been limited by relatively small sample sizes and a lack of stratified analyses, underscoring the need for more comprehensive research of this potential relationship in pediatric populations. A clear understanding of the potential correlation between vitamin D and IgE levels is expected to be clinically valuable, as it would expand our understanding of the immunoregulatory role of vitamin D and potentially guide the use of vitamin D supplementation and other strategies for the prevention and treatment of allergic diseases, particularly in the pediatric population.

Accordingly, the present study aimed to examine the association between serum vitamin D and total IgE concentrations in a large pediatric cohort and to further explore whether this relationship is influenced by age, sex, season, and allergic disease status. Using a cross-sectional design, we assessed the dose–response relationship between serum 25-hydroxyvitamin D [25(OH)D] and total IgE concentrations and performed stratified analyses to better characterize their interaction. By elucidating how demographic and seasonal factors modulate the relationship between vitamin D and IgE, this study aimed to fill existing research gaps and provide robust epidemiological evidence to guide future clinical investigations of the effectiveness of managing vitamin D status in treating allergic disease. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-773/rc).

Methods

Study population

This cross-sectional study included 9,126 pediatric patients who attended the Department of Pediatrics at Shengjing Hospital, China Medical University, between January 1 and May 31, 2024. Patients were enrolled in this study if they met the following inclusion criteria: age 1–18 years, availability of complete serum 25(OH)D and total IgE data, and provision of informed consent by guardians for their participation. Individuals were excluded from this study if they met any of the following exclusion criteria: history of a major underlying condition (e.g., immunodeficiency, malignancy), incomplete clinical records, use of mediations known to affect vitamin D and IgE levels (e.g., glucocorticoids, antihistamines) within the previous 3 months, or absence of guardians’ consent for participation. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was reviewed and approved by the Ethics Committee of Shengjing Hospital of China Medical University (No. 2025PS1453K). Informed consent was obtained from guardians of the patients for their participation. The process of participant identification, inclusion, and grouping is summarized in Figure S1.

Data collection

Fasting venous blood samples were collected from all participants. Serum 25(OH)D concentrations were measured by electrochemiluminescence immunoassay (C) using the Elecsys Vitamin D total III kit, with results reported in units of ng/mL. Total IgE concentrations were determined by electrochemiluminescence immunoassay using the Elecsys IgE II kit, with results reported in units of IU/mL. Demographic and clinical data, including age, sex, allergic disease diagnosis, and date of sample collection, were extracted from medical records.

Variable definitions

Vitamin D status was categorized as previously described (1): deficient, <30 ng/mL; insufficient, 30–50 ng/mL; and sufficient, >50 ng/mL. Seasonal grouping was applied, defining spring as March to May and winter as January to February. The participants were grouped according to age as follows: early childhood, ≤6 years; school age, >6–12; and adolescence, >12–18 years. Allergic diseases, including atopic dermatitis, allergic rhinitis, asthma, urticaria, and allergic dermatitis, were defined based on physician diagnoses documented in the electronic medical records. Diagnoses were made by pediatricians or pediatric subspecialists according to established clinical guidelines and routine clinical practice.

Statistical analysis

All statistical analyses were performed in Python using the pandas, scipy, and statsmodels libraries. Two-sided tests were used throughout, with P<0.05 defining statistical significance. Graphs were generated in GraphPad Prism 9.5. Measured 25(OH)D and IgE concentrations were reported as median and interquartile range (IQR). Between-group comparisons were conducted using the Mann-Whitney U test for non-normally distributed data. The male-to-female ratio was compared between groups using the chi-square (χ²) test, with results expressed as count and ratio. Spearman’s rank correlation analysis was applied to assess the relationship between 25(OH)D and IgE concentrations. For multivariable linear regression analyses, IgE values were log-transformed, and models were adjusted for age and sex to obtain standardized regression coefficients. For the dose–response analysis, restricted cubic spline (RCS) models were fitted to explore the nonlinear association between 25(OH)D and IgE concentrations. For stratification analyses, all analyses of 25(OH)D and IgE concentrations were repeated with stratification by age group, sex, and season to evaluate the potential effects of these factors on the tested relationship.

Results

Characteristics of the study population

The study population consisted of 9,126 pediatric patients with ages ranging from 1 to 18 years [median age, 6.0 years (IQR, 3.0–9.0 years)]. Of the included children, 5,089 (55.8%) were male, and 4,037 (44.2%) were female. A total of 1,026 children had a clinical diagnosis of allergic disease (atopic dermatitis, allergic rhinitis, asthma, allergic contact dermatitis, or urticaria) and were included in the allergic disease group, and 8,100 had no clear diagnosis of allergic disease and were included in the non-allergic disease group. The baseline characteristics of the total study population and groups based on allergic disease status are presented in Table 1. Notably, the serum 25(OH)D and total IgE concentrations were higher in the allergic disease group than in the non-allergic disease group (both P<0.0001).

Inverse correlation of serum 25(OH)D with total IgE, especially in allergic patients

Spearman’s correlation analysis demonstrated a significant inverse relationship between serum 25(OH)D and total IgE concentrations among the total cohort (r=−0.1443, P<0.0001), indicating that higher vitamin D concentrations were associated with lower IgE levels, although with a modest correlation coefficient. In subgroup analyses, this negative correlation was stronger in the allergic disease group (r=−0.2662, P<0.0001) than in the non-allergic disease group (r=−0.1354, P<0.0001), suggesting a more pronounced inverse association among children with allergic conditions (Figure 1 and Table S1).

Figure 1 Inverse correlation between serum 25(OH)D and total IgE concentrations. Scatter plots showing the linear relationship between serum 25(OH)D and total IgE concentrations in (A) the total study population (r=−0.1443, P<0.0001); (B) the allergic disease subgroup (r=−0.2662, P<0.0001); and (C) the non-allergic disease subgroup (r=−0.1354, P<0.0001). 25(OH)D, 25-hydroxyvitamin D; IgE, immunoglobulin E; VD, vitamin D.

Multivariable linear regression analysis was then performed to evaluate the independent relationship between serum 25(OH)D and total IgE concentrations. After log-transformation of IgE concentrations and adjustment for age and sex, the serum 25(OH)D concentration remained a significant negative predictor of the total IgE concentration (regression coefficient β=−0.0081, P<0.0001), although the model explained only 6.5% of IgE variance (R²=0.065), indicating that other factors (e.g., genetics, environment, immune status) account for the majority of IgE variability. In the allergic disease subgroup, the serum 25(OH)D concentration continued to show an independent inverse association with the total IgE concentration (β=−0.0125, P=0.005; R²=0.150), whereas this association was weaker in the non-allergic disease group (β=−0.0077, P<0.0001; R²=0.060) (Table 2).

Higher IgE at vitamin D deficiency with diminishing effects at higher levels

We further explored the nonlinear association between serum 25(OH)D and total IgE concentrations by performing RCS analysis. The results indicated that total IgE levels were elevated in participants with levels of 25(OH)D defining vitamin D deficiency, whereas total IgE levels showed little variation when 25(OH)D levels were in the range of insufficient vitamin D status. Moreover, IgE levels tended to decline with 25(OH)D levels in the range of sufficient vitamin D status, although this trend did not reach statistical significance. These findings indicate a non-linear, concentration-dependent association between serum 25(OH)D and total IgE in this cross-sectional population. The observed pattern reflects differences in IgE distribution across a range of 25(OH)D concentrations and should be interpreted as a descriptive statistical association rather than as evidence of a biological threshold or causal regulatory effect. Similar patterns were observed in both the allergic and non-allergic subgroups (Table 3).

Influence of age, sex, and season on the strength of the 25(OH)D-IgE association

Inverse 25(OH)D-IgE association is strongest in early childhood (≤6 years) and attenuates with age

The age distribution of the study cohort, along with the age-related variation in serum 25(OH)D and total IgE concentrations, is presented in Figure 2. We observed that serum 25(OH)D levels declined progressively with increasing age, whereas total IgE levels rose steadily before age 10 years and plateaued thereafter (Figure 2). In further subgroup analyses by age, a significant inverse correlation between serum 25(OH)D and IgE concentrations was found in the early childhood group (≤6 years; β=−1.5653, P<0.001), indicating that higher vitamin D levels were associated with lower IgE among children in this age group. In contrast, no significant correlation between serum 25(OH)D and total IgE concentrations was observed in the school-age or adolescence groups, suggesting that the impact of vitamin D on IgE may diminish with age. Similar patterns were observed for both the allergic and non-allergic disease subgroups (Table 4 and Table S2).

Figure 2 Age distribution and age-stratified serum 25(OH)D and total IgE concentrations. (A) Age distribution of the study cohort. (B) Serum 25(OH)D concentrations by age group (median, IQR). (C) Total IgE concentrations by age group (median, IQR). 25(OH)D, 25-hydroxyvitamin D; IgE, immunoglobulin E; IQR, interquartile range.

Inverse 25(OH)D-IgE association is consistent in both sexes

We further stratified the analysis by sex to examine the relationship between serum 25(OH)D and total IgE concentrations in males and females (Table 5 and Table S3). In both sexes, serum 25(OH)D and total IgE concentrations remained significantly inversely correlated (both P<0.001), with similar effect sizes, indicating minimal sex-based modification of the vitamin D-IgE relationship. Comparable findings were observed within both the allergic disease and non-allergic disease subgroups.

Inverse 25(OH)D-IgE association is stronger in winter than in spring

In the seasonal analysis, participants were grouped into cohorts for which serum 25(OH)D and total IgE concentrations were measured in spring or winter for stratified regression analysis of the association between 25(OH)D and IgE. Significant inverse associations were observed in both seasons, but the results indicated that the regulatory effect of vitamin on IgE, while evident year-round, was particularly pronounced in winter when 25(OH)D levels were lower (P<0.001). Similar patterns were observed in both the allergic and non-allergic disease subgroups (Table 6 and Table S4).

Higher total IgE in vitamin D–deficient children, with progressive decline as vitamin D status improves

Comparison of the total IgE levels among the vitamin D-deficient, insufficient, and sufficient groups showed that IgE concentrations differed significantly across all three categories (P<0.0001), with the highest IgE levels observed in the vitamin D-deficient group and the lowest in the vitamin D-sufficient group (Figure 3).

Figure 3 Differences in total IgE concentration according to vitamin D status. Box-and-whisker plots illustrating total IgE distributions in vitamin D-deficient, vitamin D-insufficient, and vitamin D-sufficient groups. ****, P<0.0001. IgE, immunoglobulin E.

Discussion

In a large cross-sectional cohort of 9,126 pediatric patients, the present study revealed a significant inverse correlation between the serum 25(OH)D concentration and total IgE concentration (Spearman’s r=−0.1443, P<0.0001). This negative association was even stronger among pediatric patients with allergic diseases (atopic dermatitis, allergic rhinitis, asthma, urticaria; r=−0.2662, P<0.0001) but remained statistically significant among those without a diagnosis of allergic disease (r=−0.1354, P<0.0001). Multivariable linear regression analysis with adjustment for age and sex confirmed that serum 25(OH)D was an independent negative predictor of log-transformed IgE (β=−0.0081, P<0.0001), although the model explained only about 6.5% of IgE variance. RCS analysis showed that, at the population level, higher total IgE concentrations were predominantly observed among children with lower serum 25(OH)D concentrations, whereas the association appeared less pronounced in cases with higher 25(OH)D levels. Given the cross-sectional design of the present study, this pattern represents a statistical feature of the data distribution rather than a within-individual dose-response relationship or evidence of a biological cutoff.

Previous studies have reported mixed results regarding the relationship between vitamin D and IgE. In one infant food-allergy cohort, vitamin D insufficiency (defined as ≤50 nmol/L) was associated with higher rates of peanut and/or egg allergy, independent of eczema status (2). In two studies in allergic rhinitis patients, lower vitamin D levels correlated with higher total IgE levels (8,9). In a cohort of 921 children hospitalized for severe bronchiolitis in infancy in the USA, a low serum 25(OH)D concentration at age 3 years predicted increased aeroallergen-specific IgE level at age 6 years (13). Conversely, a study of 365 adolescents in Korea reported positive correlations between both total and Dermatophagoides farinae-specific IgE levels and serum 25(OH)D concentration, even after adjustments for sex, age, and body mass index (BMI) (14). These contradictory findings may stem from the small sample sizes and heterogeneous designs of previous studies. The larger, stratified analysis presented in the present study provides more precise effect estimates and uniquely shows that a modest inverse 25(OH)D-IgE relationship exists even in children without a diagnosis of allergic disease.

Vitamin D encompasses ergocalciferol (D₂) and cholecalciferol (D₃) plus their active metabolites. Endogenous synthesis following ultraviolet exposure is the primary source of vitamin D in humans (15). Early epidemiological data linked latitude with food allergy prevalence, plausibly reflecting lower UV-driven vitamin D production at extreme latitudes (16). 25(OH)D binds the vitamin D receptor (VDR) on antigen-presenting cells, inhibiting dendritic cell maturation and skewing CD4⁺ T-cell differentiation away from the T helper 2 (Th2) lineage, thereby reducing interleukin-4/interleukin-13-mediated class switching to IgE in B cells (17-19). Consistently, animal models of vitamin D deficiency exhibit serum IgE concentrations, enhanced allergic inflammation, and suppressed T regulatory cell numbers (18,19). Vitamin D has been shown to exert immunomodulatory effects in experimental and mechanistic studies, including effects on antigen-presenting cells and T-cell differentiation. However, the present study was not designed to evaluate biological mechanisms. Accordingly, although prior experimental evidence provides a biological context, the observed association between serum 25(OH)D and total IgE in this cross-sectional analysis should not be interpreted as evidence of a VDR-mediated mechanism or a biological threshold effect.

Stratified analyses in the present study further refined our understanding of the relationship between vitamin D and IgE. Among the three age groups, the strongest inverse correlation between vitamin D and IgE was observed in children <6 years (β=−0.1565, P<0.001), and this relationship weakened with increasing age. This suggests early childhood immune development and vitamin D metabolism are more dynamic and sensitive to 25(OH)D fluctuations. The results with sex stratification showed similar negative associations in both boys (β=−2.53, P<0.0001) and girls (β=−2.18, P<0.0001), indicating minimal influence of gender on the relationship between vitamin D and IgE. Seasonally, a stronger inverse relationship between vitamin D and IgE was observed in winter (β=−2.62, P<0.0001) compared with spring (β=−2.11, P<0.0001), likely reflecting reduced endogenous 25(OH)D synthesis and potential amplification of Th2 skewing during low-UVB months.

Collectively, these findings highlight an epidemiological association between serum vitamin D status and total IgE concentrations in children. Given the cross-sectional study design and the modest proportion of IgE variability explained by serum 25(OH)D, these results should not be interpreted as evidence that vitamin D screening or supplementation improves allergic outcomes or reduces IgE levels at the individual level. Instead, the observed patterns may help inform the design of future prospective studies and randomized trials aimed at clarifying the causality and clinical relevance of the observed association.

The strengths of our study include its large sample size, clear stratification according to the presence or absence of allergic disease, and combined linear and nonlinear modeling to detect threshold effects. The limitations of this study include the cross-sectional design, which precludes causal inference; potential residual confounding factors (e.g., BMI, diet, indoor pollution); lack of data on vitamin D supplementation and sun-exposure duration; absence of genetic polymorphism analysis in VDR; and reliance on total IgE without specific IgE values or clinical symptom scores. Future research should include prospective cohort studies and randomized controlled trials of vitamin D supplementation in children with vitamin D deficiency to establish causality and optimal dosing strategies.

Conclusions

In this large pediatric cross-sectional cohort, serum 25(OH)D concentrations were inversely associated with total IgE levels, with the association being stronger in children with allergic diseases and in younger age groups. The relationship showed age- and season-dependent variation and a nonlinear pattern, with higher IgE concentrations predominantly observed at lower 25(OH)D levels. However, given the observational and cross-sectional nature of the study, these findings should be interpreted as epidemiological associations rather than evidence of causality or a therapeutic effect of vitamin D. Future prospective studies and interventional trials are needed to determine whether optimizing vitamin D status has clinical relevance for allergic sensitization or disease outcomes in children.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-773/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-773/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-773/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-773/coif). Q.Z. is an employee of Shenyang Paiert Technology Co., Ltd. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was reviewed and approved by the Ethics Committee of Shengjing Hospital of China Medical University (No. 2025PS1453K). Informed consent was obtained from guardians of the patients for their participation.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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