While the effects of vitamin D deficiency on bone health are well documented, its role in other health outcomes is a contentious issue in many areas of medicine, including allergy and immunology. Vitamin D is increasingly recognized for its significant role as an immunomodulatory agent, influencing various aspects of the immune system, including allergies and immunology (1, 2). Interest in the role of vitamin D in the incidence of allergic diseases has significantly increased in recent years, largely due to the perception of vitamin D supplementation as an affordable, noninvasive, and easily administered intervention. Research has shown that vitamin D deficiency is often associated with an increased risk of developing allergic diseases. For instance, children with lower vitamin D levels have been found to have a higher likelihood of food allergies, particularly in their early years (3). This association is thought to be due to vitamin D’s role in maintaining the integrity of the epithelial barrier and promoting a more tolerogenic immune response, which can prevent the immune system from overreacting to harmless antigens (4). However, the evidence regarding the impact of vitamin D on allergy-related outcomes remains inconclusive.

The proposed mechanism by which vitamin D influences immune development and immune-related diseases involves both direct and indirect effects on the immune system. In their review of the impacts of gut microbiota, probiotics, and vitamin D on allergies and asthma, Ly et al. posited that vitamin D may serve as a significant modifier in the relationship between intestinal flora and inflammatory disorders (5). Recent discussions have suggested that low levels of vitamin D may constitute a risk factor for inflammatory bowel diseases, such as Crohn’s disease, indicating that vitamin D can influence gut inflammation (6, 7). This gut inflammation, in turn, may impact immune development and function, potentially manifesting as the initial observable inflammatory diseases, such as eczema and allergies (8). The conversion of 25-hydroxyvitamin D [25(OH)D] to its active form, 1,25-dihydroxyvitamin D [1,25(OH)2D], within monocytes and macrophages enhances the synthesis of antimicrobial peptides, thereby augmenting cellular immune responses. Vitamin D inhibits the proinflammatory responses of the adaptive immune system, and promotes proliferation of immunosuppressive regulatory T cells and their accumulation at sites of inflammation (9, 10).

Given the promising data from clinical trials, the inconsistent findings from observational studies—including the German LINA cohort where higher maternal vitamin D correlated with increased food allergy risk (11)—regarding intrauterine vitamin D status and atopic disease incidence remain perplexing (12–15). The significant clustering of allergies within families indicates a genetic foundation, with several genetic polymorphisms being involved (16–19). Liu et al. proposed that vitamin D might interact with or modify genetic predispositions in children with high-risk genotypes, based on their findings of a significant interaction between an IL-4 gene polymorphism and vitamin D deficiency (20). This interaction was associated with an increased risk of food sensitization among children with CC/CT genotypes (OR = 1.79, 95% CI: 1.15–2.77). To comprehensively understand the relationship between intrauterine vitamin D exposure and allergic diseases, it is essential to conduct analyses using well-designed, large-scale prospective cohorts of maternal–infant dyads. These studies should account for individual genetic risk, early life exposures, and environmental confounders. This study aims to assess the relationship between maternal and cord blood vitamin D status and atopic outcomes within a thoroughly characterized prospective birth cohort, featuring clinically validated outcomes and long-term follow-up.

The influence of early-life vitamin D on the development of childhood allergies remains a subject of debate. Polymorphisms in genes are hypothesized to modulate the effects of vitamin D in vivo. This study aims to investigate the associations between vitamin D exposure and genetic polymorphisms in the context of childhood food allergy development.

This prospective birth cohort study provides novel insights into the complex relationship between early-life vitamin D exposure, genetic susceptibility, and childhood allergy development. As visualized in Figure 2, the U-shaped relationship between cord blood 25(OH)D and food allergy risk was statistically robust (p < 0.001 for non-linearity) during infancy, echoing prior reports of non-linear vitamin D effects on respiratory sensitization (32). However, our study extends this paradigm in three key dimensions: First, our U-shaped risk curve reflects dual genetic modulation: (i) risk amplification via Th2-pathway variants (IL4R/IL-4/IL13) under low vitamin D; (ii) protection attenuation in FcεRIβ (MS4A2) carriers at high vitamin D. Second, we establish this U-shaped relationship for clinically confirmed food allergy—a distinct phenotype from respiratory outcomes. Third, we reveal temporal dynamics: vitamin D’s protective effects attenuate by 24 months, suggesting critical developmental windows for intervention. While prior studies predominantly emphasize vitamin D deficiency as a risk amplifier for allergic disorders (5), our observation of heightened FA susceptibility at both low [25(OH)D <15 ng/mL] and elevated [25(OH)D >25 ng/mL] vitamin D levels challenges the linear “deficiency-risk” paradigm. This aligns with emerging evidence suggesting that excessive vitamin D may paradoxically impair immune tolerance by over-suppressing Th1/Th2 balance (16), though contrasting with reports advocating higher postnatal vitamin D supplementation for allergy prevention (20). Our observation of a U-shaped relationship between cord blood 25(OH)D and clinical food allergy contrasts with null findings for food sensitization in the Danish COPSAC2000 cohort (12), where vitamin D deficiency (<50 nmol/L [20 ng/mL]) only associated with respiratory outcomes. This discrepancy may reflect key methodological differences: (i) COPSAC assessed IgE sensitization rather than clinically confirmed food allergy; (ii) their cohort had substantially lower mean cord 25(OH)D (12.9 ng/mL) with minimal high-exposure representation (<1.5% > 30 ng/mL), potentially limiting detection of non-linear effects; and (iii) population-specific genetic/epigenetic factors may modulate vitamin D’s immunoregulatory effects. Importantly, our gene–environment interaction analyses suggest vitamin D’s impact is modified by genetic susceptibility, a dimension absent in prior null reports.

The gene–environment interactions we identified reveal a triad of Th2-sensitizing genotypes—IL4R rs1801275 AA, IL-4 rs2243250 CC, and IL13 rs20541 GG—that confer 4- to 26-fold elevated food allergy risk under vitamin D deficiency. This synergistic effect aligns with vitamin D’s role in suppressing IL-4/STAT6 signaling and Th2 differentiation via VDR-mediated chromatin remodeling (6). Our observation that deficiency overrides this suppression in specific genotypes suggests certain variants may create a “genetic vulnerability window” during fetal immune programming. This contrasts with studies where vitamin D supplementation mitigated allergy risk even in high-risk genotypes (6), highlighting the need for genotype-stratified intervention trials. Our results suggest that vitamin D sufficiency may be particularly critical for children with genetic variants predisposing to enhanced Th2 responses, potentially through restoration of immune balance between regulatory T cells and Th2 effectors. Unlike the uniformly risk-amplifying effects of Th2-pathway variants (IL4R/IL-4/IL13) under vitamin D deficiency, MS4A2’s role is protective and vitamin D-dependent.

The dual role of MS4A2 (rs569108) in vitamin D-dependent allergy modulation refines our understanding of genetic regulation in IgE-mediated responses. MS4A2 encodes the β-chain of the high-affinity IgE receptor (FcεRIβ) (23), a key amplifier of mast cell signaling. Contrary to initial hypotheses, we observed that the GG genotype conferred significant protection against allergy at reference vitamin D levels (15–25 ng/mL; adjusted OR = 0.55, p = 0.016), suggesting FcεRIβ may participate in vitamin D-mediated tolerance induction. However, this protective effect was attenuated at high vitamin D levels (>25 ng/mL; OR = 0.68, p = 0.149), indicating a therapeutic ceiling for supplementation in GG carriers. Notably, the absence of risk amplification under vitamin D deficiency (OR = 3.12, p = 0.095) diverges from Th2 gene interactions but aligns with vitamin D’s dose-dependent suppression of FcεRIβ expression (20). This complex gene–environment interplay underscores that genetic effects on IgE pathways are contextually modified by vitamin D status. Thus, while our U-shaped association aligns with broader evidence of vitamin D’s dual immunomodulatory roles, the discovery of genotype-dependent risk thresholds and age-specific susceptibility windows provides unprecedented mechanistic and translational insights for allergy prevention in genetically predisposed infants.

The transient nature of vitamin D’s protective effects—strongest at 6–12 months but diminishing by 24 months—echoes murine models where neonatal dendritic cell programming by vitamin D dictates long-term immune trajectories (9), yet diverges from birth cohort studies reporting persistent vitamin D-FA associations beyond infancy (12). The temporal pattern of vitamin D’s protective effects aligns with emerging concepts of developmental immunotoxicity windows. Experimental models demonstrate that vitamin D regulates neonatal dendritic cell function and gut barrier integrity during critical periods of microbial colonization (33). Our observation that vitamin D insufficiency during this period correlates with persistent food allergy risk underscores the importance of prenatal and perinatal vitamin D optimization, particularly given the rapid placental transfer of 25(OH)D during late gestation.

Notably, our finding of increased allergy risk at cord blood 25(OH)D levels >25 ng/mL warrants careful consideration. This aligns with findings from the Boston Birth Cohort, which indicated that persistently low vitamin D status at birth and in early childhood increased the risk of food sensitization, particularly among children with specific genetic susceptibilities (34). While the Institute of Medicine defines 20 ng/mL as sufficient for bone health (23), our data suggest potential immune system hypersensitivity to higher concentrations (35). The immunomodulatory effects of vitamin D are further illustrated by its impact on regulatory T cells (Tregs), which play a crucial role in maintaining immune tolerance (35). A study investigating the Urban Environment and Childhood Asthma cohort found that higher cord blood 25(OH)D concentrations were inversely related to the number of Tregs, suggesting that elevated vitamin D levels might reduce the capacity for immune regulation, thereby increasing allergy risk (36). This is supported by another study that found a negative correlation between cord blood 25(OH)D levels and Treg numbers, indicating that high vitamin D levels might impair the development of these critical immune cells (11). Such alterations in immune cell populations could contribute to the increased risk of food allergies observed at elevated vitamin D levels. Moreover, the role of vitamin D in allergy development is complicated by genetic factors. Polymorphisms affecting vitamin D-binding protein (DBP) can modify the relationship between serum vitamin D levels and food allergy risk. A study found that genetic variations leading to lower DBP levels, which increase the bioavailability of vitamin D, could attenuate the association between low serum vitamin D levels and food allergy, suggesting that genetic factors may influence how vitamin D impacts immune responses (37). Our observed U-shaped risk curve—particularly the vulnerability at high vitamin D levels—likely stems from genotype-dependent saturation of vitamin D receptor (VDR) signaling pathways, where excessive ligand promotes pathological immune remodeling in predisposed infants. This underscores that optimal vitamin D ranges for allergy prevention may be genotype-specific, with deficiency posing greater threat to Th2-sensitized infants. This genetic interplay highlights the complexity of vitamin D’s role in allergy development and suggests that individual genetic makeup can significantly alter the effects of vitamin D on immune function. However, the biological plausibility of this U-shaped association requires further investigation through mechanistic studies.

Several limitations should be acknowledged. First, while we adjusted for key covariates (e.g., maternal allergy history, smoking, and antibiotic use), residual confounding by unmeasured environmental factors may influence observed associations, especially maternal dietary patterns during pregnancy (38)—such as intake of allergenic foods (e.g., peanuts, eggs) or micronutrients (e.g., omega-3 fatty acids)—were not captured. Future studies should integrate dietary assessments to disentangle nutritional influences on fetal immune development. Second, the single-center design and ethnic homogeneity (Chinese Han population) may limit generalizability. Third, while cord blood 25(OH)D serves as a well-validated indicator of late-gestation fetal vitamin D exposure (25), we lacked maternal prenatal or infant postnatal vitamin D measurements. This precludes analysis of how maternal status independently influences allergy risk or whether postnatal supplementation modifies associations observed at birth. Future studies integrating longitudinal maternal–infant vitamin D trajectories would strengthen causal inference. Fourth, while our U-shaped association aligns with emerging evidence of vitamin D’s dose-dependent immune effects, it diverges from cohorts with distinct genetic backgrounds or environmental exposures. Generalizability to populations with severe vitamin D insufficiency (e.g., high-latitude cohorts) requires verification. Future multi-ethnic cohorts with repeated vitamin D measurements and detailed immune profiling could address these limitations.