Corresponding Author: Joon Mo Kim, MD, PhD. Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea. Allergic diseases, initiated by exposure to allergens, are chronic inflammatory conditions that increasingly burden global health and economies [1,2]. Allergic disorders result from sustained immune responses that trigger prolonged inflammation both at the site of allergen exposure and systemically [3]. This chronic systemic inflammation has been linked to the development of various neurodegenerative disorders [4]. Several studies have reported that allergic diseases are associated with an elevated risk of dementia, particularly Alzheimer disease, which shares common pathophysiological features with glaucoma [5-7].
Glaucoma is a leading cause of irreversible blindness worldwide, being characterized by progressive loss of retinal ganglion cells and their axons [8]. Although elevated intraocular pressure (IOP) remains the most important risk factor [9], emerging evidence suggests that immune-mediated mechanisms may also contribute to glaucomatous neurodegeneration [10,11]. Allergic sensitization, reflected by elevated serum immunoglobulin E (IgE) levels and specific antigen responses, represents an objective measure of immune activation in response to environmental allergens [12].
Previous studies focused on self-reported allergic diseases or diagnostic codes [13,14]; however, antigen testing provides a direct and quantifiable measure of sensitization. In this study, we aimed to determine the association between specific allergen sensitizations such as house dust mites (Dermatophagoides farinae), cockroaches, and dog allergens and glaucoma, using data from the 2010 Korea National Health and Nutrition Examination Survey (KNHANES). We hypothesized that sensitization to certain allergens may be associated with a higher prevalence of glaucoma, potentially through immune-mediated mechanisms affecting the optic nerve.
Materials and Methods
Ethics statement
All research using KNHANES data complied with the Declaration of Helsinki, with written informed consent obtained from all participants. The deidentified data are publicly available online (http://knhanes.cdc.go.kr), and the study protocol received approval from the Institutional Review Board of the Kangbuk Samsung Hospital (No. 2016-06-049).
Study participants
This study used data from the 2010 KNHANES, a nationwide, cross-sectional survey conducted by the Korea Centers for Disease Control and Prevention and the Korean Ministry of Health and Welfare. KNHANES employs a stratified, multistage, probability-cluster sampling design based on age, sex, economic status, and geographic region, ensuring that the data are nationally representative of South Korea’s civilian, noninstitutionalized population. Detailed methodologies for KNHANES have been described elsewhere. Notably, the 2010 KNHANES initially enrolled 8,958 participants; however, 2,743 individuals were excluded from analysis because they had aphakia or intraocular lens implantation, a history of refractive or retinal surgery, were using antiglaucoma medications, or showed evidence of retinal detachment or age-related macular degeneration. Crucially, the allergen-specific IgE testing was not universally administered but was conducted on a randomly selected sub-cohort according to the survey protocol. Consequently, further exclusions were made for individuals not selected for this module or with missing data on glaucoma status, resulting in a final analytic sample of 1,334 subjects (Fig. 1). Since this subsampling was pre-determined by the survey design, the risk of systematic selection bias was minimized.
Serum IgE measurement
Fasting blood samples were drawn, processed immediately, kept refrigerated, and transported on ice to the Central Testing Institute in Seoul, Korea. All samples were analyzed within 24 hours of delivery. Both total IgE and allergen-specific IgE levels were determined using an immunoradiometric assay (ImmunoCAP 100, Phadia) along with a 1470 Wizard gamma-counter (PerkinElmer). In South Korea, prevalent inhalant allergens include house dust mites, cockroaches, mugwort, oak, Japanese hop, ragweed, and dog dander—with house dust mites being the most common and cockroaches being the second most prevalent [15]. This study focused on three common indoor allergens: house dust mites (D. farinae), cockroaches, and dog dander.
Ophthalmic examination
All participants underwent comprehensive ophthalmic evaluations performed by certified ophthalmologists, which included detailed eye-focused interviews. A slitlamp examination was carried out to assess the peripheral anterior chamber depth (PACD) using the Van Herick technique on a Haag-Streit BQ-900 system (Haag-Streit AG). IOP was measured with a Goldmann applanation tonometer, and digital nonmydriatic fundus photographs were obtained using a Topcon TRC-NW6S and a Nikon D-80 fundus camera. Visual field testing was performed using frequency doubling technology (FDT) with the Humphrey Matrix (Carl Zeiss Meditec Inc.) following the N-30-1 screening protocol. An abnormal test location was defined as one that failed to be identified after two attempts at a contrast level that correctly detects 99% of healthy individuals; a visual field defect was diagnosed if two or more distinct locations were abnormal.
FDT was administered to participants suspected of glaucoma if any of the following criteria were met: (1) IOP ≥22 mmHg; (2) a horizontal or vertical cup-disc ratio of ≥0.5; (3) deviation from the typical neuroretinal rim thickness pattern (inferior→superior→nasal→temporal, known as the ISNT rule); (4) the presence of optic disc hemorrhage; or (5) a retinal nerve fiber layer (RNFL) defect. If the fixation error rate or false-positive rate exceeded 33%, the FDT was considered invalid, and the test was repeated for accurate glaucoma classification.
Definitions of open-angle glaucoma and control groups
The diagnosis of open-angle glaucoma (OAG) was established according to the International Society of Geographical and Epidemiological Ophthalmology criteria, along with methods from previous studies [16-18]. Subjects were classified as having OAG if they exhibited an open angle with a PACD of greater than one-quarter of the corneal thickness (as determined by the Van Herick method) and met either category I or II diagnostic criteria.
For subjects with reliable FDT perimetry results (i.e., with a false-positive error rate and fixation error of ≤1), category I criteria were applied. These required the presence of at least one of the following: (1) loss of the neuroretinal rim with either a vertical or horizontal cup-disc ratio of ≥0.7 or an intereye asymmetry in cup-disc ratio of ≥0.2 (values based on the ≥97.5th percentile for the normal KNHANES population); (2) presence of optic disc hemorrhage; or (3) the presence of an RNFL defect. Additionally, abnormal FDT perimetry, characterized by at least one location of reduced sensitivity consistent with an RNFL defect or optic disc abnormality, was required. For patients without valid FDT perimetry results or for those with fixation errors or false-positive errors of ≥2, category II criteria were used. These criteria included either of the following: (1) the loss of the neuroretinal rim with a vertical cupdisc ratio of ≥0.9 or an intereye asymmetry of ≥0.3 or (2) the presence of an RNFL defect consistent with the optic disc appearance.
Control subjects were defined as individuals meeting the following criteria in both eyes: (1) an IOP of ≤21 mmHg; (2) an open angle (PACD >0.25 corneal thickness); (3) a nonglaucomatous optic disc, indicated by vertical and horizontal cup-disc ratios of <0.7 and an intereye difference in these ratios of <0.2; (4) no evidence of an RNFL defect or optic disc hemorrhage; and (5) an optic disc that adheres to the ISNT rule. Following initial grading, a separate team of glaucoma specialists, blinded to other participant information, conducted a detailed review. Any discrepancies between the preliminary and detailed assessments were resolved by a third panel of glaucoma experts.
Statistical analysis
All statistical analyses were performed using R statistical ver. 4.4.1 (R Foundation for Statistical Computing) to account for the complex sampling design. We applied stratification, clustering, and weighting to calculate standard errors (SEs) for means and point estimates, using Taylor linearization methods for population estimates. Participant characteristics were summarized using means and SEs for continuous variables and percentages, frequencies, and SEs for categorical variables.
Baseline demographic and clinical parameters were compared between groups with Pearson chi-square tests for categorical data and general linear models for continuous data. General linear models were also employed to evaluate the relationship between allergen sensitization and OAG. Variables that differed significantly between groups at baseline (p < 0.05) were adjusted for age, sex, body mass index, diabetes mellitus, systemic hypertension, total cholesterol, alcohol consumption, and smoking. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for OAG risk. To facilitate clinical interpretation and compare the magnitude of associations, ORs were calculated per one standard deviation (1-SD) increase in log-transformed allergen-specific IgE levels. β-Coefficients and their 95% CIs were also reported. All p-values were two-tailed, with p < 0.05 was considered statistically significant, for multivariable analyses.
Results
Baseline characteristics
A total of 1,334 subjects were included in the analysis, with 62 subjects (4.6%) diagnosed with OAG and 1,272 subjects (95.4%) classified as nonglaucoma controls (Table 1). Compared to nonglaucoma participants, those with OAG were significantly older (mean age, 50.26 years [95% CI, 45.06-55.11] vs. 42.95 years [95% CI, 41.17-43.20]; p = 0.003) and included a higher proportion of men (72.6% vs. 47.3%, p = 0.042). OAG subjects also exhibited significantly higher systolic (126.73 mmHg vs. 118.43 mmHg, p = 0.008) and diastolic blood pressures (81.58 mmHg vs. 77.44 mmHg, p = 0.021), lower high-density lipoprotein cholesterol levels (44.05 mg/dL vs. 48.74 mg/dL, p < 0.001), and greater prevalence rates of diabetes mellitus (16.1% vs. 6.1%, p = 0.014) and systemic hypertension (45.2% vs. 26.7%, p = 0.008). Other characteristics, including smoking status, drinking habits, body mass index, waist circumference, serum glucose, total cholesterol, low-density lipoprotein cholesterol, triglycerides, presence of myopia and glaucoma family history, and intraocular pressure, did not differ significantly between groups.
Association between allergen sensitization and glaucoma
Multivariate logistic regression analyses were performed to evaluate the association between allergen sensitization and OAG (Table 2). Total IgE levels were not significantly associated with OAG in any model (model 3: OR, 1.05; 95% CI, 0.81-1.36; p = 0.697). In contrast, sensitization to house dust mite allergens was inversely associated with OAG; in the fully adjusted model (model 3), the OR was 0.56 (95% CI, 0.31-1.00; p = 0.049). Conversely, sensitization to cockroach allergens demonstrated a significant positive association with OAG, with an OR of 1.19 (95% CI, 1.02-1.38; p = 0.028) in model 3. Sensitization to dog allergens was not significantly associated with OAG across all models.
Discussion
In this nationwide, cross-sectional study using KNHANES 2010 data, we investigated the relationship between specific allergen sensitizations and OAG. Our findings demonstrate that, while total IgE levels and sensitization to dog allergens were not significantly associated with OAG, a differential pattern was observed for the other allergens. Specifically, cockroach allergen sensitization was significantly associated with greater odds of glaucoma, whereas house dust mite sensitization showed a weak inverse association. Although the magnitude of the observed associations might appear modest at the individual level, the ORs are presented per 1-SD increase to reflect clinically relevant variations. Given that indoor allergen exposure is widespread in the general population, even a modest shift in risk distribution can have substantial public health implications at the population level. These results align with emerging evidence suggesting that specific environmental allergens may trigger or exacerbate neuro-inflammatory pathways, potentially contributing to optic nerve vulnerability.
The positive association between cockroach allergen sensitization and glaucoma aligns with previous findings suggesting that exposure to certain environmental allergens may provoke robust inflammatory responses, potentially triggering neuroinflammatory cascades that contribute to optic nerve damage [12]. Specifically, cockroach allergen exposure initiates a potent type 2 (Th2)-mediated immune response marked by interleukin 4 (IL-4) and IL-13 secretion, IgE production, and subsequent mast cell degranulation, which releases pro-inflammatory cytokines such as tumor necrosis factor α [19,20]. This cascade not only elevates systemic oxidative stress but also disrupts vascular and tissue barriers, facilitating inflammatory mediator spillover that primes microglial activation and compromises ocular immune privilege [21,22]. Ultimately, these processes may render the optic nerve more susceptible to injury, thereby supporting the notion that allergic neuroinflammation plays a critical role in glaucomatous neurodegeneration.
In contrast, the inverse relationship observed with house dust mite sensitization is somewhat unexpected. This finding may indicate that the immune response elicited by house dust mite allergens differs qualitatively from that of cockroach allergens, possibly involving mechanisms of immune tolerance or less-aggressive inflammatory pathways [19]. Chronic, low-dose exposure to house dust mite allergens appears to promote regulatory pathways such as the expansion of FoxP3+ regulatory T-cells producing IL-10 and transforming growth factor β, induction of tolerogenic dendritic cells, and generation of IgG4-blocking antibodies that effectively counterbalance Th2-mediated inflammatory responses [19,23]. This immunoregulatory environment mitigates the release of pro-inflammatory cytokines and limits systemic oxidative stress, potentially safeguarding the optic nerve from chronic neuroinflammation and reducing the risk of OAG.
Moreover, our study confirms that OAG patients differ significantly from controls in terms of traditional risk factors such as age, sex, blood pressure, and metabolic conditions, in line with previous reports [24-27]. Notably, even after adjusting for these confounders, the distinct associations between specific allergen sensitizations and OAG persisted, suggesting that antigen-specific immune responses may independently or synergistically contribute to glaucoma development. In addition, our findings highlight a broader impact of systemic allergic inflammation on ocular neurodegeneration. Chronic atopic conditions may compromise the integrity of the blood-brain and blood-retinal barriers [28,29], allowing inflammatory mediators to access ocular tissues and prime microglial activation, thereby intensifying neuroinflammatory responses within the optic nerve. In this study, while cockroach allergen sensitization appears to trigger deleterious inflammatory cascades that promote retinal ganglion cell loss, the tolerogenic response associated with house dust mite exposure may counterbalance these adverse effects. Thus, these observations underscore the critical balance between pro-inflammatory and regulatory immune mechanisms in preserving ocular integrity and preventing glaucomatous damage.
While our study provides valuable insights into the relationship between allergen sensitization and OAG, it has several limitations that should be noted. First, its cross-sectional design precludes definitive causal inferences between allergen sensitization and glaucoma. Specifically, the possibility of reverse causality cannot be excluded; systemic inflammation associated with glaucoma itself could secondarily alter immune responses or IgE levels, rather than sensitization contributing to the disease. Second, despite adjustment for multiple confounders, residual confounding from unmeasured variables, such as eye-rubbing behavior, genetic predisposition, detailed corticosteroid use, or socioeconomic status, may have influenced the observed associations. Third, our allergen panel focused on three common indoor antigens but excluded other prevalent sensitizers (e.g., pollen, mold), potentially overlooking broader immune interactions. Additionally, we did not apply statistical corrections for multiple testing, such as Bonferroni or false discovery rate adjustments. Given the exploratory nature of this study, which aimed to identify potential epidemiological signals rather than definitively confirm them, we prioritized minimizing the risk of type II errors (false negatives) to avoid prematurely dismissing relevant associations. Consequently, the observed statistical significance should be interpreted with caution, and these findings require validation in independent future cohorts. Finally, the ethnically homogeneous South Korean cohort limits generalizability to diverse populations with differing genetic and environmental allergen profiles. Despite these constraints, our use of objective allergen-specific IgE measurements (rather than self-reported data) strengthens the validity of sensitization assessments, and the use of a nationally representative sample minimizes selection bias. Future longitudinal studies incorporating advanced ocular imaging, expanded allergen panels, and multi-ethnic cohorts will help clarify these associations.
Our findings provide evidence for a differential association between sensitizations to specific indoor allergens and OAG. Sensitization to cockroach allergens was associated with a greater likelihood of glaucoma, whereas sensitization to house dust mites was associated with lower odds of glaucoma in the 2010 KNHANES population. These results underscore the complex interplay between immune responses and glaucomatous neurodegeneration, and they pave the way for further research into targeted preventive strategies. In conclusion, this study demonstrates that sensitization to specific indoor allergens exhibits divergent associations with primary OAG, thereby highlighting the complex role of immune-mediated mechanisms in glaucoma pathogenesis. Furthermore, our findings underscore specific inflammatory pathways that warrant further investigation as potential etiological factors.
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