Kavita Reginald

Genome‐wide association studies (GWAS) have uncovered multiple loci associated with atopic dermatitis (AD), although mechanistic understanding remains limited. Here, we examine a risk variant in the aquaporin 3 ( AQP3 ) promoter and propose a mechanistic link between genotype to altered autophagy, skin barrier integrity, and wound healing in AD. A GWAS involving 1261 AD cases and 4062 controls of Chinese ancestry from the Singapore–Malaysia cohort was performed. Linkage disequilibrium (LD) analysis and cis‐eQTL datasets were used to assess regulatory associations. Functional effects of promoter variants were validated using in vitro luciferase assays and ex vivo transcriptomic profiling. In vitro experiments in HaCaT keratinocytes investigated the effect of siRNA‐mediated AQP3 knockdown on autophagy, skin barrier integrity, and wound closure. A discovery GWAS identified significant association between AD and SNP rs12555686 ( p = 1.67 × 10 ⁻¹¹ , OR = 1.89), located in the promoter of AQP3 . Two additional SNPs in strong LD (rs2231225, rs3758279) formed a major haplotype associated with reduced AQP3 expression. Reduced AQP3 expression was associated with decreased autophagy markers ( Beclin1 , ATG5 , ATG12 , GABARAPL2, LAMP2, ATG4C ), increased senescence markers ( p21 , GADD45A , SERPINE1 ), and elevated inflammatory cytokines ( IL8 , IL1B , TNF ). Lastly, AQP3 knockdown in HaCaT keratinocytes reduced steady‐state LC3B‐II/LC3B‐I ratio, reduced occludin expression, and delayed wound healing in vitro. Promoter variants in AQP3 link genetic susceptibility to gene signatures consistent with altered autophagy, cellular senescence, and inflammation in AD. These findings highlight AQP3 as a potential modulator of both epithelial and immune‐related mechanisms in AD pathogenesis.

Summary: A ubiquitin D (UBD) promoter haplotype was identified to confer protection against atopic dermatitis (AD). The rs362513‐G allele suppresses UBD transcription and downstream NF‐κB–regulated cytokine production, independent of the AD‐risk SNP rs995185.

Summary Box: 8p21.3 polymorphisms associate with lower BMP1 expression, lower skin hydration and increased AD susceptibility. Regulatory variants at 8p21.3 reduce BMP1 promoter activity in dermal fibroblasts, mediating its downregulation.

Allergic rhinitis (AR) is a common inflammatory disorder of the upper airway that is primarily managed with pharmacotherapy, biologics and allergen immunotherapy. However, a substantial proportion of patients experience incomplete or insufficient symptom control, treatment-related adverse effects, or poor adherence. Increasing evidence has linked AR with alterations in microbial composition across multiple mucosal sites, including the gut, highlighting potential roles for host-microbiome interactions in the regulation of allergic inflammation, although causal relationships remain incompletely defined. This narrative mini-review synthesizes current evidence on gut microbiome-based interventions for allergic rhinitis (AR), including probiotics, prebiotics, synbiotics, postbiotics, and emerging approaches such as fecal microbiota transplantation, engineered microbes, and bacteriophage-based therapies. It examines proposed immunological mechanisms involving type 2 inflammation, regulatory immune pathways, and gut–airwa y axis signalling, while distinguishing clinically evaluated strategies from experimental or preclinical and assessing their translational readiness. Collectively, available evidence suggests that microbiome-targeted therapies represent a promising conceptual avenue for understanding and potentially modulating AR. However, their clinical application remains constrained by heterogeneous study designs, reliance on extrapolated data from preclinical studies, limited standardized outcome measures, insufficient long-term safety data, and evolving regulatory frameworks. Addressing these challenges through well-designed clinical trials and improved mechanistic characterization will be essential to clarify the role of microbiome-based interventions as adjunctive strategies in AR management.

Summary: Atopy (66.1%) and HDM sensitisation (63.5%) were highly prevalent in the SMCGES cohort. In this tropical Singapore–Malaysia cohort, HDM sensitisation demonstrated high concordance with atopic status.

Summary: Pro‐inflammatory diets were associated with higher odds of atopic dermatitis (AD), but not non‐atopic dermatitis, suggesting specificity to atopic mechanisms. Directionally consistent associations observed using both a nutrient‐based (Dietary Inflammatory Index) and a food‐based (Mediterranean‐like) dietary score support the potential robustness of diet‐AD relationships.

Background: Indoor allergen sensitization to cockroach (CR) is clinically relevant and exhibits substantial geographic heterogeneity. However, its relationship with pre‐existing atopy and allergic symptom burden in tropical urban environments remains uncertain considering the overwhelming influence of house dust mite (HDM) sensitization. This study aimed to characterize sensitization to the major indoor CR allergens— Periplaneta americana and Blattella germanica —and to evaluate its association with allergic disease prevalence, symptom severity, and exacerbation. Methods: A total of 5350 young adults from the Singapore–Malaysia Cross‐sequential Genetics and Epidemiology Study (SMCGES) were assessed for sensitization to common indoor allergens, including HDM and CR, using skin prick testing. Associations between sensitization and clinical allergic outcomes were analyzed. In a sub‐cohort ( n = 736), serum specific IgE (SSIgE) profiling against 40 aeroallergens and seafood allergens was performed to assess co‐sensitization patterns. Results: CR sensitization was identified in 23.1% of participants, with 19.7% sensitized to both HDM and CR. CR sensitization was associated with higher prevalence of asthma (OR 1.59; 95% CI 1.31–1.93), allergic rhinitis (AR; OR 1.42; 95% CI 1.22–1.65), atopic dermatitis (AD; OR 1.55; 95% CI 1.33–1.80), and atopic multimorbidity (OR 1.91; 95% CI 1.61–2.28). CR sensitization was also associated with higher frequencies of rhinitis symptoms, greater rhinitis symptom severity (OR 1.26; 95% CI 1.07–1.48), and higher total nasal symptom scores (OR 1.32; 95% CI 1.07–1.63). While HDM monosensitization was strongly associated with allergic outcomes, concurrent HDM and CR sensitization conferred additional risk and symptom burden. Polysensitized individuals also exhibited higher likelihood of developing CR‐specific IgE responses. Conclusion: CR sensitization is prevalent in the tropical Singapore–Malaysia population and is strongly associated with polysensitization, higher allergic disease prevalence, and increased symptom burden. These findings emphasize the clinical significance of CR allergy and support targeted strategies for indoor allergen avoidance and environmental control.

Background: Asthma is a chronic respiratory condition affecting 3,340 cases per 100,000 individuals globally. The significant global health burden of asthma necessitates the development and use of valid diagnostic tools for epidemiological purposes. Objective: This study evaluated the diagnostic accuracy of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire among participants from the Singapore/Malaysia Cross-sequential Genetic Epidemiology Study (SMCGES). Methods: Investigators administered the ISAAC survey questionnaire to SMCGES participants. Symptoms related to asthma were compared against diagnosed asthma, which was characterized by a questionnaire-reported history of asthma and exhibiting a positive skin prick reaction to allergen extracts from 2 dust mite species. Diagnostic accuracy was assessed via sensitivity (Se), specificity (Sp), positive and negative predictive values, and Youden’s Index ( J ). Results: This study analyzed data from 4,028 participants from Malaysia and 11,473 participants from Singapore. Asthma symptom prevalence differed between Malaysia and Singapore, with ever wheeze being the most prevalent in both populations. Diagnosed asthma was more prevalent in Singapore (17.3%, 95% confidence interval [CI]: 16.6–18.1%) than in Malaysia (9.7%, 95% CI: 8.8–10.7%). Ever wheeze showed the best diagnostic performance for diagnosed asthma in Malaysia (Se = 0.548, Sp = 0.831, J = 0.379) and Singapore (Se = 0.679, Sp = 0.888, J = 0.566). Combining symptoms or asthma medication usage improved accuracy slightly, with the most valid combinations being ever wheeze or exercise-induced wheeze in Malaysia (Se = 0.557, Sp = 0.824, J = 0.381) and usage of bronchodilators, beta-agonists, inhaled steroids, or leukotriene modifiers in Singapore (Se = 0.771, Sp = 0.871, J = 0.642). Conclusion: The modified ISAAC questionnaire used by the SMCGES showed good Se and Sp for diagnosed asthma, especially when combining various symptom indicators or usages of different asthma medications. These findings substantiate the continued use of the ISAAC questionnaire as a valuable survey tool in epidemiological studies across diverse populations.