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  1. Teo WY, Lim YYE, Sio YY, Say YH, Reginald K, Chew FT
    World Allergy Organ J, 2024 Feb;17(2):100869.
    PMID: 38298829 DOI: 10.1016/j.waojou.2023.100869
    BACKGROUND: Atopic dermatitis (AD) is a complex inflammatory disease with a strong genetic component. A singular approach of genome wide association studies (GWAS) can identify AD-associated genetic variants, but is unable to explain their functional relevance in AD. This study aims to characterize AD-associated genetic variants and elucidate the mechanisms leading to AD through a multi-omics approach.

    METHODS: GWAS identified an association between genetic variants at 6p21.32 locus and AD. Genotypes of 6p21.32 locus variants were evaluated against LOC100294145 expression in peripheral blood mononuclear cells (PBMCs). Their influence on LOC100294145 promoter activity was measured in vitro via a dual-luciferase assay. The function of LOC100294145 was then elucidated through a combination of co-expression analyses and gene enrichment with g:Profiler. Mendelian randomization was further used to assess the causal regulatory effect of LOC100294145 on its co-expressed genes.

    RESULTS: Minor alleles of rs116160149 and rs115388857 at 6p21.32 locus were associated with increased AD risk (p = 2.175 × 10-8, OR = 1.552; p = 2.805 × 10-9, OR = 1.55) and higher LOC100294145 expression in PBMCs (adjusted p = 0.182; 8.267 × 10-12). LOC100294145 expression was also found to be increased in those with AD (adjusted p = 3.653 × 10-2). The genotype effect of 6p21.32 locus on LOC100294145 promoter activity was further validated in vitro. Co-expression analyses predicted LOC100294145 protein's involvement in interleukin-27 and type 1 interferon signaling, which was further substantiated through mendelian randomization.

    CONCLUSION: Genetic variants at 6p21.32 locus increase AD susceptibility through raising LOC100294145 expression. A multi-omics approach enabled the deduction of its pathogenesis model comprising dysregulation of hub genes involved in type 1 interferon and interleukin 27 signaling.

  2. Ng JY, Chew FT
    Skin Res Technol, 2024 Feb;30(2):e13620.
    PMID: 38376131 DOI: 10.1111/srt.13620
    BACKGROUND: We evaluate skin sagging phenotypes (eyebags, droopy eyelids, low eyebrow positioning) using written descriptive scales and photo-numeric scales. We also study how anti-ageing interventions and digital screen time influence skin sagging.

    AIM: We compare the two phenotype assessment methods with each other.

    METHOD: Skin sagging and personal lifestyle data obtained from 2885 ethnic Chinese young adults from the Singapore/Malaysia cross-sectional genetics epidemiology study (SMCGES) cohort were collated and compared.

    RESULTS: Significant correlations (p-value 

  3. Wong QYA, Lim JJ, Ng JY, Lim YYE, Sio YY, Chew FT
    J Physiol Anthropol, 2024 Jan 30;43(1):6.
    PMID: 38291494 DOI: 10.1186/s40101-024-00356-5
    BACKGROUND AND OBJECTIVE: Sleep disruption has been shown to affect immune function and thus influence allergic disease manifestation. The specific effects of sleep on allergic diseases, however, are less well-established; hence, in a unique population of young Chinese adults, we investigated the association between sleep and allergic disease.

    METHODS: Young Chinese adults recruited from Singapore in the Singapore/Malaysia Cross-Sectional Genetic Epidemiology Study (SMCGES) were analyzed. We used the International Study of Asthma and Allergies in Childhood (ISAAC) protocol and a skin prick test to determine atopic dermatitis (AD), allergic rhinitis (AR), and asthma status. Information regarding total sleep time (TST) and sleep quality (SQ) was also obtained.

    RESULTS: Of 1558 participants with a mean age of 25.0 years (SD = 7.6), 61.4% were female, and the mean total sleep time (TST) was 6.8 h (SD = 1.1). The proportions of AD, AR, and asthma were 24.5% (393/1542), 36.4% (987/1551), and 14.7% (227/1547), respectively. 59.8% (235/393) of AD cases suffered from AD-related sleep disturbances, 37.1% (209/564) of AR cases suffered from AR-related sleep disturbances, and 25.1% (57/227) of asthma cases suffered from asthma-related sleep disturbances. Only asthma cases showed a significantly lower mean TST than those without asthma (p = 0.015). Longer TST was significantly associated with lower odds of AR (OR = 0.905, 95% CI = 0.820-0.999) and asthma (OR = 0.852, 95% CI = 0.746-0.972). Linear regression analyses showed that lower TST was significantly associated with asthma (β =  - 0.18, SE = 0.076, p-value = 0.017), and AR when adjusted for AR-related sleep disturbances (β =  - 0.157, SE = 0.065, p-value = 0.016). Only sleep disturbances due to AR were significantly associated with a poorer SQ (OR = 1.962, 95% CI = 1.245-3.089).

    CONCLUSIONS: We found that sleep quality, but not sleep duration was significantly poorer among AD cases, although the exact direction of influence could not be determined. In consideration of the literature coupled with our findings, we posit that TST influences allergic rhinitis rather than vice versa. Finally, the association between TST and asthma is likely mediated by asthma-related sleep disturbances, since mean TST was significantly lower among those with nighttime asthma symptoms. Future studies could consider using objective sleep measurements coupled with differential expression analysis to investigate the pathophysiology of sleep and allergic diseases.

  4. Sio YY, Victoria Nanong GA, Lim JA, Matta SA, Say YH, Teh KF, et al.
    World Allergy Organ J, 2024 Jan;17(1):100853.
    PMID: 38235258 DOI: 10.1016/j.waojou.2023.100853
    BACKGROUND: Elaeis guineensis (Ela g, oil palm) pollen is one of the most predominant species of inhalant allergens in the tropical Southeast Asia region; however, its association with the manifestation of allergic diseases remains largely unexplored. This study aimed to determine the sensitization pattern of oil palm pollen and associate this with the risk and severity of allergic diseases.

    METHODS: Participants were recruited as a part of the Singapore and Malaysia cross-sectional genetic and epidemiological study (SMCSGES). Two independent cohorts were recruited: n = 564 serum samples were collected and serological assessment was performed against a panel of 16 crude inhalant allergens including house dust mite, pet, insect, pollen, and fungal allergens; n = 13 652 Singapore/Malaysia Chinese young adults were recruited and skin prick test was used to assess oil palm sensitization, which was tested for its association with the risk and severity of asthma, allergic rhinitis (AR), and atopic dermatitis (AD).

    RESULTS: The sensitization rate of oil palm pollen is 9.6% in the n = 564 Singapore/Malaysia cohort. In the n = 13 652 Singapore/Malaysia Chinese cohort, oil palm sensitization significantly associates with increased risks of asthma (p = 1.34x10-4), AR (p = 2.91x10-13), and AD (p = 6.95x10-7). Asthmatic patients with oil palm sensitization have increased risks of wheezing (p = 0.00995), nocturnal cough (p = 0.0122), and exacerbations (p = 0.00139) in the past 12 months. AR patients with oil palm sensitization also have an increased risk of developing moderate-to-severe symptoms (p = 0.00113).

    CONCLUSIONS: We have identified significant associations of oil palm sensitization with increased risks, exacerbations, and the severity of symptoms of allergic diseases in the tropical Southeast Asian region (Singapore/Malaysia).

  5. Lim JJ, Lim YYE, Ng JY, Malipeddi P, Ng YT, Teo WY, et al.
    Dermatology, 2024;240(1):77-84.
    PMID: 37666213 DOI: 10.1159/000533942
    BACKGROUND: We see increasing evidence that dietary and nutrients factors play a pivotal role in allergic diseases and recent global findings suggest that dietary habits influence the pathogenesis of atopic dermatitis (AD). Frequent consumption of fast food diets is associated with AD development. Despite the rising prevalence of AD in Asia, efforts in investigating the role of dietary habits and AD in adults are still lacking.

    METHODS: We evaluated the association between the dietary intake of 16 food types and AD manifestations using our Singapore/Malaysia Cross-sectional Genetics Epidemiology Study (SMCGES) population. Dietary habits profiles of 11,494 young Chinese adults (1,550 AD cases/2,978 non-atopic controls/6,386 atopic controls) were assessed by an investigator-administered questionnaire. AD cases were further evaluated for their chronicity (550 chronic) and severity (628 moderate-to-severe). Additionally, we derived a novel food index, Quality of Diet based on Glycaemic Index Score (QDGIS), to examine the association between dietary intake of glycaemic index (GI) and various AD phenotypes.

    RESULTS: The majority of AD subjects are distributed in the good (37.1%) and moderate (36.2%) QDGIS classes. From the multivariable analyses for age and gender, a moderate QDGIS class was significantly associated with a lower odds of AD (adjusted odds ratio (AOR): 0.844; 95% confidence interval (CI): 0.719-0.991; p < 0.05) and moderate-to-severe AD (AOR: 0.839; 95% CI: 0.714-0.985; p < 0.05). A good QDGIS class was only significantly associated with a lower odds of chronic AD (AOR: 0.769; 95% CI: 0.606-0.976; p < 0.05). Among high GI foods, frequent consumption of burgers/fast food was strongly associated with an increased risk of chronic and moderate-to-severe AD. Among low GI foods, increased intake frequencies of fruits, vegetables, and pulses decreased the odds of AD. Finally, we identified significant associations between frequent seafood, margarine, butter, and pasta consumption with an increased odds of AD despite them having little GI values.

    CONCLUSION: While genetic components are well-established in their risks associated with increased AD prevalence, there is still a lack of a focus epidemiology study associating dietary influence with AD. Based on the first allergic epidemiology study conducted here in Singapore and Malaysia, it laid the groundwork to guide potential dietary interventions from changing personal dietary habits.

  6. Lim JJ, Reginald K, Say YH, Liu MH, Chew FT
    JID Innov, 2023 Nov;3(6):100224.
    PMID: 37731471 DOI: 10.1016/j.xjidi.2023.100224
    Through an investigator-administered questionnaire that follows the standard protocol of the International Study of Allergy and Asthma in Childhood, data on symptomatic histories of eczema and dietary habits were collected from 11,494 young Chinese adults in Singapore/Malaysia. Allergic sensitization status was assessed through a skin prick test reactivity to common house dust mites. Using three dietary indices (dietary protein score, animal protein score, and plant protein score), the associations between atopic dermatitis, intrinsic eczema, allergic sensitization, and intake of various proteins were estimated. On average, most subjects frequently eat meat, vegetables, and rice in their diets. Through a multivariable logistic regression adjusted for age, sex, body mass index, and parental eczema, subjects with high dietary protein score (adjusted OR = 1.397; 95% confidence interval = 1.133-1.724; P < 0.003) and high animal protein score (adjusted OR = 1.353; 95% confidence interval = 1.106-1.682; P < 0.003) were associated with increased risk of atopic dermatitis. Interestingly, synergy factor analysis revealed that a higher intake of plant proteins than animal proteins in diets significantly reduced overall associated risks of atopic dermatitis and allergic sensitization but not those of intrinsic eczema. Most importantly, these associations are independent of dietary fat intake. Taken together, frequent adherence to diets rich in plant proteins reduced associated risks of atopic dermatitis in Singapore/Malaysia Chinese adults.
  7. Lim JJ, Reginald K, Say YH, Liu MH, Chew FT
    BMC Public Health, 2023 Sep 19;23(1):1818.
    PMID: 37726698 DOI: 10.1186/s12889-023-16736-y
    BACKGROUND: The prevalence of atopic dermatitis (AD) has been increasing in recent years, especially in Asia. There is growing evidence to suggest the importance of dietary patterns in the development and management of AD. Here, we seek to understand how certain dietary patterns in a Singapore/Malaysia population are associated with various risks of AD development and exacerbation.

    METHODS: A standardized questionnaire following the International Study of Asthma and Allergies in Childhood (ISAAC) guidelines was investigator-administered to a clinically and epidemiology well-defined allergic cohort of 13,561 young Chinese adults aged 19-22. Information on their sociodemographic, lifestyle, dietary habits, and personal and family medical atopic histories were obtained. Allergic sensitization was assessed by a skin prick test to mite allergens. Spearman's rank-order correlation was used to assess the correlation between the intake frequencies of 16 food types. Dietary patterns were identified using principal component analysis. Four corresponding dietary scores were derived to examine the association of identified dietary patterns with allergic sensitization and AD exacerbations through a multivariable logistic regression that controlled for age, gender, parental eczema, BMI, and lifestyle factors.

    RESULTS: The correlation is the strongest between the intake of butter and margarine (R = 0.65). We identified four dietary patterns, "high-calorie foods", "plant-based foods", "meat and rice", and "probiotics, milk and eggs", and these accounted for 47.4% of the variance in the dietary habits among the subjects. Among these patterns, moderate-to-high intake of "plant-based foods" conferred a negative association for chronic (Adjusted odds ratio (AOR): 0.706; 95% confidence interval (CI): 0.589-0.847; p 

  8. Reginald K, Chew FT
    Mol Immunol, 2023 Sep;161:11-24.
    PMID: 37480600 DOI: 10.1016/j.molimm.2023.07.004
    PURPOSE OF REVIEW: This review evaluates the current modes of allergen-specific immunotherapy for cockroach allergens, in terms of clinical outcomes and explores future trends in the research and development needed for a more targeted cockroach immunotherapy approach with the best efficacy and minimum adverse effects.

    SUMMARY: Cockroach allergy is an important risk factor for allergic rhinitis in the tropics, that disproportionately affects children and young adults and those living in poor socio-economic environments. Immunotherapy would provide long-lasting improvement in quality of life, with reduced medication intake. However, the present treatment regime is long and has a risk of adverse effects. In addition, cockroach does not seem to have an immuno-dominant allergen, that has been traditionally used to treat allergies from other sources. Future trends of cockroach immunotherapy involve precision diagnosis, to correctly identify the offending allergen. Next, precision immunotherapy with standardized allergens, which have been processed in a way that maintains an immunological response without allergic reactions. This approach can be coupled with modern adjuvants and delivery systems that promote a Th1/Treg environment, thereby modulating the immune response away from the allergenic response.

  9. Wise SK, Damask C, Roland LT, Ebert C, Levy JM, Lin S, et al.
    Int Forum Allergy Rhinol, 2023 Apr;13(4):293-859.
    PMID: 36878860 DOI: 10.1002/alr.23090
    BACKGROUND: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document.

    METHODS: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work.

    RESULTS: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost.

    CONCLUSION: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.

  10. Wong QYA, Lim JJ, Ng JY, Malipeddi P, Lim YYE, Sio YY, et al.
    World Allergy Organ J, 2023 Mar;16(3):100757.
    PMID: 36968625 DOI: 10.1016/j.waojou.2023.100757
    BACKGROUND: Asthma is a chronic inflammatory disease of the airway characterized by respiratory symptoms: wheezing, shortness of breath, coughing, and chest tightness. Globally, asthma affects over 300 million individuals and carries high morbidity and mortality burden. Previous studies have estimated the prevalence of asthma; however, prevalence estimates have been changing over time. Here, in a population of young Chinese adults from Singapore, we aimed to obtain an updated prevalence of asthma and its phenotypes, and identify potential associated risk factors.

    METHODS: The Singapore/Malaysia Cross-Sectional Genetics Epidemiology Study (SMCGES) is an ongoing study which uses established ISAAC guidelines to collect epidemiological data and information pertaining to allergic diseases such as asthma. Responses from young Chinese adults recruited in the National University of Singapore were analyzed.

    RESULTS: Lifetime asthma prevalence rate was estimated at 19.1% (2049/10,736), while current asthma prevalence rate was estimated at 6.3% (679/10,736). For ever asthma, the most important risk factor was a parental history of asthma. Increased consumption of pulses (aOR: 0.822, 95% CI: 0.706-0.958) was associated with a lowered odds of ever asthma, but cereals (aOR: 1.256, 95% CI: 1.006-1.580), pasta (aOR: 1.265, 95% CI: 1.027-1.553), butter (aOR: 1.350, 95% CI: 1.113-1.632), and margarine (aOR: 1.343, 95% CI: 1.081-1.660) were associated with a higher risk of ever asthma. Increased television/computer usage was associated with a decreased risk of ever asthma (aOR: 0.448, 95% CI: 0.367-0.545). Conversely, genetic factors had a lower strength of effect on current asthma (parental history of asthma - OR: 1.465, 95% CI: 1.135-1.888) as compared to ever asthma. Only increased potato consumption was significantly associated with an increased risk of current asthma (most or all days per week vs never or only occasionally - aOR: 1.577, 95% CI: 1.145-2.180). Physical activity (aOR: 0.693, 95% CI: 0.542-0.885) was associated with a lower odds of asthma, while second-hand smoke exposure was associated with an increased risk for current asthma (aOR: 1.435, 95% CI: 1.001-2.047).

    CONCLUSION: Overall, the prevalence of lifetime asthma and current asthma among young Chinese adults was 19.1% and 6.3%, higher than that of previous studies. Our results suggested a stronger association between genetic factors and ever asthma as compared to current asthma. Parental asthma was the most important intrinsic epidemiological factor for asthma manifestation, while various foods, physical activity levels, and television or computer usage were also significantly associated with asthma. Future studies should consider risk factors in conjunction with other accompanying variables given the potential interactions between them, to discern the effects of environment and lifestyle on asthma more distinctly.

  11. Tiew PY, Narayana JK, Quek MSL, Ang YY, Ko FWS, Poh ME, et al.
    Eur Respir J, 2023 Jan;61(1).
    PMID: 35926878 DOI: 10.1183/13993003.00507-2022
    BACKGROUND: Variable clinical outcomes are reported with fungal sensitisation in chronic obstructive pulmonary disease (COPD), and it remains unclear which fungi and what allergens associate with the poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown.

    METHODS: A prospective multicentre assessment of stable COPD (n=614) was undertaken in five hospitals across three countries: Singapore, Malaysia and Hong Kong. Clinical and serological assessment was performed against a panel of 35 fungal allergens including crude and recombinant Aspergillus and non-Aspergillus allergens. Unsupervised clustering and topological data analysis (TDA) approaches were employed using the measured sensitisation responses to elucidate if sensitisation subgroups exist and their related clinical outcomes.

    RESULTS: Aspergillus fumigatus sensitisation was associated with increased exacerbations in COPD. Unsupervised cluster analyses revealed two "fungal sensitisation" groups. The first was characterised by Aspergillus sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group conferred even poorer outcome. The second group, characterised by Cladosporium sensitisation, was more symptomatic. Significant numbers of individuals demonstrated sensitisation responses to only recombinant (as opposed to crude) A. fumigatus allergens f 1, 3, 5 and 6, and exhibited increased exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a subgroup within Aspergillus-sensitised COPD of patients with frequent exacerbations.

    CONCLUSION: Aspergillus sensitisation is a treatable trait in COPD. Measuring sensitisation responses to recombinant Aspergillus allergens identifies an important patient subgroup with poor COPD outcomes that remains overlooked by assessment of only crude Aspergillus allergens.

  12. Lim JJ, Reginald K, Say YH, Liu MH, Chew FT
    Int Arch Allergy Immunol, 2023;184(10):975-984.
    PMID: 37393903 DOI: 10.1159/000530948
    INTRODUCTION: Frequent dietary patterns for fast food diets are suggested to be a risk factor for atopic disease development. Excessive dietary fats in fast foods are postulated to promote low-grade chronic inflammation. However, no studies in Asia have yet to characterize the dietary pattern for high-fat foods with atopic diseases. Thus, this study aims to assess the association between dietary fats with the prevalence of atopic diseases in an allergic cohort.

    METHODS: Through an investigator-administered questionnaire that follows the International Study of Asthma and Allergies in Childhood (ISAAC) protocol, we evaluated the eating habits, lifestyle behaviours, sociodemographics, and atopic symptoms, and history among 11,494 young Chinese adults in Singapore and Malaysia. A skin prick test (SPT) for common house dust mites was also conducted to determine the atopic (allergic) status. We identified 1,550 atopic dermatitis (AD), 1,301 allergic asthma (AS), and 3,757 allergic rhinitis (AR) atopic cases. We derived a novel dietary index, Diet Quality based on Total Fat Amount (DQTFA), to examine the association between eating patterns for estimated total fat amount with various atopic outcomes.

    RESULTS: There was a preponderance of subjects having positive SPT reaction (69.0%) with the prevalence of AR being the highest (32.7%), then AD (13.5%), and AS (11.3%). Additionally, there is a significantly higher proportion of subjects with an atopy background and atopic diseases consume diets with a high estimated mean fat amount. The adherence to a dietary pattern of the higher estimated total fat amount was shown to be strongly associated with all atopic diseases and exhibited dose-dependent responses in the univariate analysis. These associations remained significant even with the adjustments for age, gender, body mass index, use of alcohol, sedentary lifestyles, and physical activity. A dietary pattern for high-fat amount is more strongly associated with AS (adjusted odds ratio [AOR]: 1.524; 95% confidence interval [CI]: 1.216-1.725; p < 0.001) and AR (AOR: 1.294; 95% CI: 1.107-1.512; p < 0.001) compared to AD (AOR: 1.278; 95% CI: 1.049-1.559; p < 0.05). Finally, it was shown that having either one of the atopic comorbidities was strongly associated with a dietary pattern of high-fat amounts (AOR: 1.360; 95% CI: 1.161-1.594; p < 0.001).

    CONCLUSION: Our findings altogether provide initial evidence that the dietary pattern of a diet high in fat amount is associated with an increased risk of atopy and atopic diseases in young Chinese adults in Singapore and Malaysia. Balancing the consumption of dietary fats and changing personal dietary habits by choosing foods of the lower fat amount may reduce the associated odds of atopic diseases.

  13. Sio YY, Shi P, Matta SA, Fok YTR, Chiang WC, Say YH, et al.
    Int Arch Allergy Immunol, 2023;184(6):609-623.
    PMID: 37231900 DOI: 10.1159/000530393
    INTRODUCTION: The arachidonic acid (AA) pathway plays a crucial role in allergic inflammatory diseases; however, the functional roles of allergy-associated single nucleotide polymorphisms (SNPs) in this pathway remain incompletely illustrated.

    METHODS: This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). We performed population genotyping on n = 2,880 individuals from the SMCSGES cohort to assess the associations of SNPs in the AA pathway genes with asthma and allergic rhinitis (AR). Spirometry assessments were performed to identify associations between SNPs and lung function among n = 74 pediatric asthmatic patients from the same cohort. Allergy-associated SNPs were functionally characterized using in vitro promoter luciferase assay, along with DNA methylome and transcriptome data of n = 237 peripheral blood mononuclear cell (PBMC) samples collected from a subset of the SMCSGES cohort.

    RESULTS: Genetic association analysis showed 5 tag-SNPs from 4 AA pathway genes were significantly associated with asthma (rs689466 at COX2, rs35744894 at hematopoietic PGD2 synthase (HPGDS), rs11097414 at HPGDS, rs7167 at CRTH2, and rs5758 at TBXA2R, p < 0.05), whereas 3 tag-SNPs from HPGDS (rs35744894, rs11097414, and rs11097411) and 2 tag-SNPs from PTGDR (rs8019916 and rs41312470) were significantly associated with AR (p < 0.05). The asthma-associated rs689466 regulates COX2 promoter activity and associates with COX2 mRNA expression in PBMC. The allergy-associated rs1344612 was significantly associated with poorer lung function, increased risks of asthma and AR, and increased HPGDS promoter activity. The allergy-associated rs8019916 regulates PTGDR promoter activity and DNA methylation levels of cg23022053 and cg18369034 in PBMC. The asthma-associated rs7167 affects CRTH2 expression by regulating the methylation level of cg19192256 in PBMC.

    CONCLUSIONS: The present study identified multiple allergy-associated SNPs that modulate the transcript expressions of key genes in the AA pathway. The development of a "personalized medicine" approach with consideration of genetic influences on the AA pathway may hopefully result in efficacious strategies to manage and treat allergic diseases.

  14. Sio YY, Gan WL, Ng WS, Matta SA, Say YH, Teh KF, et al.
    Int Arch Allergy Immunol, 2023;184(10):1010-1021.
    PMID: 37336194 DOI: 10.1159/000530960
    INTRODUCTION: Previous studies have indicated the ERBB2 genetic variants in the 17q12 locus might be associated with asthma; however, the functional effects of these variants on asthma risk remain inconclusive. This study aimed to characterize the functional roles of asthma-associated ERBB2 single nucleotide polymorphisms (SNPs) in asthma pathogenesis by performing genetic association and functional analysis studies.

    METHODS: This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). Genotype-phenotype associations were assessed by performing a genotyping assay on n = 4,348 ethnic Chinese individuals from the SMCSGES cohort. The phosphorylation levels of receptors and signaling proteins in the MAPK signaling cascades, including ErbB2, EGFR, and ERK1/2, were compared across the genotypes of asthma-associated SNPs through in vitro and ex vivo approaches.

    RESULTS: The ERBB2 tag-SNP rs1058808 was significantly associated with allergic asthma, with the allele "G" identified as protective against the disease (adjusted logistic p = 6.56 × 10-9, OR = 0.625, 95% CI: 0.544-0.718). The allele "G" of rs1058808 resulted in a Pro1170Ala mutation that results in lower phosphorylation levels of ErbB2 in HaCat cells (p < 0.001), whereas the overall ERBB2 mRNA expression and the phosphorylation levels of EGFR remained unaffected. In the SMCSGES cohort, individuals carrying the genotype "GG" of rs1058808 had lower phosphorylated ERK1/2 proteins in the MAPK signaling cascade. A lower phosphorylation level of ERK1/2 was also associated with reduced asthma risk.

    CONCLUSIONS: The present findings highlighted the involvement of a functional exonic variant of ERBB2 in asthma development via modulating the MAPK signaling cascade.

  15. Lim JJ, Lim YYE, Ng JY, Malipeddi P, Ng YT, Teo WY, et al.
    World Allergy Organ J, 2022 Dec;15(12):100722.
    PMID: 36438192 DOI: 10.1016/j.waojou.2022.100722
    BACKGROUND: Atopic Dermatitis (AD) is a highly pruritic, chronic-recurrent inflammatory skin condition associated with erythematous lesions that affect a significant proportion of the population. Although AD is a non-communicable disease, it can cause pain, unbearable itchiness, sleep disturbance, loss of work productivity, and reduced quality of life. As a heterogeneous disease, AD is influenced by multiple genes and environmental triggers. As such, it is imperative to gain a deeper insight into the intricate gene-environment relationship that results in the manifestation of AD.

    METHODS: There are 3 objectives in our study. We first aim to update the epidemiological status of AD amongst young adults in Singapore and Malaysia, in particular amongst the Chinese ethnic background. Next, we re-evaluated the possible associated risk factors, identified in our previous meta-analysis and review studies, on the current cohort. Finally, we described here a detailed disease presentation and symptoms profile of our Singapore and Malaysia Cross-Sectional Genetics Epidemiology Study (SMCGES) cohort, which forms the base population for the discovery of associated genetic factors in relation to asthma, allergic diseases and skin conditions. Based on a skin prick test (SPT) and investigator-administered medical history responses, we assessed the AD profiles of 11 494 participants and the significant modifiable and non-modifiable factors associated with disease presentation.

    RESULTS: The prevalence of AD in the combined population was 13.5%. Chronic and moderate/severe AD were observed in 35.5% and 40.5% of the individuals with AD, respectively. Family history of atopic diseases, prior history of drug allergies, a history of acne, increased household family monthly income, higher number of individuals in the shared household, parental education, sedentary lifestyle, physical activities, alcoholic consumption, and even quality of diet was significantly associated with AD presentation, chronicity, and severity. Among all the factors evaluated, family and personal history of atopic diseases imposed the strongest associated risk.

    CONCLUSIONS: These findings supported our previous review studies and affirmed that familial history or genetic factors critically influence the development of AD in our population and environment. Environmental and other modifiable factors can also trigger AD throughout the lifetime of individuals who have especially inherited the atopic disease disposition. A better understanding of how these risk factors affect AD individuals in our population can facilitate disease surveillance, monitor disease control, and serve as a description for our future genetic epidemiology studies.

  16. Sio YY, Shi P, Say YH, Chew FT
    Clin Exp Allergy, 2022 01;52(1):127-136.
    PMID: 33866639 DOI: 10.1111/cea.13883
    BACKGROUND: Previous haplotype-based association studies identified chromosome 4q21 as an allergic rhinitis (AR) susceptibility locus; however, the functional role of 4q21 single nucleotide polymorphisms (SNPs) on AR risk remains unclear.

    OBJECTIVE: To investigate the functional effect of 4q21 SNPs on AR risk by conducting cohort-based functional genomics and genetic association analyses.

    METHODS: The associations between 4q21 SNPs and mRNA expression levels of three 4q21-associated genes (SDAD1, NAAA and CXCL9) in peripheral blood mononuclear cells (PBMCs) were assessed in a Singapore/Malaysia Chinese cohort (n = 291). Exon expression levels of these genes in PBMCs were tested against the tag-SNP genotypes in a Singapore Chinese cohort (n = 30). Serum protein levels of these genes were assessed with tag-SNP genotypes in a Singapore Chinese cohort (n = 193). SNP functions were characterized through luciferase assay. In a Singapore Chinese cohort (n = 1794), we confirmed the associations between functional SNPs and AR.

    RESULTS: Forty SNPs in 4q21 showed significant associations with NAAA (but not SDAD1 or CXCL9) mRNA expression in PBMCs, of which were tagged by two tag-SNPs, rs17001237 and rs2242470. Both tag-SNPs rs2242470 and rs12648687 (a proxy for rs17001237) were also significantly associated with the expression level of NAAA exon 1. Tag-SNP rs12648687 was correlated with serum NAAA level. A four promoter SNPs-haplotype tagged by rs17001237 influenced the NAAA promoter activity in HEK293T cells. Lastly, individuals carrying the risk allele A of rs12648687 exhibited significantly higher AR risk in the Singapore Chinese population.

    CONCLUSIONS & CLINICAL RELEVANCE: The rs17001237 linkage set SNPs in the 4q21 locus are associated with NAAA expression at both gene and protein levels ex vivo, have functional consequences in vitro and contribute to AR susceptibility in our study population. Our findings provided a better understanding of the genetic mechanism that contributes to AR pathogenesis.

  17. Tiew PY, Lim AYH, Keir HR, Dicker AJ, Mac Aogáin M, Pang SL, et al.
    Chest, 2022 01;161(1):40-53.
    PMID: 34364870 DOI: 10.1016/j.chest.2021.07.2165
    BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is associated with frequent exacerbations and poor outcomes in chronic respiratory disease, but remains underdiagnosed. The role of fungal sensitization in bronchiectasis-COPD overlap (BCO) is unknown.

    RESEARCH QUESTION: What is the occurrence and clinical relevance of Aspergillus sensitization and ABPA in BCO when compared with individuals with COPD or bronchiectasis without overlap?

    STUDY DESIGN: Prospective, observational, cross-sectional study.

    METHODS: We prospectively recruited 280 patients during periods of clinical stability with bronchiectasis (n = 183), COPD (n = 50), and BCO (n = 47) from six hospitals across three countries (Singapore, Malaysia, and Scotland). We assessed sensitization responses (as specific IgE) to a panel of recombinant Aspergillus fumigatus allergens and the occurrence of ABPA in relationship to clinical outcomes.

    RESULTS: Individuals with BCO show an increased frequency and clinical severity of ABPA compared with those with COPD and bronchiectasis without overlap. BCO-associated ABPA is associated with more severe disease, higher exacerbation rates, and lower lung function when compared with ABPA occurring in the absence of overlap. BCO with a severe bronchiectasis severity index (BSI; > 9) is associated significantly with the occurrence of ABPA that is unrelated to underlying COPD severity.

    CONCLUSIONS: BCO demonstrates a high frequency of ABPA that is associated with a severe BSI (> 9) and poor clinical outcomes. Clinicians should maintain a high index of suspicion for the potential development of ABPA in patients with BCO with high BSI.

  18. Sio YY, Pang SL, Say YH, Teh KF, Wong YR, Shah SMR, et al.
    Mycopathologia, 2021 Oct;186(5):583-588.
    PMID: 34258653 DOI: 10.1007/s11046-021-00532-6
    Fungal spores and conidia are the major components of total airspora in the tropical Asia environment, and their sensitization patterns are often associated with allergic diseases such as asthma, allergic rhinitis (AR), and atopic dermatitis. Hence, we recruited a cross-sectional cohort of 9223 Singapore/Malaysia Chinese adults and assessed their sensitization against Curvularia lunata allergen using the skin prick test approach. A subset of this cohort (n = 254) was also screened for specific Immunoglobulin E (sIgE) titers against a panel of 11 fungal allergens. We found significant association of Curvularia lunata sensitization with the risk of asthma (OR = 1.66, 95% CI: 1.17-2.33; p = 0.00391) and AR (OR = 1.69, 95% CI: 1.18-2.41; p = 0.00396). Among asthmatic patients (n = 1680), Curvularia lunata sensitization also increased frequencies of wheezing symptoms (OR = 1.81, 95% CI: 1.05-2.96; p = 0.0239), general practitioner/specialist visits (OR = 2.37, 95% CI: 1.13-4.61; p = 0.0157), and other asthma-related exacerbation events (OR = 2.14, 95% CI: 1.04-4.10; p = 0.0289). In our serum cohort, sensitization to Aspergillus spp. was the most common fungal sensitization, with 23.6% (n = 60) had a class 3 and above sensitization (positive sensitization; sIgE titers of > 3.5 kU/L) against this allergen. Increasing sIgE titer against Aspergillus spp. was also correlated with increased AR risk and AR-related symptoms. In conclusion, our findings emphasize an important role of fungal sensitization in the manifestations of asthma and AR in the Southeast Asian Chinese population.
  19. Say YH, Heng AHS, Reginald K, Wong YR, Teh KF, Rawanan Shah SM, et al.
    BMC Public Health, 2021 03 27;21(1):601.
    PMID: 33773591 DOI: 10.1186/s12889-021-10681-4
    BACKGROUND: Acne vulgaris, a highly prevalent multifactorial inflammatory skin disease, can be categorised into different severity and scarring grades based on the type, number, and severity of lesions. While many epidemiology studies have investigated the risk factors for acne presentation, fewer studies have specifically studied the risk factors for acne severity and scarring. Therefore, this study investigated the prevalence of acne, acne severity and scarring grades, and their associated non-modifiable and modifiable epidemiological risk factors among Malaysian Chinese.

    METHODS: A total of 1840 subjects (1117 cases/723 controls) completed an investigator-administered questionnaire as part of a cross-sectional study, which include socio-demographics, familial history, lifestyle factors, dietary habits, and acne history. Acne cases were further evaluated for their severity (n = 1051) and scarring (n = 1052) grades by a trained personnel.

    RESULTS: Majority of the acne cases (up to 69%) had mild acne or Grade 1/2 scarring, while 21.6% had moderate/severe acne and 5.5% had Grade 3/4 scarring. Males had significantly higher risk of presenting with higher grades of acne scarring. Those who had acne, regardless of severity and scarring grades, had strong positive familial history (either in parents and/or sibling). Frequent consumption (most or all days) of foods that are commonly consumed during breakfast (butter, probiotic drinks, cereals and milk) decreased the risk for acne presentation and higher acne scarring, while periodic consumption (once/twice per week) of nuts and burgers/fast food decreased the risk for higher acne severity. Alcohol drinking was significantly associated with increased risk for acne presentation, while paternal, parental and household smoking were associated with reduced risk of more severe acne.

    CONCLUSIONS: In conclusion, positive familial history is a strong predisposing factor in influencing acne presentation, severity and scarring. Frequent consumption of foods that are commonly consumed during breakfast is protective against acne presentation.

  20. Tiew PY, Dicker AJ, Keir HR, Poh ME, Pang SL, Mac Aogáin M, et al.
    Eur Respir J, 2021 Mar;57(3).
    PMID: 32972986 DOI: 10.1183/13993003.02050-2020
    INTRODUCTION: The chronic obstructive pulmonary disease (COPD) bacteriome associates with disease severity, exacerbations and mortality. While COPD patients are susceptible to fungal sensitisation, the role of the fungal mycobiome remains uncertain.

    METHODS: We report the largest multicentre evaluation of the COPD airway mycobiome to date, including participants from Asia (Singapore and Malaysia) and the UK (Scotland) when stable (n=337) and during exacerbations (n=66) as well as nondiseased (healthy) controls (n=47). Longitudinal mycobiome analysis was performed during and following COPD exacerbations (n=34), and examined in terms of exacerbation frequency, 2-year mortality and occurrence of serum specific IgE (sIgE) against selected fungi.

    RESULTS: A distinct mycobiome profile is observed in COPD compared with controls as evidenced by increased α-diversity (Shannon index; p<0.001). Significant airway mycobiome differences, including greater interfungal interaction (by co-occurrence), characterise very frequent COPD exacerbators (three or more exacerbations per year) (permutational multivariate ANOVA; adjusted p<0.001). Longitudinal analyses during exacerbations and following treatment with antibiotics and corticosteroids did not reveal any significant change in airway mycobiome profile. Unsupervised clustering resulted in two clinically distinct COPD groups: one with increased symptoms (COPD Assessment Test score) and Saccharomyces dominance, and another with very frequent exacerbations and higher mortality characterised by Aspergillus, Curvularia and Penicillium with a concomitant increase in serum sIgE levels against the same fungi. During acute exacerbations of COPD, lower fungal diversity associates with higher 2-year mortality.

    CONCLUSION: The airway mycobiome in COPD is characterised by specific fungal genera associated with exacerbations and increased mortality.

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