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Abstract Background Recent genome-wide association studies (GWAS) for asthma have been successful in identifying novel associations which have been well replicated. The aim of this study is to identify the genetic variants that influence predisposition towards asthma in an ethnic Chinese population in Singapore using a GWAS approach. Methods A two-stage GWAS was performed in case samples with allergic asthma, and in control samples without asthma and atopy. In the discovery stage, 490 case and 490 control samples were analysed by pooled genotyping. Significant associations from the first stage were evaluated in a replication cohort of 521 case and 524 control samples in the second stage. The same 980 samples used in the discovery phase were also individually genotyped for purposes of a combined analysis. An additional 1445 non-asthmatic atopic control samples were also genotyped. Results 19 promising SNPs which passed our genome-wide P value threshold of 5.52 × 10-8 were individually genotyped. In the combined analysis of 1011 case and 1014 control samples, SNP rs2941504 in PERLD1 on chromosome 17q12 was found to be significantly associated with asthma at the genotypic level (P = 1.48 × 10-6, ORAG = 0.526 (0.369-0.700), ORAA = 0.480 (0.361-0.639)) and at the allelic level (P = 9.56 × 10-6, OR = 0.745 (0.654-0.848)). These findings were found to be replicated in 3 other asthma GWAS studies, thus validating our own results. Analysis against the atopy control samples suggested that the SNP was associated with allergic asthma and not to either the asthma or allergy components. Genotyping of additional SNPs in 100 kb flanking rs2941504 further confirmed that the association was indeed to PERLD1. PERLD1 is involved in the modification of the glycosylphosphatidylinositol anchors for cell surface markers such as CD48 and CD59 which are known to play multiple roles in T-cell activation and proliferation. Conclusions These findings reveal the association of a PERLD1 as a novel asthma candidate gene and reinforce the involvement of genes on the 17q12-21 chromosomal region in the etiology of asthma.

Abstract Background Uteroglobin-Related Protein 1 (UGRP1) is a secretoglobulin protein which has been suggested to play a role in lung inflammation and allergic diseases. UGRP1 has also been shown to be an important pneumoprotein, with diagnostic potential as a biomarker of lung damage. Previous genetic studies evaluating the association between variations on UGRP1 and allergic phenotypes have yielded mixed results. The aim of this present study was to identify genetic polymorphisms in UGRP1 and investigate if they were associated with asthma and allergic rhinitis in the Singapore Chinese population. Methods Resequencing of the UGRP1 gene was conducted on 40 randomly selected individuals from Singapore of ethnic Chinese origin. The polymorphisms identified were then tagged and genotyped in a population of 1893 Singapore Chinese individuals. Genetic associations were evaluated in this population comparing 795 individuals with allergic rhinitis, 718 with asthma (of which 337 had both asthma and allergic rhinitis) and 717 healthy controls with no history of allergy or allergic diseases. Results By resequencing the UGRP1 gene within our population, we identified 11 novel and 16 known single nucleotide polymorphisms (SNPs). TagSNPs were then genotyped, revealing a significant association between rs7726552 and allergic rhinitis (Odds Ratio: 0.81, 95% Confidence Interval: 0.66-0.98, P = 0.039). This association remained statistically significant when it was analyzed genotypically or when stratified according to haplotypes. When variations on UGRP1 were evaluated against asthma, no association was observed. Conclusion This study documents the association between polymorphisms in UGRP1 and allergic rhinitis, suggesting a potential role in its pathogenesis.

Abstract Background The International Hapmap project serves as a valuable resource for human genome variation data, however its applicability to other populations has yet to be exhaustively investigated. In this paper, we use high density genotyping chips and resequencing strategies to compare the Singapore Chinese population with the Hapmap populations. First we compared 1028 and 114 unrelated Singapore Chinese samples genotyped using the Illumina Human Hapmap 550 k chip and Affymetrix 500 k array respectively against the 270 samples from Hapmap. Secondly, data from 20 candidate genes on 5q31-33 resequenced for an asthma candidate gene based study was also used for the analysis. Results A total of 237 SNPs were identified through resequencing of which only 95 SNPs (40%) were in Hapmap; however an additional 56 SNPs (24%) were not genotyped directly but had a proxy SNP in the Hapmap. At the genome-wide level, Singapore Chinese were highly correlated with Hapmap Han Chinese with correlation of 0.954 and 0.947 for the Illumina and Affymetrix platforms respectively with deviant SNPs randomly distributed within and across all chromosomes. Conclusions The high correlation between our population and Hapmap Han Chinese reaffirms the applicability of Hapmap based genome-wide chips for GWA studies. There is a clear population signature for the Singapore Chinese samples and they predominantly resemble the southern Han Chinese population; however when new migrants particularly those with northern Han Chinese background were included, population stratification issues may arise. Future studies needs to address population stratification within the sample collection while designing and interpreting GWAS in the Chinese population.

Background: Allergic rhinitis is a common disorder that affects 10% to 40% of the population worldwide. Allergen immunotherapy (AIT) represents the only therapy that has the potential to resolve clinical symptoms of allergic rhinitis. However, up to 30% of patients do not respond to AIT. Biomarkers predicting the clinical efficacy of AIT as early as possible would significantly improve the patient selection and reduce unnecessary societal costs. Methods: Artemisia pollen allergic patients who received at least 1-year AIT were enrolled. Clinical responses before and after 1-year AIT were evaluated to determine AIT responders. Artemisia specific IgE and IgG4 levels were measured by using ImmunoCAP and enzyme-linked immunosorbent assay (ELISA) separately. Stepwise regression analysis was performed to identify which rhinitis-relevant parameters explained the most variability in AIT results. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics was applied to identify the potential candidate biomarkers in the sera of responders and non-responders collected before and after 1-year therapy. The diagnostic performance of the potential biomarkers was then assessed using enzyme-linked immunosorbent assay (ELISA) in 30 responders and 15 non-responders. Results: Artemisia specific IgE and IgG4 levels were elevated only in the responders. Regression analysis of allergic rhinitis-relevant parameters provided a robust model that included two most significant variables (sneeze and nasal congestion). Thirteen candidate biomarkers were identified for predicting AIT outcomes. Based on their association with allergy and protein fold change (more than 1.1 or less than 0.9), four proteins were identified to be potential biomarkers for predicting effective AIT. However, further ELISA revealed that only leukotriene A4 hydrolase (LTA4H) was consistent with the proteomics data. The LTA4H level in responders increased significantly (P < 0.001) after 1-year therapy, while that of non-responders remained unchanged. Assessment of LTA4H generated area under curve (AUC) value of 0.844 (95% confidence interval: 0.727 to 0.962; P < 0.05) in distinguishing responders from the non-responders, suggesting that serum LTA4H might be a potential biomarker for predicting the efficiency of AIT. Conclusion: Serum LTA4H may be a potential biomarker for early prediction of an effective AIT. [ABSTRACT FROM AUTHOR]

Our understanding of the pathophysiology of chronic rhinosinusitis (CRS) is continuously evolving. The traditional description of CRS in terms of two phenotypes based on the presence or absence of nasal polyps belies the underlying intricate immunopathophysiological processes responsible for this condition. CRS is being increasingly recognized as a disease spectrum encompassing a range of inflammatory states in the sinonasal cavity, with non‐type 2 inflammatory disease on one end, type 2 inflammatory, eosinophil‐heavy disease on the other and an overlap of both in different proportions in between. Abundance in research on the immune mechanisms of CRS has revealed various new endotypes that hold promise as biomarkers for the development of targeted therapies in severe, uncontrolled CRS. The introduction of precision medicine to manage this chronic, complex condition is a step forward in providing individualized care for all patients with CRS. In this review, the latest research on the pathophysiology of CRS with a focus on potential novel biomarkers and treatment options over the last 2 years are summarized and integrated into a suggested model of precision medicine in CRS. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a functional gastrointestinal disease and the most common cause of prolonged abdominal pain and bowel disturbances in the developed world. While initially thought to be functional or psychosomatic in nature, IBS is now recognized as a heterogeneous group of conditions. A subset of IBS patients and patients with allergic diseases share some characteristic inflammatory features. In fact, atopic children show an increased likelihood of developing IBS as adults. Given these findings, a subset of IBS may be suffering from allergy-related gut diseases. In this review, we present the allergy-related comorbidities of IBS, including genetic, environmental, and immunologic factors. We discuss studies demonstrating an increased sensitization of IBS patients to aeroallergens compared to food allergens. We then postulate potential pathophysiological mechanisms underlying both IBS and aeroallergens in the gut, followed by potential implications in the screening and treatment of allergies in IBS patients. [ABSTRACT FROM AUTHOR]

Background: Gene expression patterns (particularly, cilia-associated genes) of nasal mucosa, the first-line defense system, in allergic rhinitis (AR) are not well understood. Objective: We sought to screen for AR-associated genes in inferior turbinate (IT) from patients with AR, and to validate the expression of common cilia-related genes and ciliary shedding. Methods: Prime View™ Human Gene Expression Array, which consisted of more than 530 000 probes covering more than 36 000 transcripts and variants, was employed to compare individual gene expression of ITs from control subjects (n = 11) and patients with AR (n = 19). Gene ontology (GO) analysis was performed with Cytoscape software. Eight of the common cilia-related genes were validated with quantitative polymerase chain reaction. We applied a semiquantitative scoring system for immunofluorescence assay to demonstrate ciliary shedding in 5 areas per paraffin section, with individual sections being scored between 0 (normal ciliary distribution) and 1 (ciliary shedding). Results: Compared with control subjects, 160 (38 upregulated and 122 downregulated) genes were differentially expressed for at least 2 folds (all P <.05) in AR. Seven GO categories were significantly enriched, 4 of which were related to cilium assembly and motility. Quantitative polymerase chain reaction validated the predicted direction of change for common cilia-related gene expression. The ciliary distribution score was significantly higher (more prominent ciliary shedding) in AR than in controls (P <.05). Conclusion: The significant aberrant cilia-related gene expression, revealed by microarray assays, might be the critical driver of AR where ciliary shedding is prominent. [ABSTRACT FROM AUTHOR]

H1-antihistamines are recognized to be effective for conditions such as allergic rhinitis and chronic spontaneous urticaria. However, management of such conditions in the real-world primary care setting may be challenging due to diverse patient-specific considerations, the wide range of antihistamines available, choice of other treatment modalities, and the complexity of interpreting specialist treatment algorithms. Despite regular updates to international guidelines, regional/national surveys of healthcare professionals show a clear gap between guidelines and real-world practice, particularly at the primary care level. This article thus presents the consensus opinion of experts from relevant specialties in Malaysia - allergology, pediatrics, otorhinolaryngology, and dermtology - on harmonizing the use and choice of antihistamines in primary care. Patient profiling is recommended as a tool to guide primary care practitioners in prescribing the appropriate antihistamine for each patient. Patient profiling is a three-step approach that involves 1) identifying the individual's needs; 2) reviewing patient-specific considerations; and 3) monitoring treatment response and referral to specialists in more severe or difficult-to-treat cases. Concurrently, guidelct 3ines should be reviewed and updated periodically to include recommendations that are easily actionable for primary care practitioners. [ABSTRACT FROM AUTHOR]

Objective: Motile cilia impairment is a common condition in patients with chronically inflamed airways, such as is seen in nasal polyps (NPs). The mechanism underlying this pathogenic condition is complex and not fully understood.Methods: We investigated the presence and localization of dynein axonemal heavy chain 5 (DNAH5) in motile cilia using immunofluorescence staining in paraffin-embedded nasal biopsies from NPs (n = 120) and inferior turbinate mucosa (n = 35) of healthy controls. We also performed single-cell staining on cytospin samples (NP = 5, control = 5). Three patterns of DNAH5 localization are defined, including pattern A (presence throughout the axoneme), pattern B (undetectable in the distal part of the axoneme), and pattern C (completely missing throughout the entire axoneme). We developed a semiquantitative scoring system for which 0 = (pattern A > 70%); 1 = (patterns A + B > 70%); and 2 = (pattern C ≥ 30%) in each high-power field (5 fields per sample).Results: Based on our DNAH5 scoring system, the median (1st and 3rd quartile) score was 0.3 (0.2 and 0.4) for samples from controls, and 1.1 (0.6 and 1.6) for samples from NPs in paraffin specimens (P < 0.001). The DNAH5 score had a significant positive relationship with the Lund-Mackay computed tomography score (r = 0.329, P = 0.005) and was higher in patients with eosinophilic NPs (P = 0.006). For cytospin samples, the mean percentage of patterns A, B, and C were 74%, 14%, and 12% in controls, and 48%, 20%, and 32% in NPs, respectively.Conclusion: Our results suggest that the absence or mislocalization of DNAH5 from motile cilia is a common and potentially important pathological phenomenon in chronically inflamed airway epithelium.Level Of Evidence: NA. Laryngoscope, 128:E97-E104, 2018. [ABSTRACT FROM AUTHOR]