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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., (© 2024. The Author(s).)

Background: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations., Objective: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles., Methods: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases., Results: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 ( C5orf46 ) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels., Conclusions: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2 ., Competing Interests: Competing interests: EH-L, and M.P.-Y. report funding from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and by “ESF Investing in your future” by the European Union. JP-G reports funding from the Spanish Ministry of Universities. M.P.-Y. and F.L.D. report grants from MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund “ERDF A way of making Europe” by the European Union. MP-Y reports grant support from GlaxoSmithKline, Spain paid to Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC) for a project outside the submitted work. MP-Y and JV reports grants from Instituto de Salud Carlos III, Madrid, Spain. JV also reports funding by ISCIII and the European Regional Development Fund “ERDF A way of making Europe”. JMH-P has received fees from CSL Behring, GSK, Astra-Zeneca, Laboratorios Menarini, Boehringer Ingelheim, FAES, Laboratorios Esteve, Laboratorios Ferrer, Mundipharma, Laboratorios Rovi, Roche, Novartis, GRIFOLS, Pfizer, Acthelion-Jansen, Chiesi y Laboratorios Bial for the realization of courses, talks, consultancies, and other activities related to his professional activity. FTC has received research support from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network (SIgN), National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore). F.T.C. has received consulting fees from Sime Darby Technology Centre; First Resources Ltd; Genting Plantation, and Olam International, outside the submitted work. YYS has received research support from the NUS Resilience & Growth Postdoctoral Fellowships. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression., Methods: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10 -5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico., Results: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (OR T allele ) = 0.82, p = 9.05 × 10 -6 and replication: OR T allele  = 0.89, p = 5.35 × 10 -3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: OR C allele  = 0.85, p = 3.10 × 10 -5 and replication: OR C allele  = 0.89, p = 1.30 × 10 -2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood., Conclusions: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense., (© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background and Objective: An increasing trend of asthma prevalence was observed in Asia; however, contributions of environmental and host-related risk factors to the development of this disease remain uncertain. This study aimed to perform a systematic review and meta-analysis for asthma-associated risk factors reported in Asia., Methods: We systematically searched three public databases (Web of Science, PubMed, and Scopus) in Feb 2021. We only included articles that reported environmental and host-related risk factors associated with asthma in the Asian population. Random-effect meta-analyses were conducted for frequently reported asthma-associated risk factors to provide an overall risk estimate of asthma development., Results: Of 4030 records obtained from public databases, 289 articles were selected for review. The most frequently reported asthma-associated risk factor was the family history of allergy-related conditions. The random-effect asthma risk estimates (pooled odds ratio, OR) were 4.66 (95% confidence interval (CI): 3.73-5.82) for the family history of asthma, 3.50 (95% CI: 2.62-4.67) for the family history of atopy, 3.57 (95% CI: 3.03-4.22) for the family history of any allergic diseases, 1.96 (95% CI: 1.47-2.61) for the family history of allergic rhinitis, and 2.75 (95% CI: 1.12-6.76) for the family history of atopic dermatitis. For housing-related factors, including the presence of mold, mold spots, mold odor, cockroach, water damage, and incense burning, the random-effect pooled OR ranged from 1.43 to 1.73. Other risk factors with significant pooled OR for asthma development included male gender (1.30, 95% CI: 1.23-1.38), cigarette smoke exposure (1.44, 95% CI: 1.30-1.60), cigarette smoking (1.66, 95% CI: 1.44-1.90), body mass index (BMI)-related parameters (pooled OR ranged from 1.06 to 2.02), various types of air pollution (NO 2 , PM10, and O 3 ; pooled OR ranged from 1.03 to 1.22), and pre- and perinatal factors (low birth weight, preterm birth, and cesarean section; pooled OR ranged from 1.14 to 1.32)., Conclusions: The family history of asthma was the most frequently reported risk factor for asthma development in Asia with the highest risk estimate for asthma development. This suggests a major role of the genetic component in asthma pathogenesis. Further study on asthma genetics is required to improve the current understanding of asthma etiology., (© 2021. The Author(s).)

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., (© 2021. The Author(s).)

Background: The polymorphism Arg16 in β 2 -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β 2 -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27., Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA., Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects., Results: In subjects treated with ICS and LABA (n = 832, age: 3-21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I 2  = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I 2  = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I 2  = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting β 2 -agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686)., Conclusion and Clinical Relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients., (© 2021 John Wiley & Sons Ltd.)

Rationale: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies., Methods: A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed., Results: 10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10 -6 ). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found., Conclusions: The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response., Competing Interests: Conflict of interest: N. Hernandez-Pacheco reports grants from Instituto de Salud Carlos III (ISCIII, FI16/00136) and co-funded by the European Social Funds from the European Union (ESF) “ESF invests in your future”, during the conduct of the study. Conflict of interest: S.J. Vijverberg has nothing to disclose. Conflict of interest: E. Herrera-Luis reports grants from the Spanish Ministry of Science, Innovation, and Universities (PRE2018-083837), during the conduct of the study. Conflict of interest: J. Li has nothing to disclose. Conflict of interest: Y.Y. Sio has nothing to disclose. Conflict of interest: R. Granell has nothing to disclose. Conflict of interest: A. Corrales has nothing to disclose. Conflict of interest: C. Maroteau has nothing to disclose. Conflict of interest: R. Lethem has nothing to disclose. Conflict of interest: J. Perez-Garcia has nothing to disclose. Conflict of interest: N. Farzan has nothing to disclose. Conflict of interest: K. Repnik has nothing to disclose. Conflict of interest: M. Gorenjak has nothing to disclose. Conflict of interest: P. Soares has nothing to disclose. Conflict of interest: L. Karimi has nothing to disclose. Conflict of interest: M. Schieck has nothing to disclose. Conflict of interest: L. Pérez-Méndez has nothing to disclose. Conflict of interest: V. Berce has nothing to disclose. Conflict of interest: R. Tavendale has nothing to disclose. Conflict of interest: C. Eng has nothing to disclose. Conflict of interest: O. Sardon has nothing to disclose. Conflict of interest: I. Kull has nothing to disclose. Conflict of interest: S. Mukhopadhyay reports grants from The Gannochy Trust, Perth and Kinross City Council and Scottish Enterprises Tayside, during the conduct of the study. Conflict of interest: M. Pirmohamed reports grants from UK Department of Health and UK Medical Research Council, during the conduct of the study; grants from MRC Clinical Pharmacology Training Scheme (joint funding by MRC and Roche, UCB, Eli Lilly and Novartis), Joint PhD studentship funded by EPSRC and Astra Zeneca and grants from Bristol Myers Squibb, outside the submitted work. Conflict of interest: K.M.C. Verhamme reports grants from ZonMw, during the conduct of the study; and works for a department who in the past received unconditional research grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis and GSK. Conflict of interest: E.G. Burchard reports grants from the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH) (X01HL134589, X01HL134589,R01HL128439, R01HL135156, R01HL141992 and R01HL141845), the National Institute of Environmental Health Sciences (NIEHS) (R01ES015794 and R21ES24844), the National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443 and R56MD013312), the National Institute of General Medical Sciences (NIGMS) (RL5GM118984), the Tobacco-Related Disease Research Program (award numbers 24RT-0025 and 27IR-0030), the National Human Genome Research Institute (NHGRI) (U01HG009080), the Sandler Family Foundation, the American Asthma Foundation, the Amos Medical Faculty Development Program from the Robert Wood Johnson Foundation, the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, during the conduct of the study. Conflict of interest: M. Kabesch reports grants from European Union, German Ministry of Education and Research, German Research Foundation, during the conduct of the study; personal fees for consultancy from Bionorica, Sanofi, Novartis and Bencard, personal fees for lectures from ERS, EAACI, ATS, Novartis, Glaxo, Nutricia, Hipp and Allergopharma, outside the submitted work. Conflict of interest: D.B. Hawcutt has nothing to disclose. Conflict of interest: E. Melén has nothing to disclose. Conflict of interest: U. Potočnik reports grants from Slovenian Research Agency (P3-0067) and Ministry of Education, Science and Sport Slovenia (MIZS) (SysPharmPediA grant C3330-16-500106), during the conduct of the study. Conflict of interest: F.T. Chew reports grants from Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore), during the conduct of the study; and consulting fees from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation and Olam International, outside the submitted work. Conflict of interest: K.G. Tantisira reports grants from U.S. National Institutes of Health, during the conduct of the study. Conflict of interest: S. Turner has nothing to disclose. Conflict of interest: C.M. Palmer has nothing to disclose. Conflict of interest: C. Flores has nothing to disclose. Conflict of interest: M. Pino-Yanes reports grants from Spanish Ministry of Economy, Industry and Competitiveness (funded by the Ramón y Cajal Program, RYC-2015-17205), and Instituto de Salud Carlos III (ISCIII) (funded by ISCIII through AES and EC within AAL framework, and the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020, AC15/00015), during the conduct of the study. Conflict of interest: A.H. Maitland-van der Zee reports grants from GSK, during the conduct of the study; grants from Boehringer Ingelheim, personal fees for advisory board work from AstraZeneca and Boehringer Ingelheim, outside the submitted work., (Copyright ©ERS 2021.)

Background: Reduced extracellular epinephrine level often associates with asthma-related symptoms; however, the correlation between asthma and genetic variants in genes participating in the epinephrine signalling pathway remains unclear., Objective: To characterize the functions of single nucleotide polymorphisms (SNPs) in phenylethanolamine N-methyltransferase (PNMT) and β2-adrenergic receptor (ADRB2), and to study the effects, including both direct and epistatic, of these SNPs on serum epinephrine level and asthma susceptibility., Methods: Single nucleotide polymorphisms functions were characterized through in vitro luciferase assay. ADRB2 gene expression level in peripheral blood mononuclear cell (PBMC) was measured by transcriptome sequencing and expression microarray on two separate Asian cohorts (NUS-UTAR, n = 278 and NUS-TA, n = 58). Serum epinephrine level was assessed on a Singapore Chinese cohort (NUS-SH, n = 314) with 155 asthmatic and 159 non-asthmatic subjects. A separate Singapore Chinese cohort (NUS-G, n = 3009) was genotyped to show disease association (direct and epistatic effect) of functional SNPs in PNMT and ADRB2., Results: Reduced serum epinephrine level was associated with increased asthma risk in Singapore Chinese. The minor allele of rs876493 was shown to increase PNMT promoter activity and reduce asthma risk. Multiple SNPs in ADRB2 forms a haplotype that was associated with the differential promoter activity of this gene. In this haplotype, rs11168070 was associated directly with ADRB2 expression in PBMCs. Both minor alleles from rs876493 and rs11168070 contribute synergistically to reduce asthma risk and increase serum epinephrine level., Conclusion and Clinical Relevance: Epistatic interaction between genetic variants from PNMT (rs876493) and ADRB2 (rs11168070) is associated with serum epinephrine level and the susceptibility of asthma. Our findings improved the current understanding of the genetic basis of this disease, while genotypic states of these SNPs may serve as potential biomarkers to predict susceptibility to the disease., (© 2019 John Wiley & Sons Ltd.)

Post-glycosylphosphatidylinositol (GPI) attachment to proteins 3, also known as PGAP3 or PERLD1 (PER1-like domain-containing protein 1), participates in the lipid remodeling process of glycosylphosphatidylinositol (GPI) anchor proteins during post-translational modification. Functional defect in PERLD1 was previously hypothesized to influence this process in T-cells and their subsequent activation and proliferation. This current study aims to functionally characterize PERLD1 genetic variants and relate this with human immune cells proliferation rate upon stimulation. We first showed the association between a PERLD1 tag-single nucleotide polymorphism (tagSNP), rs2941504, and the development of asthma in our study population. This association remained significant after conditioning for the other asthma-associated SNP rs8076131 that is also located within the 17q12-21 region. Subsequent sequencing of 40 unrelated Singapore Chinese individuals identified 12 more common PERLD1 SNPs (minor allele frequency > 5%) that are in linkage disequilibrium (LD, r 2  > 0.8) with rs2941504. Through in vitro studies, 7 of these SNPs were found to form a functional haplotype that influences alternative splicing of PERLD1 transcript. This result was validated in human peripheral blood mononuclear cell (PBMC), where the minor haplotype (Hap2) was shown to be associated with significantly increased PERLD1 truncated transcript. Additionally, Hap2 was found to be related to increased levels of several soluble GPI-anchored proteins (such as sCD55 and sCD59) in serum. Elevated sCD55 in the serum was demonstrated to reduce the proliferation rate of PBMCs upon phytohaemagglutinin (PHA) stimulation. Taken together, the current study has shown a functional PERLD1 haplotype, which modifies PBMC sensitivity upon stimulation and may contribute to the individual's susceptibility to allergic asthma.

Rationale: Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non-cystic fibrosis bronchiectasis remain unclear., Objectives: To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis., Methods: Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles ("immunoallertypes"), were determined., Measurements and Main Results: A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. "Sensitized bronchiectasis" was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome., Conclusions: Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a "treatable trait" permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.

Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium., Materials & Methods: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire., Results: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed., Conclusion: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.

Background: Allergic rhinitis (AR) and asthma are common allergic conditions with a shared genetic component to their cause. The 17q12-21 locus includes several genes that have been linked to asthma susceptibility, but the role of this locus in AR is unclear. Asthma and AR in adults of Chinese ethnicity in Singapore are predominately caused by sensitization against house dust mites with a nearly complete penetrance of the allergen, which presents a unique opportunity for accurately identifying genetic associations with allergic diseases., Objective: We sought to define the functional role of 17q12-21 in patients with AR and allergic asthma., Methods: We asked whether single nucleotide polymorphisms (SNPs) in the 17q12-21 locus were associated with AR or asthma in a cohort of 3460 ethnic Chinese subjects residing in Singapore (1435 in the discovery phase and 2025 in the validation phase). Full-blood mRNA gene expression data, plasma IgE levels, and immune cell frequencies in peripheral blood were tested against the tag SNP genotypes. Luciferase assays were used to measure the effect of putative promoter SNPs on expression of the asthma-associated orosomucoid-like 3 gene (ORMDL3)., Results: Within 17q12-21, only the tag SNP rs8076131 was significantly associated with asthma (P = 8.53 × 10(-10); odds ratio, 0.6715), and AR status was independent of SNPs in this region. C-A alleles at rs8076131 resulted in significantly increased ORMDL3 expression in HEK293 cells in vitro relative to T-G alleles. Moreover, subjects with the risk genotype AA exhibited significantly higher total IgE levels and higher blood eosinophil counts than those with the lower-risk genotypes., Conclusion: The 17q12-21 locus has a strong genetic association with allergic asthma but not with AR. The polymorphic effect of this locus is attributed to the linkage set tagged by rs8076131, which affects the expression of ORMDL3, protein phosphatase 1, regulatory inhibitor subunit 1B (PPP1R1B), zona pellucida binding protein 2 (ZPBP2), and gasdermin B (GSDMB) and is correlated with high IgE levels and eosinophil counts in subjects bearing the risk genotype., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The most significant association was found between the Cytosine-phosphate-Guanine (CpG) site cg08570199 and the I CCDC80 i gene (Beta coefficient: -1.249, I p i -value: 2.05 × 10 SP -4 sp ; Figure 1A-D). Two outcomes were defined according to the American Thoracic Society/European Respiratory Society 2009 statement: (1) "any exacerbation": hospitalisations, asthma-related emergency room visits, or oral corticosteroids (OCS) courses in the past 6-12 months and (2) OCS courses in the past 6-12 months. Keywords: children; exacerbations; inhaled corticosteroids; methylation quantitative trait loci (meQTL); pharmacogenetics EN children exacerbations inhaled corticosteroids methylation quantitative trait loci (meQTL) pharmacogenetics 1 5 5 09/01/22 20220801 NES 220801 DATA AVAILABILITY STATEMENT Research data are not shared. [Extracted from the article]