Genetic determinants of acute asthma therapy response in children with moderate‐to‐severe asthma exacerbations

Tse, Sze Man; Krajinović, Maja; Chauhan, Bhupendrasinh F; Zemek, Roger; Gravel, Jocelyn; Chalut, Dominic; Poonai, Naveen; Quach, Caroline; Laberge, Sophie; Ducharme, Francine M

doi:10.1002/ppul.24247

Cited by 15 publications

(9 citation statements)

References 26 publications

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“…AEs focused on polymorphisms in genes previously implicated in asthma or in viral pathways [1], such as the Interleukin 33 (IL33) [50], vitamin D receptor (VDR) [54], or SERPINE1 gene encoding for the plasminogen activator inhibitor-1 (PAI-1) [52] (Table 1). For instance, adding several asthma-related variants at SPATS2L and IL33 that were associated with ED management failure to ED-related clinical scores improved the predictive capability for ED management failure compared with the clinical model alone (area under the curve [AUC]: 0.82 vs. 0.79, p = 0.0004) [50]. Moreover, an expression quantitative trait loci (eQTL) analysis of respiratory syncytial virus (RSV)related genes narrowed down the modulatory effect of RSV infection on a CEACAM3 locus for AEs [53].…”

Section: Candidate-gene Association Studies Most Candidate-gene Assoc...mentioning

confidence: 99%

Asthma Exacerbations: The Genes Behind the Scenes

Luis¹,

Forno²,

Celedón³

et al. 2023

J Investig Allergol Clin

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The clinical and socioeconomic burden of asthma exacerbations (AEs) represents a major public health problem. In the last four years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies (GWAS) of AEs, which in the latter case has led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple “omic” layers have contributed to prioritizing genomic regions of interest and/or understanding the functional consequences of genetic variation. Despite this, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (e.g., gene-environment interactions, next-generation sequencing, or polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have been scarcely investigated, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of host-airway microbiome interaction in the modulation of AEs risk. Leveraging -omics and deep-phenotyping data from sub-types or homogenous subgroups of patients will be crucial to overcome the inherent heterogeneity of AEs, and boost the identification of potential therapeutic targets and the implementation of precision medicine in clinical practice for AEs.

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Section: Candidate-gene Association Studies Most Candidate-gene Assoc...mentioning

confidence: 99%

Asthma Exacerbations: The Genes Behind the Scenes

Luis¹,

Forno²,

Celedón³

et al. 2023

J Investig Allergol Clin

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“…For instance, rs928413 is a SNP significantly associated with increased risk of asthma when carrying the AA genotype, while individuals with the heterozygous genotype (GA) have a decreased risk of asthma compared to those who do not carry the mutated allele [ 233 ]. While most association studies of SNPs focus on the risk and susceptibility of asthma, Tse et al demonstrated that SNPs rs1342326 and rs7037276 are inversely associated with emergency department failure in children with moderate to severe asthma [ 232 ], suggesting those that carry these SNPs may have a better response to common asthma therapy. Findings of genome-wide association studies show that ethnic background can have an essential role in determining the direction of association between different SNPs and disease risk or susceptibility [ 240 ].…”

Section: Variants Of Alarmins Genes In Asthmamentioning

confidence: 99%

The Role of Airway Epithelial Cell Alarmins in Asthma

Whetstone

Ranjbar

Omer

et al. 2022

Cells

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The airway epithelium is the first line of defense for the lungs, detecting inhaled environmental threats through pattern recognition receptors expressed transmembrane or intracellularly. Activation of pattern recognition receptors triggers the release of alarmin cytokines IL-25, IL-33, and TSLP. These alarmins are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Many of the key effector cells in the allergic cascade also produce alarmins, thereby contributing to the airways disease by driving downstream type 2 inflammatory processes. Randomized controlled clinical trials have demonstrated benefit when blockade of TSLP and IL-33 were added to standard of care medications, suggesting these are important new targets for treatment of asthma. With genome-wide association studies demonstrating associations between single-nucleotide polymorphisms of the TSLP and IL-33 gene and risk of asthma, it will be important to understand which subsets of asthma patients will benefit most from anti-alarmin therapy.

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“…We next examined 47 previous genetic loci for asthma exacerb ations 7,8,12,13,[34][35][36] and moderate-to-severe asthma 37 for association with asthma exacerbations in the discovery phase. A total of 5 variants had p < .05 in Europeans, 2 in Hispanics/Latinos, 5 in African Americans, and 1 in Singaporean Chinese (Table S16).…”

Section: Validationofpreviousassociationsmentioning

confidence: 99%

Multi‐ancestry genome‐wide association study of asthma exacerbations

Herrera‐Luis

Ortega

Ampleford

et al. 2022

Pediatric Allergy Immunology

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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 (ORT allele) = 0.82, p = 9.05 × 10−6 and replication: ORT allele = 0.89, p = 5.35 × 10−3) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10−5 and replication: ORC 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.

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Genetic determinants of acute asthma therapy response in children with moderate‐to‐severe asthma exacerbations

Cited by 15 publications

References 26 publications

Asthma Exacerbations: The Genes Behind the Scenes

Asthma Exacerbations: The Genes Behind the Scenes

The Role of Airway Epithelial Cell Alarmins in Asthma

Multi‐ancestry genome‐wide association study of asthma exacerbations

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