Genome‐wide association studies of exacerbations in children using long‐acting beta2‐agonists

Costa

et al. 2021

IJMS

Severe asthma is a multifactorial disorder with marked phenotypic heterogeneity and complex interactions between genetics and environmental risk factors, which could, at least in part, explain why during standard pharmacologic treatment, many patients remain poorly controlled and at an increased risk of airway remodeling and disease progression. The concept of “precision medicine” to better suit individual unique needs is an emerging trend in the management of chronic respiratory diseases. Over the past few years, Genome-Wide Association Studies (GWAS) have revealed novel pharmacogenetic variants related to responses to inhaled corticosteroids and the clinical efficacy of bronchodilators. Optimal clinical response to treatment may vary between racial/ethnic groups or individuals due to genetic differences. It is also plausible to assume that epigenetic factors play a key role in the modulation of gene expression patterns and inflammatory cytokines. Remarkably, specific genetic variants related to treatment effectiveness may indicate promising pathways for novel therapies in severe asthma. In this review, we provide a concise update of genetic determinants of poor response to treatment in severe asthma and future directions in the field.

Section: Pharmacogenomics Of the Therapeutic Response Of Asthmamentioning

confidence: 97%

Genetic Determinants of Poor Response to Treatment in Severe Asthma

Costa

et al. 2021

IJMS

Pediatric Allergy Immunology

“…[7][8][9][10][11][12][13][14] Pharmacogenomics studies of asthma exacerbations as an outcome of treatment response have identified five suggestive associations for asthma exacerbations despite inhaled corticosteroids (CMTR1, 9 APOBEC3B-APOBEC3C, 8 and CACNA2D3-WNT5A 11 ), or long-acting beta2-agonists (TBX3 and EPHA7). 10 Beyond pharmacogenomics, other studies have focused on asthma exacerbations independently of treatment. In European-descent populations, CDHR3, CTNNA3, and HLA-DQB1 have been associated with severe asthma exacerbations.…”

Section: Editor: öMer Kalaycimentioning

confidence: 99%

“…With the advent of high-throughput sequencing and genotyping technologies, the study of the genetic contributions to asthma exacerbations has shifted from hypothesis-driven, limited candidategene strategies to genome-wide association studies (GWAS). [7][8][9][10][11][12][13][14] Pharmacogenomics studies of asthma exacerbations as an outcome of treatment response have identified five suggestive associations for asthma exacerbations despite inhaled corticosteroids (CMTR1, 9 APOBEC3B-APOBEC3C, 8 and CACNA2D3-WNT5A 11 ), or long-acting beta2-agonists (TBX3 and EPHA7). 10 Beyond pharmacogenomics, other studies have focused on asthma exacerbations independently of treatment.…”

Section: Editor: öMer Kalaycimentioning

confidence: 99%

Multi‐ancestry genome‐wide association study of asthma exacerbations

Herrera‐Luis

Ortega

Ampleford

et al. 2022

Self Cite

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.

“…Despite this, considerable variation in outcomes for children and young people (CYP) remains. At an individual patient level, there is known interindividual variability in treatment response 5–7. Most cases of asthma in children are mild, but severe disease occurs, and sadly, 15–20 CYP die from asthma annually in the UK 8…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomics and asthma treatment: acceptability to children, families and healthcare professionals

et al. 2022

BackgroundEvidence supporting personalised treatment for asthma based on an individual’s genetics is mounting. The views of children and young people (CYP), parents and healthcare professionals (HCPs) about this evolution of clinical care are not known.MethodsA pilot prospective questionnaire-based study was undertaken of CYP with asthma, their parents and HCPs at a secondary/tertiary children’s hospital in the UK.ResultsFifty-nine questionnaires were distributed and 50 returned (response rate 84.7%), comprising 26 CYP (10 were 5–11 years, 11 were 12–15 years and 5 were 16–18 years old), 13 parents and 11 HCPs. For all types of data, personal information was ranked as the ‘most important’ (n=19, 47.5%) and ‘most private’ (n=16, 40%), but with considerable variation across groups. Within health data, allergies were rated as ‘most important’ (n=12, 30.8%), and mental health records the ‘most private’ (n=21, 53.8%), again with variation across groups. A ‘personalised genetic asthma plan’ was acceptable to the majority overall (n=40, 80.0%). With regard to sharing CYP’s genetic data, 23 (46%) of participants were happy for unconditional sharing between HCPs, and 23 (46%) agreed to sharing solely in relation to the CYP’s asthma management. Forty-two (84.0%) of participants felt CYP should be informed about genetic data being shared, and the majority felt this should commence by 12 years of age.ConclusionThe use of genetic information to guide management of asthma in CYP is largely acceptable to CYP, parents/guardians and HCPs. However, there are key differences between the opinions of CYP, parents and HCPs.