Abstract
Background:
Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes.
Methods:
We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9,568 individuals from five UK birth-cohorts.
Results:
44 independent SNPs were associated with early-onset persistent, 25 with preschool remitting, 33 with mid-childhood remitting and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 (ANXA1), p<6.7×10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge.
Conclusions:
Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.
Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes.
Methods:
We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9,568 individuals from five UK birth-cohorts.
Results:
44 independent SNPs were associated with early-onset persistent, 25 with preschool remitting, 33 with mid-childhood remitting and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 (ANXA1), p<6.7×10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge.
Conclusions:
Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.
| Original language | English |
|---|---|
| Article number | e84315 |
| Number of pages | 57 |
| Journal | eLife |
| Volume | 12 |
| DOIs | |
| Publication status | Published - 25 May 2023 |
Bibliographical note
Funding Information: Funding P Supported by the UK Medical Research Council 縀MRC 缀 ProgramGmraen t MR 氀S ? ? 氃? ?
Funding Information:
Simpson P Medical research council Research grant JP Moulton Charitable Foundation Research
Funding Information:
wide genotyping was funded by the European Commission as part of GABRIEL 縁?rant number
Funding Information:
F unding P UK Medical Research Council Programme Grant MR 氀S the W氃ellc aonmde Trust
Funding Information:
縁?esearch grants 缀 EPSRC 縁?esearch grant 缀 Wellcome Tcrhu sgtr a 縁nt 谁缀ḁ W? orega Prharmaceoticals
Funding Information:
PIAMA was funded by the Netherlands Lung Foundation ?grant 堃? 堃? ? 唀 堃堃堃? 唀 ? 堃堃堃?
Funding Information:
UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust 109 Strategic Award (108,818/15/Z) provided most of the funding for this study.
Publisher Copyright:
© The Authors.
Research Groups and Themes
- ALSPAC