Artikel ; Online: A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing
eLife, Vol
2023 Band 12
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 ... ...
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 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school 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. Funding: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study. |
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Schlagwörter | GWAS ; ALSPAC ; wheezing phenotypes ; meta-analysis ; MAAS ; ANXA1 ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5 |
Thema/Rubrik (Code) | 616 |
Sprache | Englisch |
Erscheinungsdatum | 2023-05-01T00:00:00Z |
Verlag | eLife Sciences Publications Ltd |
Dokumenttyp | Artikel ; Online |
Datenquelle | BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl) |
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