A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing
- University of Bristol, United Kingdom
- University of Manchester, United Kingdom
- Imperial College London, United Kingdom
- University of Southampton, United Kingdom
- Queen Mary University of London, United Kingdom
- University of Groningen, Netherlands
- David Hide Asthma and Allergy Research Centre, United Kingdom
- University of Aberdeen, United Kingdom
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.
Funding:
UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108,818/15/Z) provided most of the funding for this study.
Data availability
The informed consent obtained from all included participants does not allow the data to be made freely available through any third party maintained public repository.However, data used for this submission can be made available on request to the corresponding cohort Executive. Researchers will need to submit a research proposal to each cohort Executive Committee. Data access will have a cost, for more details re. ALSPAC contact alspac-data@bristol.ac.uk, for any other cohort contact philip.couch@manchester.ac.uk.The ALSPAC website provides information on how to request and access its data ( http://www.bristol.ac.uk/alspac/researchers/access/). For queries regarding access of data from MAAS, IoW, SEATON or Ashford please contact Philip Couch philip.couch@manchester.ac.uk). All code used to analyse the individual level data and all summary data and code used to plot the figures in our manuscript has been deposited in Dryad.
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A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing (GWAS ANXA1)Dryad Digital Repository, doi:10.5061/dryad.3r2280gm3.
Article and author information
Author details
Negusse Tadesse Kitaba
Funding
UK Medical Research Council (MR/S025340/1)
- Raquel Granell
- Adnan Custovic
Wellcome Trust (108818/15/Z)
- Raquel Granell
- Adnan Custovic
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: In accordance with the Animals (scientific procedures) act 1986, all animal experiments were conducted under the approved UK Home Office Project License No: PPL 70/7643, reviewed by Imperial College's Animal Welfare and Ethical Review body.
Human subjects: ALSPAC: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. All self-completion questionnaire content is approved by the ALSPAC Ethics and Law Committee. Bristol and Weston Health Authority: E1808 Children of the Nineties: Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). (28th November 1989); Southmead Health Authority: 49/89 Children of the Nineties -"ALSPAC". (5th April 1990); Frenchay Health Authority: 90/8 Children of the Nineties. (28th June 1990).MAAS: The study was approved by the North West - Greater Manchester East Research Ethics Committee. ERP/94/032 Up to 5 yrs. Allergen avoidance, Primary Prevention, genetics, sRaw age 3 and 5; SOU/00/259 5 year; ERP/95/137 Exposure to pet allergens, atopy, genetics; ERP/97/023 IFWIN, genetics; 03/SM/400 8 year; 06/Q1403/142 10-12 years; 11/NW/0228 13-15 years; 14/NW/1309 18+ years.SEATON: The study was approved by the North of Scotland Research Ethics Committee. REC reference: 13/NS/0108; Protocol number: 2/048/13; Amendment number: AM03.Ashford: The Asthma in Ashford study was reviewed by the Imperial College Research Ethics Committee on 11/11/2014. On 08/01/2015 the Joint Research Compliance Office granted full approval of the study on the basis described in the revised documents. ICREC reference: 14|C2288.IOW: Ethics approval for the IoW cohort was originally given by the Isle of Wight local research ethics committee in 1989 and at each subsequent follow up (1,2 and 4 years) (this is pre "numbers")Age 10 follow up (including DNA and genotyping): Isle of Wight Health Authority Local Research Ethics Committee 18/98. Age 18 Follow up(including DNA and genotyping): Isle of Wight, Portsmouth & South East Hampshire Research Ethics Committee 06/Q1701/34.
Copyright
© 2023, Granell et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing
eLife 12:e84315.
https://doi.org/10.7554/eLife.84315
Further reading
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background:
In many settings, a large fraction of the population has both been vaccinated against and infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, quantifying the protection provided by post-infection vaccination has become critical for policy. We aimed to estimate the protective effect against SARS-CoV-2 reinfection of an additional vaccine dose after an initial Omicron variant infection.
Methods:
We report a retrospective, population-based cohort study performed in Shanghai, China, using electronic databases with information on SARS-CoV-2 infections and vaccination history. We compared reinfection incidence by post-infection vaccination status in individuals initially infected during the April–May 2022 Omicron variant surge in Shanghai and who had been vaccinated before that period. Cox models were fit to estimate adjusted hazard ratios (aHRs).
Results:
275,896 individuals were diagnosed with real-time polymerase chain reaction-confirmed SARS-CoV-2 infection in April–May 2022; 199,312/275,896 were included in analyses on the effect of a post-infection vaccine dose. Post-infection vaccination provided protection against reinfection (aHR 0.82; 95% confidence interval 0.79–0.85). For patients who had received one, two, or three vaccine doses before their first infection, hazard ratios for the post-infection vaccination effect were 0.84 (0.76–0.93), 0.87 (0.83–0.90), and 0.96 (0.74–1.23), respectively. Post-infection vaccination within 30 and 90 days before the second Omicron wave provided different degrees of protection (in aHR): 0.51 (0.44–0.58) and 0.67 (0.61–0.74), respectively. Moreover, for all vaccine types, but to different extents, a post-infection dose given to individuals who were fully vaccinated before first infection was protective.
Conclusions:
In previously vaccinated and infected individuals, an additional vaccine dose provided protection against Omicron variant reinfection. These observations will inform future policy decisions on COVID-19 vaccination in China and other countries.
Funding:
This study was funded the Key Discipline Program of Pudong New Area Health System (PWZxk2022-25), the Development and Application of Intelligent Epidemic Surveillance and AI Analysis System (21002411400), the Shanghai Public Health System Construction (GWVI-11.2-XD08), the Shanghai Health Commission Key Disciplines (GWVI-11.1-02), the Shanghai Health Commission Clinical Research Program (20214Y0020), the Shanghai Natural Science Foundation (22ZR1414600), and the Shanghai Young Health Talents Program (2022YQ076).
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- Epidemiology and Global Health
Background:
The role of circulating metabolites on child development is understudied. We investigated associations between children’s serum metabolome and early childhood development (ECD).
Methods:
Untargeted metabolomics was performed on serum samples of 5004 children aged 6–59 months, a subset of participants from the Brazilian National Survey on Child Nutrition (ENANI-2019). ECD was assessed using the Survey of Well-being of Young Children’s milestones questionnaire. The graded response model was used to estimate developmental age. Developmental quotient (DQ) was calculated as the developmental age divided by chronological age. Partial least square regression selected metabolites with a variable importance projection ≥1. The interaction between significant metabolites and the child’s age was tested.
Results:
Twenty-eight top-ranked metabolites were included in linear regression models adjusted for the child’s nutritional status, diet quality, and infant age. Cresol sulfate (β=–0.07; adjusted-p <0.001), hippuric acid (β=–0.06; adjusted-p <0.001), phenylacetylglutamine (β=–0.06; adjusted-p <0.001), and trimethylamine-N-oxide (β=–0.05; adjusted-p=0.002) showed inverse associations with DQ. We observed opposite directions in the association of DQ for creatinine (for children aged –1 SD: β=–0.05; pP=0.01;+1 SD: β=0.05; p=0.02) and methylhistidine (–1 SD: β = - 0.04; p=0.04;+1 SD: β=0.04; p=0.03).
Conclusions:
Serum biomarkers, including dietary and microbial-derived metabolites involved in the gut-brain axis, may potentially be used to track children at risk for developmental delays.
Funding:
Supported by the Brazilian Ministry of Health and the Brazilian National Research Council.
