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.
Reviewing Editor
- Anurag Agrawal, Ashoka University, India
Version history
- Received: October 19, 2022
- Preprint posted: March 5, 2023 (view preprint)
- Accepted: May 22, 2023
- Accepted Manuscript published: May 25, 2023 (version 1)
- Version of Record published: June 26, 2023 (version 2)
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
Background:
The Coronavirus Disease of 2019 (COVID-19) has impacted the health and day-to-day life of individuals, especially the elderly and people with certain pre-existing medical conditions, including cancer. The purpose of this study was to investigate how COVID-19 impacted access to cancer screenings and treatment, by studying the participants in the Multiethnic Cohort (MEC) study.
Methods:
The MEC has been following over 215,000 residents of Hawai‘i and Los Angeles for the development of cancer and other chronic diseases since 1993–1996. It includes men and women of five racial and ethnic groups: African American, Japanese American, Latino, Native Hawaiian, and White. In 2020, surviving participants were sent an invitation to complete an online survey on the impact of COVID-19 on their daily life activities, including adherence to cancer screening and treatment. Approximately 7,000 MEC participants responded. A cross-sectional analysis was performed to investigate the relationships between the postponement of regular health care visits and cancer screening procedures or treatment with race and ethnicity, age, education, and comorbidity.
Results:
Women with more education, women with lung disease, COPD, or asthma, and women and men diagnosed with cancer in the past 5 years were more likely to postpone any cancer screening test/procedure due to the COVID-19 pandemic. Groups less likely to postpone cancer screening included older women compared to younger women and Japanese American men and women compared to White men and women.
Conclusions:
This study revealed specific associations of race/ethnicity, age, education level, and comorbidities with the cancer-related screening and healthcare of MEC participants during the COVID-19 pandemic. Increased monitoring of patients in high-risk groups for cancer and other diseases is of the utmost importance as the chance of undiagnosed cases or poor prognosis is increased as a result of delayed screening and treatment.
Funding:
This research was partially supported by the Omidyar 'Ohana Foundation and grant U01 CA164973 from the National Cancer Institute.
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- Epidemiology and Global Health
Background:
Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.
Methods:
This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.
Results:
1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32–1.67]); Black patients (aOR 1.74; 95 CI 1.24–2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70–6.79) and Other (aOR 2.97; 95 CI 1.71–5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83–12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63–3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20–2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66–3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89–22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status.
Conclusions:
Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients.
Funding:
This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication.
Clinical trial number:
CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.
