Gene and environmental influences on childhood asthma: STELAR (Study Team for Early Life Asthma Research) collaboration

Lead Research Organisation: University of Manchester
Department Name: Medical and Human Sciences

Abstract

Asthma is the most common chronic disease of childhood and the number of children suffering from asthma has increased dramatically over the past 30 years. We do not fully understand what aspects of changing life style have caused this increase, but many things such as diet, immunizations and smoke exposure have been implicated. We have created a network of researchers from Aberdeen, Ashford, Bristol, Isle of White and Manchester and we have studied several thousand children from their birth and measured lots of factors in the environment (e.g. collecting dust form the home, recording dietary intake etc). Using questionnaires and lung function and allergy testing we have a clear description of which children have and have not got asthma and allergies. In each of the centres the study has used slightly different ways of measuring things. In this research project we will review the children in Manchester, Aberdeen and Ashford at age 10 -12 years and measure things in the same way. By working together as a research network we will be able to reproduce the findings of one cohort in another where similar measurements have been taken, making the research findings much stronger and more reliable. We are also collecting DNA from the study children and so in the future will be able to investigate how the genes and environment interact to cause disease. Understanding the causes of asthma will allow us to identify strategies to prevent asthma in susceptible children, and may improve treatment for asthma sufferers into adulthood.

Technical Summary

Background: Asthma and allergies start early in life and are phenotypically unstable, progressing or remitting over time. The increase in their prevalence is consequent to environmental factors increasing the risk in genetically susceptible individuals (gene-environment interaction). Power to detect such interactions depends not only on size of population, but critically on accurate phenotyping and measurement of environmental exposures.
Aim: To study gene-environment interactions in the development of asthma and allergies
Methods: The STELAR group comprises all UK asthma/allergy birth cohorts (AMICS, SEATON, IoW, ALSPAC, MAAS). All cohorts are well established, all subjects are recruited and retention has been excellent. We propose to obtain a minimum set of common outcomes to provide comparable phenotypic definitions at similar time point (age 10-12 years) across the cohorts (?minimum dataset?) to allow pooling of data to increase power for genetic association studies. This includes:
Phenotyping: to collect outcome measures across 3 cohorts (AMICS, MAAS, SEATON) to give comparable phenotypes with that already collected in IoW and ALSPAC. Common phenotypic outcomes will comprise: physician-diagnosed asthma, current wheeze/wheeze phenotypes, lung function, airway reactivity, allergic sensitisation, Eczema/rhinitis.
Environmental exposures: to define a common set of environmental exposures (passive smoking, pet ownership, socioeconomic status, vaccination, childcare arrangements, position in sibship, allergen exposure, diet, household characteristics, antibiotic use, vitamin d, endotoxin)
Genotyping: to genotype for a common panel of SNPs to test for association with objective measures of lung function, sensitization and asthma. Our strategy will focus on specific gene-environment hypotheses including: TIM-1 and hepatitis A; Vitamins D and E, asthma and immune system; Environmental tobacco smoke exposure (ETS), polymorphisms in GST and changes in lung function; ADAM33 and ETS; Pattern recognition receptors, microbial exposures and allergy; ADRB2 and lung function; Leukotriene pathway and n-3 PUFA. In addition, we will investigate associations between putative candidate genes and asthma/allergy. This approach recognises that: each cohort is unique and has its strengths-there are unique hypotheses to test within each; where outcome measures are identical data can be merged to test the whole population; where outcome measures are similar (but not identical), findings can be replicated from one cohort in others.
Conclusions: This unique collaboration between all UK asthma/allergy birth cohorts will enable the establishment of a common genetic and environmental exposure database in children aged 10-12 years, exceeding the sum of the cohorts acting individually and putting UK in the forefront of the investigation of genetic and environmental influences on asthma.

Publications

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Belgrave D (2014) Trajectories of Lung Function during Childhood in American Journal of Respiratory and Critical Care Medicine

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Bousquet J (2014) Birth cohorts in asthma and allergic diseases: Report of a NIAID/NHLBI/MeDALL joint workshop in Journal of Allergy and Clinical Immunology

 
Guideline Title Allergic Rhinitis and its Impact on Asthma (ARIA)
Description ARIA Guidelines: Data on ptrevalence of allergic rhinitis in pre-school children
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
 
Guideline Title British guideline on the management of asthma
Description BTS/SIGN. British guideline on the management of asthma advice on prevention
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
 
Description Citation by Academy of Medical Sciences
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Description Development and implementation of guidelines in allergic rhinitis
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description European Respiratory Society: Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description House of Lords Select Committee enquiry into Allergy
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Scottish Government's Good Places Better Health workshop on asthma and diet.
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Unmet needs in severe chronic upper airway disease: Global Allergy and Asthma European Network, World Allergy Organization and Allergic Rhinitis and its Impact on Asthma
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description World Allergy Organisation White Book on Allergy
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Description expert advisor to the Food Standards Agency
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description expert advisor to the Governmental Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT)
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description BLF funding (Epigenetic factors in the development of childhood Asthma)
Amount £54,000 (GBP)
Organisation British Lung Foundation (BLF) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Chief Scientists Office of the Scottish Executive
Amount £209,642 (GBP)
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 08/2010 
End 07/2013
 
Description Chief Scientists Office of the Scottish Executive, meta analysis
Amount £61,221 (GBP)
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 01/2008 
End 01/2009
 
Description Chief Scientists Office of the Scottish Executive, pilot study
Amount £24,566 (GBP)
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 07/2008 
End 06/2009
 
Description European Union Seventh Framework Programme
Amount € 9,000,000 (EUR)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 03/2013 
End 03/2017
 
Description MRC E-Health Informatics Research Centres
Amount £4,500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 01/2017
 
Description MRC Research Grant
Amount £1,500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2013 
End 03/2016
 
Description MRC/BBSRC Flagship Consortium in Systems Immunology of the Human Life Course
Amount £2,200,000 (GBP)
Funding ID MR/L012693/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2014 
End 01/2019
 
Description Moulton Charitable Foundation project grant
Amount £318,005 (GBP)
Organisation J P Moulton Charitable Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description NIHR Clinicla Resreach facilites
Amount £2,500,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description NIHR Manchester Biomedical Research Centre ( Asthma programme )
Amount £28,500,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2017 
End 04/2022
 
Description NIHR Translational Research Facility in Respiratory Medicine
Amount £2,180,344 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2008 
End 03/2012
 
Description Novel Tests of Small Airway Physiology and Biomarkers for Asthma Diagnosis and Predicting Response to Inhaled Corticosteroids
Amount £236,090 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2019 
End 01/2022
 
Description The Freemasons Grand Charity
Amount £400,000 (GBP)
Organisation The Freemasons' Grand Charity 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title STELAR databases and samples 
Description Databases in Manchester, Aberdeen and Imperial College to collect phenotypic information from the MAAS, SEATON and Ashford birth cohorts, linking them to appropriate biological samples (blood and DNA) 
Type Of Material Biological samples 
Year Produced 2014 
Provided To Others? Yes  
Impact work in progress 
 
Description Baxters 
Organisation Baxters Food Group
Country United Kingdom 
Sector Private 
PI Contribution based on the results of the dieatry work done in the Aberdeen cohort
Collaborator Contribution develop a food based intervention
Impact presentation to British Science Festival Aberdeen Sept 2012
Start Year 2010
 
Description EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium 
Organisation University of Bristol
Department MRC Centre for Causal Analyses in Translational Epidemiology
Country United Kingdom 
Sector Public 
PI Contribution the EAGLE collaboration contains many partners, the two leading ones only ahve been listed. Our contribution was to analyse GWA data against eczema outcomes and supply data for meta aanalysis. We contributed to the original study design and drafting of the manuscript. Multiple other projects within this consortium are nearing completion
Collaborator Contribution Collaboration in genome wide association study, meta- anlaysis conducted by other partners. manuscript in press META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS paternoster et al nature geneticsCollaboration in genome wide association study, meta- anlaysis conducted by this partners. manuscript in press META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS paternoster et al nature genetics
Impact manuscript in press META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS paternoster et al nature genetics. Multidisciplinary from epidemiologists, clinicians, statisticians, bioinformaticians
Start Year 2010
 
Description EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium 
Organisation University of Copenhagen
Department Faculty of Health and Medical Sciences
Country Denmark 
Sector Academic/University 
PI Contribution the EAGLE collaboration contains many partners, the two leading ones only ahve been listed. Our contribution was to analyse GWA data against eczema outcomes and supply data for meta aanalysis. We contributed to the original study design and drafting of the manuscript. Multiple other projects within this consortium are nearing completion
Collaborator Contribution Collaboration in genome wide association study, meta- anlaysis conducted by other partners. manuscript in press META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS paternoster et al nature geneticsCollaboration in genome wide association study, meta- anlaysis conducted by this partners. manuscript in press META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS paternoster et al nature genetics
Impact manuscript in press META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS paternoster et al nature genetics. Multidisciplinary from epidemiologists, clinicians, statisticians, bioinformaticians
Start Year 2010
 
Description Microsoft Research, Cambridge and Northwest Institute for Bio-Health Informatics 
Organisation Microsoft Research
Country Global 
Sector Private 
PI Contribution Collecting data form MAAS cohort and guiding the analysis
Collaborator Contribution Machine learning analysis of data in MAAS cohort
Impact 20. Simpson A, Tan VYF, Winn J, Svensén M, Bishop CM, Heckerman DE, Buchan I, Custovic A. Beyond atopy: Multiple patterns of sensitization in relation to asthma in a birth cohort study. American Journal of Respiratory and Critical Care Medicine 2010;181(11):1200-6. others papers in prepaprtion
Start Year 2008
 
Description Interview on BBC breakfast on 24th August 2018 broadcast live nationally on asthma, pollution, inhalers (recorded at media City) followed by a piece to camera on twitter feed. 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was interviewed live on BBC breakfast ( daily audience ~ 5 million) about asthma exacerbations and air pollution. I then recorded a piece to camera for the twitter feed
Year(s) Of Engagement Activity 2018
 
Description Open meeting for public in Aberdeen 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Open audience of ~ 100 people. presented results of the SEATON study, generated lots of interets form the audience

An audience member now fundraises for the resarch project
Year(s) Of Engagement Activity 2010
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Gave lecture entitled 'Too dirty or too clean - why are allergies increasing?'

Increasing awareness of the research topic
Year(s) Of Engagement Activity 2008
 
Description School Visit WHGS 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Delivered talks during science lessons to years 8 pupils describing air pollution, and the Manchester Asthma and Allergy Study.

Collected data which has been shared with the school and is used in science lessons. follow up visits will be arranged
Year(s) Of Engagement Activity 2009,2010
 
Description School visit - Urmston 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Invited lecture about Asthma, in which the manchester Asthma and Allergy Study, the STELAR collaboration and the funding form the MRC were discussed

Students had lots of questions about studying science and medicine
Year(s) Of Engagement Activity 2007
 
Description Special report on how Air pollution is reducing life expectancy in manchester, Broadcast on 2nd October 2018 - prerecorded 30 minute programme on ITV 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact I was interviewed by a journalist on the effects of air pollution on asthma. I discussed the results that we had found in the Manchester Asthma and Allergy Study. this becamse part of a 30 minute programme broadcast at 6.30 on ITV
Year(s) Of Engagement Activity 2018
 
Description Trust Me I'm A Doctor 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Recorded footage for Trust Me I'm A Doctor: Episode 3: The great allergy mystery! (Michael Mosley meets a team at Manchester University trying to understand allergies). Broadcast on BBC2 8pm Thursday 23rd October. We filmed a consultation with the presenter Dr Michael Moseley at UHSM in the allergy clinic which involved skin testing and interpreting skin test results an explaining part of the research programme.

Very Recent so impact not clear yet
Year(s) Of Engagement Activity 2013
URL http://www.uhsm.nhs.uk/allergy/Pages/videos.aspx
 
Description newsletter for MAAS parents 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Study participants or study members
Results and Impact Newsletter allows parents to find out about published results of the study

research particpants have requested to do work experience in our research department and have used details of the research project for school dissertations and presentations as part of GCSE work.
Year(s) Of Engagement Activity 2009,2010,2011