Defining the genetic contribution and functional role to altered lung function of genes identified by GWAS meta-analysis

Lead Research Organisation: University of Nottingham
Department Name: School of Medicine

Abstract

Chronic obstructive pulmonary disease (COPD) is a common cause of illness, occuring mostly in smokers, which results in worsening cough and breathlessness and which is responsible for 30,000 deaths per year in the UK. It is recognised that genetics plays a role in the development of COPD, and recently we have identified that genetic variants in three genes called glutathione S transferase CD (GSTCD), HTR4 and AGER are risk factors for the development of abnormal lung function and COPD. The aims of this programme of research are to find out the role of these genes in the lungs, to determine how genetic variability in these genes alters lung function, and to assess how different genetic variants contribute to the development of airways disease focusing initially on COPD.

Technical Summary

We have recently identified GSTCD, AGER and HTR4 as key genetic factors which in part determine lung function and risk of COPD at the population level. Little is known regarding the function of GSTCD, although homology searches suggest it may act either as a regulator of GST activity, a modifier of Ca2+ signalling, or as a regulator of Cl- homeostasis. The role of HTR4 in determining airway function is also unclear although it may modify either cholinergic neurotransmission or potentially epithelial function. AGER is known to be a marker of epithelial injury in the lungs, but characterisation of functional variants has not been performed to date. The key hypothesis underlying this proposal is that functional variants in genes identified by genome wide association study are an important determinant of FEV1 in both the general population and in patients with respiratory diseases such as COPD.
In order to address this hypothesis the programme has four main aims: (i) to determine the key genetic variants in these 3 genes, (ii)to define the functional role for these genes in relevant airway and inflammatory cells, (iii) to identify key functional variants of GSTCD, AGER and HTR4 and (iv) to determine the contribution of variants in these genes to lung function in the general population and subjects with COPD and asthma.

Publications

10 25 50
 
Description Association of Physicians links in developing countries award
Amount £9,000 (GBP)
Organisation Association of Physicians of Great Britain and Ireland 
Sector Learned Society
Country United Kingdom
Start 04/2015 
 
Description BI research collaboration
Amount € 250,000 (EUR)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 01/2018 
End 12/2018
 
Description Chiesi foundation
Amount € 50,000 (EUR)
Organisation Chiesi 
Sector Private
Country United Kingdom
Start 07/2013 
End 07/2014
 
Description GSK research collaboration
Amount £1,000,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 12/2017 
End 12/2020
 
Description MRC strategic award
Amount £3,240,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 04/2015
 
Description Nottingham BRC
Amount £23,600,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description Pfizer internal funds
Amount £540,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 12/2012 
End 12/2014
 
Description Pfizer internal funds
Amount £400,000 (GBP)
Organisation Pfizer Inc 
Sector Private
Country United States
Start 01/2015 
End 12/2016
 
Description industry collaboration,
Amount £180,000 (GBP)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 11/2016 
End 10/2017
 
Description research collaboration Biotest
Amount € 60,000 (EUR)
Organisation Biotest AG 
Sector Private
Country Germany
Start 06/2017 
End 10/2017
 
Title GWAS lung function dataset 
Description association values for lung function SNPs from joint SPIROMETA/CHARGE analyses 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact provides open access to GWAS dataset 
 
Title Genotype data for UK Biobank 
Description As above: provosion of genotype data on 50,000 individuals in UK biobank 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Publications in preparation. 
 
Title Genotype data from Spirometa studies 
Description Genetic data from combined Spirometa and CHARGE meta analyses, plus 1000 genomes imputed data from Spirometa 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact contribution to publications, look ups for other research groups 
 
Description Joint studentship on lung development 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint studentship to explore functinal genetics (UoN) and developmental biology (ICL)
Collaborator Contribution Access to laboratory faciliites, expertise, access to mice from the International Mouse Consortium
Impact none at present
Start Year 2013
 
Description Kathmandu University 
Organisation Kathmandu University
Country Nepal 
Sector Academic/University 
PI Contribution Host laboratory for visiting PhD student from engineering faculty working on impact of low emission stove systems in COPD
Collaborator Contribution Salary and local support for student whilst in Nepal, provision of samples from Nepal
Impact Grant form Association of Physicians developing countries links programme. This is a multidisciplinary award involving medicine, engineering, social sceince and architecture/built environment partners
Start Year 2015
 
Description Ningbo hospitals 
Organisation Ningbo Number One Hospital
Country China 
Sector Hospitals 
PI Contribution Provision of laboratory facilities for visiting scholar during 2015 for 12 months to study molecular genetics of lung function associated genes
Collaborator Contribution Salary, travel and living costs for visiting fellow
Impact formal agreement with Ningbo number 1 hospital and planned additional academic exchanges
Start Year 2015
 
Description cornell 
Organisation Cornell University
Department Cornell High Energy Synchrotron Source (CHESS)
Country United States 
Sector Academic/University 
PI Contribution Data on knock out mouse model for paper
Collaborator Contribution Generation of knock out mouse
Impact Paper submitted
Start Year 2015
 
Description follow on studies on functional genetics 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution laboratory studies, ex vivo human studies
Collaborator Contribution provision of materials/compounds/funding
Impact none to date
Start Year 2012
 
Description Media interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Series of interviews following publication of Lancet Resp Med paper on UK biobank, coupled with media releases from MRC and Univeristy of Nottingham. Interviews included multiple local radio stations, Today programme, ABC News 24, San Francisco Bay radio and others
Year(s) Of Engagement Activity 2015
 
Description NG paper 2017 media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release and consequent media interviews including TV and radio interviews
Year(s) Of Engagement Activity 2017
 
Description NIHR Nottingham BRC conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Key note presentation at inaugural NIHR Nottingham BRC conference, associated video interviews and press releases
Year(s) Of Engagement Activity 2017
 
Description Press release, lung function genetics and smoking Nature Genetics paper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release highlighting use of genetic strategies to address COPD, both in smokers and nonsmokers
Year(s) Of Engagement Activity 2019
 
Description Royal Society science week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact contribution to stand at royal society science exhibition summer 2012 (main presenter Martin Tobin) based on respiratory genetics

>2000 visitors over the week
Year(s) Of Engagement Activity 2012
 
Description UK biobank regional event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk to UK Biobank regional event for research participants
Year(s) Of Engagement Activity 2015
 
Description radio interview 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Radio interview on collaboration between Nottingham, Leicester and GSK on lung function genetic studies
Year(s) Of Engagement Activity 2018
 
Description uk biobank meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact UK Biobank workshop, Houses of Parliament
Year(s) Of Engagement Activity 2017