Principal Investigator: Professor Martin Tobin
Department: Department of Health Sciences
Institution: University of Leicester
Lung function is an important indicator of respiratory health and
mortality. Measures of lung function show irreversible airway
obstruction in chronic obstructive pulmonary disease (COPD), a
progressive condition affecting 900,000 people in the UK. Smoking is a
strong risk factor for COPD but not all smokers are equally susceptible.
Genetic approaches to understanding the mechanisms underlying the
maintenance of good lung function in some people, and underlying the
development of COPD in others, aim to reveal previously unknown
molecular targets for drug development and to facilitate stratified
approaches to treatment and care. This project aims to detect rare
genetic variants associated with lung function. Once discovered, such
variants would be very useful tools for the scientific community, because
such variants tend to exert a large effect on disease risk and provide a
means to translate findings from genetic studies of lung function to
clinical relevant research and development. The proposed study
leverages the power of UK Biobank and the resources and experience of
an expert group of UK collaborators in respiratory genomics to advance
understanding of lung function and COPD. This project will use a
customised respiratory exome chip in 50,000 UK Biobank participants,
selected according to their smoking history and lung function status at
baseline. This project therefore requires the use of data (spirometry,
smoking and other lifestyle factors) and DNA samples.
We currently have applications 648 and 8389 approved and both relate to lung health and disease. Application 648 is the original UK BiLEVE application and 8389 was for analyses of asthma and idiopathic pulmonary fibrosis (IPF) (application led by Ian Sayers at Nottingham) – for both applications, the genetic analyses are being run by our group here in Leicester using two distinct copies of the genotype and phenotype data. As part of our ongoing research aims to understand the genetic basis of lung health and disease, we would like to be able to directly compare the genetic associations with lung function and COPD (648) and IPF and asthma (8389). This requires us to compare results from analyses of independent sets of individuals. Although the final association results relating to both applications will be made publicly available at the time of completion, the two applications currently have different ids and we know that the UK Biobank individuals contributing to the 648 and 8389 analyses are overlapping which precludes us from being able to use those final results in their present form.
Studies by ourselves and others, including those we have undertaken in UK Biobank under application 648 (UK BiLEVE), have led to the identification of 97 genetic signals of association with lung function and COPD. We would like to continue to follow-up these variants to further characterise their role. Given that the objective of the PheWAS would still be to address the original aims of our initial application 648 (i.e. the genetics of lung health and disease), I am writing to ask whether access to additional fields to enable PheWAS analysis would be granted under our existing application. As stated, this would still be with the aim of understanding the genetics of lung health and disease but by looking to see whether the lung function genes affect other traits and using that information to gain insight into the biological/pathological pathways that those genes are involved in.
- One approach that we would like to use is “PheWAS” where the effects of these 97 variants on a broad range of human phenotypes are tested to gain further insight into the functional role of these variants.
- To be able to do this in UK Biobank, we would use the available HES data and the primary care data (when available) and there are also additional fields, particularly within the Medical conditions and Medical information categories that we may choose to request.
- It would be all outcomes (or some selection from all outcomes that would be deemed representative of a wide range of traits).
Lung function is an important indicator of respiratory health and mortality. Measures of lung function show irreversible airway obstruction in chronic obstructive pulmonary disease (COPD), a progressive condition affecting 900,000 people in the UK. Smoking is a strong risk factor for COPD but not all smokers are equally susceptible. Genetic approaches to understanding the mechanisms underlying the maintenance of good lung function in some people, and underlying the development of COPD in others, aim to reveal previously unknown molecular targets for drug development and to facilitate stratified approaches to treatment and care and to study the relationship between genetic variation, respiratory health and disease and blood biomarkers as intermediates on the causal pathway between genes and disease.
In observational studies, impaired forced expiratory volume in 1 second (FEV1) predicts all-cause mortality, including CVD, the second most common cause of death in COPD. We propose to use genetic associations identified in project 648 in Mendelian randomization (MR) analyses of lung function/COPD, mortality, and cardiovascular diseases (CVD). We would like to study lung function in relation to multiple CVDs (including but not limited to: myocardial infarction, stroke, cardiac arrest, peripheral vascular disease) defined from HES/primary care data. The lung function and mortality MR would require individual-level genetic data, plus lung function and mortality data (by cause). The bidirectional lung function and CVD MR uses summary data, but we would like to compare MR estimates with observational associations between lung function/COPD, CVDs, and mortality. Therefore, we also request permission to use or access important covariates, e.g. traditional cardiovascular risk factors, alcohol, and air pollution.
Finally, we would like to analyse prescribing data, to estimate the proportion of CVD risk in COPD attributable to differential prescribing of CVD secondary prevention, e.g. !-blockers (since concerns about bronchospasm may lead to their non-prescription in CVD patients with COPD). We would explore prescribing patterns in relation to CVD and mortality, by COPD status.
Project extension – April 2020
We propose a set of aims to address the COVID-19 pandemic: we would like to study observational (including lung function) and genomic vulnerability factors predisposing to COVID-19 infection and to severe infection – including using UKB as a control group(s) for external case collections. We will also study response to the respiratory consequences of COVID-19 and its treatments.
Linking to our specific interests in respiratory and environmental epidemiology, and multimorbidity, we propose to study the respiratory sequelae of COVID-19 infection, and whether air pollution may modify infection risk or case fatality. We also propose monitoring changes in chronic disease as a direct consequence of COVID-19, and indirectly due to isolation of the elderly, financial hardship, and equity issues in access to health care.
We request access to data fields relevant to COVID-19 infection status, severity and healthcare utilisation, including questionnaires, serology assays, linked PHE, ICNARC, hospital, primary care and mortality data as they become available.
Last updated Apr 27, 2020