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In this project we identify associations between both rare and common single nucleotide polymorphisms (SNPs) and phenotypes defined by the extremes of the lung function distribution in heavy smokers and in never-smokers in the UK Biobank population.
Recent genome-wide association studies (GWAS) have shown genetic variants in 26 regions of the genome associated with lung function (2-5), 7 of which have been so far shown to be associated with COPD . The proportion of the variance in lung function accounted for by these common genetic variants (MAF >5%) remains however modest (~7.5% for FEV1/FVC after accounting for putative undiscovered common variants of similar effect size) . A more complete picture of genetic determinants will emerge when we also understand rarer genetic variants that affect risk of COPD. Identifying such variants could be very important for the next steps in new drug discovery and testing, because genetic variants that are less common in the population tend to have much larger effects.
The common variants associated with lung function to date have similar effect sizes in smokers as in non-smokers, but it is too early to say whether the same will be true for rare variants. As a corollary, understanding why the lung function of some smokers appears to be well-preserved could provide insight into the mechanisms which also affect susceptibility to tobacco smoke. Furthermore, a sizeable proportion of older patients with fixed airflow obstruction have had little or no exposure to tobacco smoke, but the causal mechanisms of their disease and the extent to which these mechanisms overlap with COPD in smokers are poorly understood.
To address these issues we propose a study which would leverage the power of UK Biobank and which will harness the resources and experience of an expert group of UK investigators in respiratory genomics to advance understanding of these phenotypes.
Common and rare genetic variants in respiratory health: the UK Biobank Lung Exome Variant Evaluation (UK BiLEVE) consortium
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.