Characterising the shared and disease-specific genetic determinants of asthma and COPD

Two of the most common long-term lung diseases are asthma and chronic obstructive pulmonary disease (often known as COPD, or sometimes called emphysema or chronic bronchitis). It is known that an individual's risk of developing one of these diseases is influenced by factors in our living environment (such as smoking and air pollution) but also by our genetic make-up (the DNA we inherit from our parents). Because COPD and asthma have some shared characteristics, it is likely that some of the genetic influences are also shared between both diseases. Identifying these could contribute to understanding of how these diseases develop and eventually lead to better diagnosis and treatment in the future.

This project will therefore investigate the regions of our DNA that contribute to the development of asthma and COPD. In the first part of the project I will use specialised statistical techniques to investigate whether the same regions of DNA are involved in both diseases, and whether there are a small number of shared regions with strong effects, or a larger number of regions, each with a relatively small effect. I will also aim to identify where any shared regions are in our DNA.

The second part will look at different ways to define asthma, COPD and a disease known as "asthma-COPD overlap syndrome" (ACOS) where patients show signs of both asthma and COPD, and often have more severe breathing problems than those who have asthma or COPD alone. I will determine the most accurate way of defining these diseases using information which is routinely collected by health services, or which is quick and easy to collect, and can therefore be used widely by health researchers. I will then use the best definition to study which regions of DNA are associated specifically with ACOS, and will check whether these differ in smokers and non-smokers.

Regions which seem to be involved in both asthma and COPD, or in ACOS, will be further investigated by repeating the tests using data from other, independent research studies to check whether they produce the same result. If I do confirm the results in these independent studies, I will aim to further investigate those regions of the DNA to see what their role is and how they may influence development of asthma and COPD, which may help in future to develop new treatments or select the best treatments for different people with these diseases.

This project aims to investigate to what extent the genetic determinants of asthma and COPD are shared or disease-specific, and to identify and characterise those shared determinants.

This will involve two complementary approaches undertaken in parallel. The first will use a polygenic risk score approach in UK Biobank, a large cohort of 500,000 individuals, to identify the extent of overlap between genetic variants associated with asthma and those associated with COPD. This will use pragmatic definitions of COPD and asthma similar to those used successfully in genome-wide association studies of the two diseases to date. Sensitivity analyses will be undertaken separately in smokers and never-smokers. By varying the statistical significance thresholds for inclusion of variants in the risk score model, I will examine the contribution of SNPs showing strong association and those with weaker association (which may be rare SNPs or those with small effect size). Specific variants which meet genome-wide significance thresholds for both diseases would also be identified.

The second approach will refine epidemiological definitions of asthma, COPD, and the clinical syndrome of asthma-COPD overlap (ACOS), which is associated with more rapid decline in lung function and significantly worse outcomes but lacks clear consensus on the most appropriate definition. I will explore self-reported data and electronic primary care records in up to 10,000 participants in the EXCEED study and 500,000 participants in UK Biobank to develop definitions suitable for use in genetic and epidemiological studies. I will then apply these in a genome-wide association study to identify specific genetic determinants of ACOS. Replication of any associations identified will be undertaken in independent cohorts and the functional role of variants investigated through the use of appropriate bioinformatic resources.

This project aims to characterise shared genetic determinants of COPD and asthma, contributing to understanding of the molecular pathways that lead to these diseases. Ultimately, this will help to refine diagnostic criteria, identify possible targets for drug treatment, and identify subgroups of patients who may be at higher risk of severe disease to enable better clinical risk prediction and tailored treatment.

Both asthma and COPD are extremely common, affecting 5.4 million people and over 900,000 people in the UK respectively. Despite advances in treatment, both continue to cause considerable disability and indeed mortality, with approximately 30,000 deaths due to COPD and over 1000 deaths due to asthma per year. The annual cost to the NHS is estimated to be around £800m for COPD and £1bn for asthma, with the costs to wider society running into several billion, in part due to reduced productivity of people living with COPD and asthma.

Long-term beneficiaries of this research could therefore include:
-patients with asthma and COPD and their families, through improved treatment, less frequent exacerbations, reduced mortality and better quality of life;
-the NHS, through reduction of costs due to more effective identification and management of COPD, asthma and ACOS;
-the pharmaceutical industry (through identification of targets for drug development); and
-the UK economy, through improved productivity as well as outputs from the pharmaceutical industry.