Genetics Of Rare Polygenic Interstitial Lung Disease 

The Interstitial Lung Diseases (ILDs) are a group of rare diseases characterised by inflammation and scarring in the lungs. ILDs can occur as a consequence of inhalation of specific causative agents (e.g., chronic hypersensitivity pneumonitis due to pigeon exposure), as a complication of some types of autoimmune disease (e.g., rheumatoid arthritis, systemic sclerosis, sarcoidosis), or with no known cause ('idiopathic').

Idiopathic pulmonary fibrosis (IPF) is the most prevalent ILD, affecting fewer than 1 in 2000 people in the UK. Unlike many other rare diseases, ILDs are not caused by a single deleterious gene mutation, but rather by a combination of environmental factors and a background of genetic risk involving multiple genes. Identification of these genes can give us valuable insight into the disease but to do this, large datasets (upwards of a few hundred ILD cases) are needed.

Genetic studies of ILD have been disadvantaged by the challenges in generating sufficient data given the rarity of the disease. For IPF, we united the international IPF research community bringing together data from 1000s of cases and controls and have identified multiple associations with genes that could help us to determine why and how IPF develops.

By investigating those genes in human cell and tissue models with our collaborators, we are beginning to understand how they drive disease and, ultimately, whether this can lead us to new effective treatments. However, understanding the relevance of those genes to other ILDs beyond IPF, and identification of genes that might be specific to development of other ILDs, is still lacking because there simply is not enough data available.

This proposal will directly address that challenge by performing the largest study of ILD genetics to date. We will generate new genetic data for ILD, including exposure-related ILDs, autoimmune-related ILDs and 'unclassifiable' ILDs, from existing stored sample sets through our established collaborative network (Aim 1). We will use analytic approaches that optimise our ability to discover genes that are either shared across multiple ILDs (Aim 2) or that might be specific to certain types or groups of ILDs (Aim 3).

We will utilise biobank data to validate findings and will integrate our results with large molecular datasets to develop working hypotheses of how each gene might drive disease. Together with our collaborators with expertise in molecular techniques and access to human tissue samples, we will co-develop further gene-specific project proposals to functionally characterise their pathological role.

The data generated by our proposal will be shared with the scientific community to support wider research into ILD.

Our vision is that our findings will ultimately help patients by increasing our knowledge of the shared and distinct molecular pathways that drive different ILDs and be used to develop and target treatments. As it has been shown that medicines that target genes implicated by genetic studies are more likely to be effective, and recent clinical trials have shown that two drugs licensed for IPF are also effective in some other ILD types, this proposal is especially timely.