Work package 2

Identifying gene candidates and pathways involved in aberrant damage and repair responses to cigarette smoking in existing cohorts

One of the factors in the exposome that will also be studied in WP1 and that is a major risk factor for the loss of lung function is (environmental) cigarette smoke exposure. In this work package, existing cohorts will be studied to identify novel therapeutic targets involved in lung damage and repair upon cigarette smoke exposure.

Although we know that smoking is unhealthy and it is the major risk factor for the development of COPD, not all COPD patients smoke and moreover, not all smokers develop COPD (15-20% does). This indicates that besides smoke and other environmental factors, (epi)genetic factors are involved in the susceptibility for the disease. We need better insights into the mechanisms involved in the development of aberrant repair and lung damage in response to smoking.

The first aim of this work package is identification of candidate genes and signaling pathways that are differently expressed in the airway epithelium upon acute cigarette smoke exposure. The second aim is identification of cigarette smoke-influenced COPD susceptibility genes by investigating which candidate genes identified in aim 1 are also differently expressed in lung tissue of COPD patients compared to (non-)smoking controls. The third aim is validation of previously identified COPD susceptibility genes, and identify whether these are influenced by acute cigarette smoke exposure.

In our gene expression dataset from the TIP cohort (n=61), which contains bronchial brushings taken at baseline and 24 hours after smoking, we will assess which airway epithelial genes respond to smoking. In a second dataset, which contains lung tissue of current and ex-smokers with (n=100) and without (n=45) chronic obstructive pulmonary disease (COPD), we will investigate which of the smoking related candidate genes overlap with genes that are differently expressed between these groups, with a special focus on patients at high risk to develop lung damage and rapid lung function decline, i.e. severe early onset COPD.

Using a more focused approach, we will assess whether susceptibility genes identified as previous GWAS hits for lung function decline and COPD (or genes being epigenetically regulated by smoking [e.g. by methylation] and associated with lung function) are different between smokers with and without COPD. The difference in expression of risk genes 24 hours after smoking in people without COPD will be compared to the differences seen in patients with COPD 24 hours after they smoked. Also differences at baseline between smokers with and without COPD will be studied.

The deliverable of this working package is identification of novel therapeutic targets for cigarette smoke-induced lung damage. At a later stage, the same bioinformatics approaches that will be used in this work package will be applied to the PRIL cohort (WP6) and novel therapeutic targets identified in this work package will later be validated in the PRIL cohort in the search for treatable targets. Identified targets will also be studied in the mechanistic studies using advanced models and in intervention studies for lung repair in COPD (WP10 & WP11). 

Figure 4 Set up of the study in work package 2.