Defining the genetic contribution and functional role to altered lung function of genes identified by GWAS meta-analysis

Chronic obstructive pulmonary disease (COPD) is a common cause of illness, occuring mostly in smokers, which results in worsening cough and breathlessness and which is responsible for 30,000 deaths per year in the UK. It is recognised that genetics plays a role in the development of COPD, and recently we have identified that genetic variants in three genes called glutathione S transferase CD (GSTCD), HTR4 and AGER are risk factors for the development of abnormal lung function and COPD. The aims of this programme of research are to find out the role of these genes in the lungs, to determine how genetic variability in these genes alters lung function, and to assess how different genetic variants contribute to the development of airways disease focusing initially on COPD.

We have recently identified GSTCD, AGER and HTR4 as key genetic factors which in part determine lung function and risk of COPD at the population level. Little is known regarding the function of GSTCD, although homology searches suggest it may act either as a regulator of GST activity, a modifier of Ca2+ signalling, or as a regulator of Cl- homeostasis. The role of HTR4 in determining airway function is also unclear although it may modify either cholinergic neurotransmission or potentially epithelial function. AGER is known to be a marker of epithelial injury in the lungs, but characterisation of functional variants has not been performed to date. The key hypothesis underlying this proposal is that functional variants in genes identified by genome wide association study are an important determinant of FEV1 in both the general population and in patients with respiratory diseases such as COPD.
In order to address this hypothesis the programme has four main aims: (i) to determine the key genetic variants in these 3 genes, (ii)to define the functional role for these genes in relevant airway and inflammatory cells, (iii) to identify key functional variants of GSTCD, AGER and HTR4 and (iv) to determine the contribution of variants in these genes to lung function in the general population and subjects with COPD and asthma.