Genetic determinants of lung function measures

Abstract

The evidence of a genetic contribution to lung function measures, both baseline and in response to bronchodilator has been well established. Candidate gene studies have identified more than 100 genes suggested to contribute to variability in lung function. Apart from alpha 1 antitrypsin (AA T) gene; which is the most documented genetic risk factor for COPD, the findings were not consistent and replication of findings was limited. Similarly, most P2-adrenergic receptor agonist pharmacogenetic studies focused on the ADRB2 gene, yet with conflicting reports. Unravelling genetic determinants of lung function measures will help us better understand the normal functioning of the airways, the pathophysiology of respiratory diseases and help develop novel therapies. Work presented in this thesis describes a series of studies undertaken to examine the contribution of common single nucleotide polymorphisms (SNPs) to variability in lung function. Through contributing to large scale meta-analysis of genome-wide association studies (GWASs) in the SpiroMeta consortium (discovery n= 20,288 and replication n=54,276), we were able to identify five novel loci influencing forced expiratory volume in one second (FEV I) or its ratio to forced vital capacity (FEVIIFVC): GSTCD-INTS12(4q24), HTR4 (5q31-q33), AGER(6p21.3), TNS1 (2q35-q36), and THSD4 (15q23). I also showed their corresponding mRNAs to be expressed in airway related cell types. These loci point to novel pathways regulating lung function; potentially through lung development and tissue remodelling pathways, and were at large independent from smoking behaviour. Molecular characterisation of GSTCD-INTSl2identified novel transcripts in the lung, and putative promoter regions were mapped. Interestingly, a degree of correlation of expression was found for GSTCD- INTS 12 mRNAs in multiple airway cell types, suggesting shared regulatory mechanisms. Given the absence of any overlap between previously reported candidate genes for lung function and SpiroMeta GW AS loci, an evaluation of candidate genes was undertaken in theunique SpiroMeta sample (n=20,288) which did not support a role for the majority of the candidate genes tested. A potential role for AAT among smokers and PDE4D in the general population was however, suggested. The GW AS of response to salbutamol in severe asthma subjects has identified a number of novel loci; particularly the association of DLClon chromosome 8.This novel pathway association (GTPase activating protein! GTP-GDP/ Rho A) offers the potential to develop new therapies and to design personalised medicine approaches to help individuals with asthma. Future work will involve refining the association regions through population based re-sequencing approaches followed by detailed functional characterisation of associated genes to delineate the mechanisms underlying their associations with lung function.EThOS - Electronic Theses Online ServiceGBUnited Kingdo