Shared and distinct genetic determinants between idiopathic pulmonary fibrosis and other pulmonary traits

• Main Author: Allen, Richard James
• Other Authors: Tobin, Martin ; Wain, Louise
• Published: University of Leicester 2018
• Subjects: 610
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.745867

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterised by the deposit of scar tissue on the lung epithelium, reduced lung function and poor prognosis (median survival 3 years). Despite environmental and genetic factors being reported as associated with IPF, the pathogenesis of IPF is unclear and few effective treatment options are available. If the genetic basis of IPF were shared with another trait then this may aid understanding of the disease and guide research into new treatments. The aims of this thesis are to investigate variants associated with IPF and to analyse genetic overlap between IPF and other pulmonary traits. A two-stage genome-wide case-control analysis replicated previously reported signals as associated with IPF susceptibility and highlighted a novel signal near AKAP13. Functional follow-up suggests this signal increases IPF susceptibility by increased expression of AKAP13 in a tissue specific manner. This is the first time a gene in a fibrotic pathway has been implicated in an IPF genome-wide study. Furthermore, this pathway is therapeutically targetable. The first genome-wide analysis into survival time after diagnosis of IPF was also performed and highlighted 34 variants of interest. The variant showing the strongest IPF susceptibility association (in the promoter of MUC5B) showed some association with increased survival times. Finally, genetic overlap of IPF and other pulmonary traits was explored. There was little genetic overlap between IPF susceptibility and survival suggesting variants that increase susceptibility are different to those driving disease progression. Some genetic overlap was observed between variants highly associated with IPF and airflow in the lungs. Finally, the thesis provides evidence that IPF is polygenic, albeit with a small number of associated variants exhibiting a relatively large effect on disease susceptibility.