Contribution of complex genetic variation at the Human leukocyte antigen (HLA) and Killer immunoglobulin-like receptor (KIR) regions to Idiopathic pulmonary fibrosis (IPF) susceptibility

Idiopathic Pulmonary Fibrosis (IPF) is a rare lung disease characterised by inflammation and scarring of the alveoli. Although genetic and environmental factors have been reported in IPF, the biological processes underlying IPF development remain unclear. The largest genetic risk factor for IPF is a common variant in mucin gene MUC5B. It is believed that IPF develops because of microinjury in the lung from for example cigarette smoke or viral infection. The Human leukocyte antigen (HLA) and Killer immunoglobulin-like receptor (KIR) molecules play a vital role in immune response against infection. HLA allele, HLA-DQB1*06:02 has evidence for association with fibrotic idiopathic interstitial pneumonias (fIIP) (including IPF). The HLA and KIR regions harbour complex variation and although there are links between IPF and viral infection, these regions have not been studied in depth. The aims of this thesis were to investigate the contribution of complex genetic variation in these regions to IPF susceptibility.

The HLA-wide association meta-analysis identified a common novel signal near ZNRD1ASP as associated with IPF susceptibility. Bioinformatic investigation highlighted associations with immunity and respiratory traits and differential expression of HLA and non-HLA genes. The HLA-DQB1*06:02 variant did not replicate in three independent IPF datasets suggesting that the originally reported association may have been driven by the inclusion of non-IPF fIIPs. The MUC5B*HLA interaction analysis in IPF susceptibility did not present any novel signals but identified some suggestively significant signals that warrant further investigation. The KIR-wide association meta-analysis did not identify any novel signals and highlighted concerns in the KIR imputation.

Overall, this thesis did not support the previously reported association of HLA-DQB1*06:02 with IPF susceptibility. Also, there was no evidence the regions exhibit a large genetic effect on IPF risk, however the analyses were limited by sample size and the imputation quality in the KIR region.