Genome-wide analysis of longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis
Authors: Allen Richard J , Oldham Justin M , Jenkins David A , Leavy Olivia C , Guillen-Guio Beatriz , Melbourne Carl A , Ma Shwu-Fan , Jou Jonathan , Kim John S ,   CleanUP-IPF Investigators of the Pulmonary Trials Cooperative, Fahy William A , Oballa Eunice , Hubbard Richard B , Navaratnam Vidya , Braybrooke Rebecca , Saini Gauri , Roach Katy M , Tobin Martin D , Hirani Nik , Whyte Moira K B , Kaminski Naftali , Zhang Yingze , Martinez Fernando J , Linderholm Angela L , Adegunsoye Ayodeji , Strek Mary E , Maher Toby M , Molyneaux Philip L , Flores Carlos , Noth Imre , Jenkins R Gisli , Wain Louise V 
Published: March 2022

Background

Idiopathic pulmonary fibrosis (IPF) is an incurable disease characterised by progressive scarring of the lungs. This leads to the lungs becoming stiffer, reducing lung capacity, and impeding gas transfer. We aimed to identify genetic variants associated with either declining lung capacity or gas transfer after diagnosis of IPF.

Methods

We performed a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity for lung of carbon monoxide (DLco) in individuals diagnosed with IPF from three studies. Suggestively significant variants were investigated further in an additional study. Variants were defined as significantly associated if they had a meta-analysis p<5×10−8, had consistent direction of effects across all studies and were nominally significant (p<0.05) in each study.

Findings

1,048 individuals with measures of longitudinal FVC and 729 individuals with longitudinal measures of DLco passed quality control. In total, 4,560 measures of FVC and 2,795 measures of DLco and over 7 million genetic variants were included in the analysis. One variant located in an antisense RNA gene for Protein Kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (−140 ml/year per risk allele, 95% CI [−180, −100], p=9.14×10−12).

Interpretation

These results identify a possible druggable target involved in promoting IPF disease progression.

Funding

Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, National Institute of Health/National Heart, Lung and Blood Institute

Research in context

Evidence before this study

Idiopathic pulmonary fibrosis (IPF) is a devastating disease where the lungs become scarred, this scarring leads to a reduced lung capacity, poorer rates of gas transfer and is eventually fatal. However, disease progression is highly variable and it is not clear why this is. To date, genome-wide association studies (GWAS) have identified 20 genetic loci associated with susceptibility to IPF. These genetic loci implicate genes involved with host defence, regulation of TGFβ signalling, telomere maintenance, cell-cell adhesion and spindle assembly as important biological processes involved in the pathogenesis of IPF. The GWAS variant with the strongest effect on disease risk is found in the promoter region of the MUC5B gene (rs35705950). Generally, the variants associated with IPF susceptibility show little or no association with disease progression, apart from the risk allele at rs35705950 which has been reported as having an association with improved survival times.

Added value of this study

Although genetic variants associated with disease risk have been widely studied, little has been reported to investigate the effect of genetics on progression of IPF. Here we present a GWAS of progressive IPF by identifying genetic variants associated longitudinal measures of lung health after diagnosis of IPF. We identify a genetic locus associated with a more rapid decline in lung capacity that lies in the RNA antisense gene of PKN2.

Implications of all available evidence

The novel genetic locus associated with a more rapid decline in lung capacity in individuals with IPF implicates a Rho/RAC effector protein. Effective treatments for IPF are desperately needed. There are currently PKN2 inhibitors under development meaning this analysis highlights a potential therapeutic target for IPF. We also show the genetic determinants of IPF progression appear to be distinct from those that drive IPF susceptibility.