Genome-wide analysis of longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis

Abstract

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<5x10-8, 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=9.14x10-12). 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