Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis

Abstract

<b>Rationale:</b> Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.<b>Objectives:</b> To perform a genome-wide association study (GWAS) of ILAs.<b>Methods:</b> ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.<b>Measurements and Main Results:</b> Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The <i>MUC5B</i> (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (<i>P</i> = 2.6 × 10^-27) and subpleural ILAs (<i>P</i> = 1.6 × 10^-29). We discovered novel genome-wide associations near <i>IPO11</i> (rs6886640, <i>P</i> = 3.8 × 10^-8) and <i>FCF1P3</i> (rs73199442, <i>P</i> = 4.8 × 10^-8) with ILAs, and near <i>HTRE1</i> (rs7744971, <i>P</i> = 4.2 × 10^-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (<i>DPP9</i>, <i>DSP</i>, <i>FAM13A</i>, <i>IVD</i>, and <i>MUC5B</i>) were significantly associated (<i>P</i> < 0.05/12) with ILAs.<b>Conclusions:</b> In a GWAS of ILAs in six studies, we confirmed the association with a <i>MUC5B</i> promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.