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

• Published in: American journal of respiratory and critical care medicine Vol. 200; no. 11; pp. 1402 - 1413
• Main Authors: Hobbs, Brian D, Putman, Rachel K, Araki, Tetsuro, Nishino, Mizuki, Gudmundsson, Gunnar, Gudnason, Vilmundur, Eiriksdottir, Gudny, Zilhao Nogueira, Nuno Rodrigues, Dupuis, Josée, Xu, Hanfei, O'Connor, George T, Manichaikul, Ani, Nguyen, Jennifer, Podolanczuk, Anna J, Madahar, Purnema, Rotter, Jerome I, Lederer, David J, Barr, R Graham, Rich, Stephen S, Ampleford, Elizabeth J, Ortega, Victor E, Peters, Stephen P, O'Neal, Wanda K, Newell, Jr, John D, Bleecker, Eugene R, Meyers, Deborah A, Allen, Richard J, Oldham, Justin M, Ma, Shwu-Fan, Noth, Imre, Jenkins, R Gisli, Maher, Toby M, Hubbard, Richard B, Wain, Louise V, Fingerlin, Tasha E, Schwartz, David A, Washko, George R, Rosas, Ivan O, Silverman, Edwin K, Hatabu, Hiroto, Cho, Michael H, Hunninghake, Gary M
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.12.2019
• Subjects: Aged; beta Karyopherins - genetics; Biological products; Case-Control Studies; Female; Genetic Loci; Genetic Predisposition to Disease - genetics; Genetics; Genome-Wide Association Study; Humans; Idiopathic Pulmonary Fibrosis - genetics; Lung diseases; Lung Diseases, Interstitial - genetics; Male; Middle Aged; Mucin-5B - genetics; Original; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Pulmonary fibrosis; TATA Box Binding Protein-Like Proteins; genetics; idiopathic pulmonary fibrosis; interstitial lung abnormalities; SNP; genome-wide association study
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201903-0511OC

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. To perform a genome-wide association study (GWAS) of ILAs. 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. Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (  = 2.6 × 10 ) and subpleural ILAs (  = 1.6 × 10 ). We discovered novel genome-wide associations near (rs6886640,  = 3.8 × 10 ) and (rs73199442,  = 4.8 × 10 ) with ILAs, and near (rs7744971,  = 4.2 × 10 ) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five ( , , , , and ) were significantly associated (  < 0.05/12) with ILAs. In a GWAS of ILAs in six studies, we confirmed the association with a 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.