• Brian D Hobbs, Rachel K Putman, Tetsuro Araki, Mizuki Nishino, Gunnar Gudmundsson, Vilmundur Gudnason, Gudny Eiriksdottir, Nuno Rodrigues Zilhao Nogueira, Josée Dupuis, Hanfei Xu, George T O'Connor, Ani Manichaikul, Jennifer Nguyen, Anna J Podolanczuk, Purnema Madahar, Jerome I Rotter, David J Lederer, R Graham Barr, Stephen S Rich, Elizabeth J Ampleford, Victor E Ortega, Stephen P Peters, Wanda K O'Neal, John D Newell, Eugene R Bleecker, Deborah A Meyers, Richard J Allen, Justin M Oldham, Shwu-Fan Ma, Imre Noth, R Gisli Jenkins, Toby M Maher, Richard B Hubbard, Louise V Wain, Tasha E Fingerlin, David A Schwartz, George R Washko, Ivan O Rosas, Edwin K Silverman, Hiroto Hatabu, Michael H Cho, and Gary M Hunninghake.
• Channing Division of Network Medicine.
• Am. J. Respir. Crit. Care Med. 2019 Dec 1; 200 (11): 140214131402-1413.

AbstractRationale: 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.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: 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.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B 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.

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