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

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. AmplefordVictor 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, Gary M. Hunninghake

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Rationale: 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.

Original languageEnglish (US)
Pages (from-to)1402-1413
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume200
Issue number11
DOIs
StatePublished - Dec 1 2019

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Keywords

  • genetics
  • genome-wide association study
  • idiopathic pulmonary fibrosis
  • interstitial lung abnormalities
  • SNP

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Hobbs, B. D., Putman, R. K., Araki, T., Nishino, M., Gudmundsson, G., Gudnason, V., Eiriksdottir, G., Zilhao Nogueira, N. R., Dupuis, J., Xu, H., O'Connor, G. T., Manichaikul, A., Nguyen, J., Podolanczuk, A. J., Madahar, P., Rotter, J. I., Lederer, D. J., Barr, R. G., Rich, S. S., ... Hunninghake, G. M. (2019). Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine, 200(11), 1402-1413. https://doi.org/10.1164/rccm.201903-0511OC