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. 2019 Dec 1;200(11):1402-1413.
doi: 10.1164/rccm.201903-0511OC.

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

Brian D Hobbs  1   2 , Rachel K Putman  2 , Tetsuro Araki  3   4 , Mizuki Nishino  3   4 , Gunnar Gudmundsson  5 , Vilmundur Gudnason  6   7 , Gudny Eiriksdottir  7 , Nuno Rodrigues Zilhao Nogueira  7 , Josée Dupuis  8   9 , Hanfei Xu  8 , George T O'Connor  9   10 , Ani Manichaikul  11   12 , Jennifer Nguyen  11 , Anna J Podolanczuk  13 , Purnema Madahar  13 , Jerome I Rotter  14   15   16 , David J Lederer  13   17 , R Graham Barr  13   17 , Stephen S Rich  11   12 , Elizabeth J Ampleford  18 , Victor E Ortega  18 , Stephen P Peters  18 , Wanda K O'Neal  19 , John D Newell Jr  20   21 , Eugene R Bleecker  22 , Deborah A Meyers  22 , Richard J Allen  23 , Justin M Oldham  24 , Shwu-Fan Ma  25 , Imre Noth  25 , R Gisli Jenkins  26 , Toby M Maher  27   28 , Richard B Hubbard  26   29 , Louise V Wain  30 , Tasha E Fingerlin  31   32 , David A Schwartz  32   33   34 , George R Washko  2   4 , Ivan O Rosas  2 , Edwin K Silverman  1   2 , Hiroto Hatabu  3   4 , Michael H Cho  1   2 , Gary M Hunninghake  2   4
Affiliations

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

Brian D Hobbs et al. Am J Respir Crit Care Med. .

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.

Keywords: SNP; genetics; genome-wide association study; idiopathic pulmonary fibrosis; interstitial lung abnormalities.

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Figures

Figure 1.
Figure 1.
Flowchart depicting the participants included and excluded from the genome-wide association analysis by cohort and interstitial lung abnormality (ILA) status. AGES = Age Gene/Environment Susceptibility; COPD = chronic obstructive pulmonary disease; COPDGene = Genetic Epidemiology of COPD; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points; ILD = interstitial lung disease; MESA = Multi-Ethnic Study of Atherosclerosis; SPIROMICS = Subpopulations and Intermediate Outcome Measures in COPD Study.
Figure 2.
Figure 2.
Locus zoom and forest plots for the genome-wide significant loci associated with interstitial lung abnormalities (ILAs) and subpleural-predominant ILAs. (A) Comparison of participants with and without ILAs. A1 is a locus zoom plot demonstrating the genome-wide significant association at rs35705950 (nearest gene MUC5B); A2 is a forest plot demonstrating the results in each individual cohort and the overall meta-analysis, with the x-axis on the log odds scale. (B) Comparison of participants with and without ILAs. B1 is a locus zoom plot demonstrating the genome-wide significant association at rs6886640 (nearest gene IPO11); B2 is a forest plot demonstrating the results in each individual cohort and the overall meta-analysis, with the x-axis on the log odds scale. (C) Comparison of participants with and without ILAs. C1 is a locus zoom plot demonstrating the genome-wide significant association at rs73199442 (nearest gene FCF1P3); C2 is a forest plot demonstrating the results in each individual cohort and the overall meta-analysis, with the x-axis on the log odds scale. (D) Comparison of participants with subpleural-predominant ILAs and those without ILAs. D1 is a locus zoom plot demonstrating the genome-wide significant association at rs7744971 (nearest gene HTR1E); D2 is a forest plot demonstrating the results in each individual cohort and the overall meta-analysis, with the x-axis on the log odds scale. AGES = Age Gene/Environment Susceptibility; COPD = chronic obstructive pulmonary disease; COPDGene = Genetic Epidemiology of COPD; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points; MESA = Multi-Ethnic Study of Atherosclerosis; SPIROMICS = Subpopulations and Intermediate Outcome Measures in COPD Study.
Figure 2.
Figure 2.
Locus zoom and forest plots for the genome-wide significant loci associated with interstitial lung abnormalities (ILAs) and subpleural-predominant ILAs. (A) Comparison of participants with and without ILAs. A1 is a locus zoom plot demonstrating the genome-wide significant association at rs35705950 (nearest gene MUC5B); A2 is a forest plot demonstrating the results in each individual cohort and the overall meta-analysis, with the x-axis on the log odds scale. (B) Comparison of participants with and without ILAs. B1 is a locus zoom plot demonstrating the genome-wide significant association at rs6886640 (nearest gene IPO11); B2 is a forest plot demonstrating the results in each individual cohort and the overall meta-analysis, with the x-axis on the log odds scale. (C) Comparison of participants with and without ILAs. C1 is a locus zoom plot demonstrating the genome-wide significant association at rs73199442 (nearest gene FCF1P3); C2 is a forest plot demonstrating the results in each individual cohort and the overall meta-analysis, with the x-axis on the log odds scale. (D) Comparison of participants with subpleural-predominant ILAs and those without ILAs. D1 is a locus zoom plot demonstrating the genome-wide significant association at rs7744971 (nearest gene HTR1E); D2 is a forest plot demonstrating the results in each individual cohort and the overall meta-analysis, with the x-axis on the log odds scale. AGES = Age Gene/Environment Susceptibility; COPD = chronic obstructive pulmonary disease; COPDGene = Genetic Epidemiology of COPD; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points; MESA = Multi-Ethnic Study of Atherosclerosis; SPIROMICS = Subpopulations and Intermediate Outcome Measures in COPD Study.
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