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

Hobbs, Brian D.; Putman, Rachel K.; Araki, Toshimitsu; Nishino, Mizuki; Guðmundsson, Gunnar; Gudnason, Vilmundur; Eiríksdóttir, Guðný; Zilhao, Nuno R.; 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, John D.; Bleecker, Eugene R.; Meyers, Deborah A.; Allen, Richard J.; Oldham, Justin M.; Fan, Shwu; Noth, Imre; Jenkins, R Gisli; Maher, Toby M.; Hubbard, Richard; Wain, Louise V.; Fingerlin, Tasha E.; Schwartz, David A.; Washko, George R.; Rosas, Iván O.; Silverman, Edwin K.; Hatabu, Hiroto; Cho, Michael H.; Hunninghake, Gary M.

doi:10.1164/rccm.201903-0511oc

Cited by 88 publications

(72 citation statements)

References 58 publications

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“…In addition, subjects with ILA show a higher frequency of the gain-of-function MUC5B common variant gene [5][6][7]. More recently, a genome-wide association study (GWAS) performed in individuals with ILA from six different cohorts, confirmed this association and described novel genome-wide associations near IPO11 (rs6886640), FCF1P3 (rs73199442), and near HTR1E (rs7744971) gene [8].…”

Section: Introductionmentioning

confidence: 87%

Circulating microRNA Signature Associated to Interstitial Lung Abnormalities in Respiratory Asymptomatic Subjects

Ortiz‐Quintero

Buendía-Roldán

Ramírez‐Salazar

et al. 2020

Cells

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Interstitial lung abnormalities (ILA) are observed in around 9% of older respiratory asymptomatic subjects, mainly smokers. Evidence suggests that ILA may precede the development of interstitial lung diseases and may evolve to progressive fibrosis. Identifying biomarkers of this subclinical status is relevant for early diagnosis and to predict outcome. We aimed to identify circulating microRNAs (miRNAs) associated to ILA in a cohort of respiratory asymptomatic subjects older than 60 years. We identified 81 subjects with ILA from our Lung-Aging Program in Mexico City (n = 826). We randomly selected 112 subjects without ILA (Ctrl) from the same cohort. Using polymerase chain reaction PCR-Array technology (24 ILA and 24 Ctrl, screening cohort) and reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) (57 ILA and 88 Ctr, independent validation cohort) we identified seven up-regulated miRNAs in serum of ILA compared to Ctrl (miR-193a-5p, p < 0.0001; miR-502-3p, p < 0.0001; miR-200c-3p, p = 0.003; miR-16-5p, p = 0.003; miR-21-5p, p = 0.002; miR-126-3p, p = 0.004 and miR-34a-5p, p < 0.005). Pathways regulated by these miRNAs include transforming growth factor beta (TGF-β), Wnt, mammalian target of rapamycin (mTOR), Insulin, mitogen-activated protein kinase (MAPK) signaling, and senescence. Receiver operator characteristic (ROC) curve analysis indicated that miR-193a-5p (area under the curve AUC: 0.75) and miR-502-3p (AUC 0.71) have acceptable diagnostic value. This is the first identification of circulating miRNAs associated to ILA in respiratory asymptomatic subjects, providing potential non-invasive biomarkers and molecular targets to better understand the pathogenic mechanisms associated to ILA.

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Section: Introductionmentioning

confidence: 87%

Circulating microRNA Signature Associated to Interstitial Lung Abnormalities in Respiratory Asymptomatic Subjects

Ortiz‐Quintero

Buendía-Roldán

Ramírez‐Salazar

et al. 2020

Cells

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“…The MUC5B promoter variant has been associated with interstitial lung abnormalities (ILAs) in both families 132 and population-based cohorts. [133][134][135] Several peripheral blood biomarkers have been associated with early interstitial changes in families 131 or general populationbased cohorts [136][137][138][139] ; however, none of these biomarkers is currently approved or available for clinical use. The role of environmental exposures as a determinant of disease penetrance and phenotype has not been well studied; identifying modifiable risk factors could enable preventive strategies in high-risk individuals.…”

Section: Implications For Relatives Of Fip Patientsmentioning

confidence: 99%

Familial Interstitial Lung Disease

Kropski

2020

Semin Respir Crit Care Med

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The interstitial lung diseases (ILDs) are a group of progressive disorders characterized by chronic inflammation and/or fibrosis in the lung. While some ILDs can be linked to specific environmental causes (i.e., asbestosis, silicosis), in many individuals, no culprit exposure can be identified; these patients are deemed to have “idiopathic interstitial pneumonia” (IIP). Family history is now recognized as the strongest risk factor for IIP, and IIP cases that run in families comprise a syndrome termed “familial interstitial pneumonia” (FIP). Mutations in more than 10 different genes have been implicated as responsible for disease in FIP families. Diverse ILD clinical phenotypes can be seen within a family, and available evidence suggests underlying genetic risk is the primary determinant of disease outcomes. Together, these FIP studies have provided unique insights into the pathobiology of ILDs, and brought focus on the unique issues that arise in the care of patients with FIP.

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“…In the last decade, a number of studies assessing radiological changes in longitudinal cohorts of people without obvious IPF-identified parenchymal changes, referred to as interstitial lung abnormalities (ILAs), have demonstrated an increase in both all-cause mortality and mortality from pulmonary fibrosis (3, 4), raising the prospect that ILAs may be the precursor lesions for IPF. Furthermore, there is overlap in the genetic architecture of IPF and ILA (5), and, indeed, serum biomarkers associated with pulmonary fibrosis are associated with ILA (6). This raises two fundamental questions: 1) are ILAs a precursor lesion for IPF and, if so, 2) should at-risk populations be screened for them?…”

Section: Yonis H Mortaza S Baboi L Mercatmentioning

confidence: 99%

“…Frank and colleagues showed that Wnt signaling is reactivated during alveologenesis and leads to proliferation of type 2 alveolar epithelial cells (AECs), whereas inhibition of Wnt signaling decreased proliferation and promoted transdifferentiation of type 2 AECs to type 1 AECs (3). Increased Wnt/b-catenin activity occurs in patients with BPD, whereas inhibition of WNT/b-catenin signaling attenuates hyperoxia-induced lung injury in neonatal rodent models (4)(5)(6).…”

Section: The Wnt Signaling Pathway and The Development Of Bronchopulmmentioning

confidence: 99%

Three Steps to Cure Pulmonary Fibrosis. Step 1: The Runaway Train or Groundhog Day?

Jenkins

2020

Am J Respir Crit Care Med

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

Abstract: A list of SPIROMICS investigators may be found before the beginning of the REFERENCES.

Cited by 88 publications

References 58 publications

Circulating microRNA Signature Associated to Interstitial Lung Abnormalities in Respiratory Asymptomatic Subjects

Circulating microRNA Signature Associated to Interstitial Lung Abnormalities in Respiratory Asymptomatic Subjects

Familial Interstitial Lung Disease

Three Steps to Cure Pulmonary Fibrosis. Step 1: The Runaway Train or Groundhog Day?

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