Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants

Peljto, Anna L.; Blumhagen, Rachel Z.; Walts, Avram; Cardwell, Jonathan; Powers, Julia; Corte, Tamera J.; Dickinson, Joanne L.; Glaspole, Ian; Moodley, Yuben; Vašáková, Martina; Bendstrup, Elisabeth; Davidsen, Jesper Rømhild; Borie, Raphaël; Crestani, Bruno; Dieudé, Philippe; Bonella, Francesco; Costabel, Ulrich; Guðmundsson, Gunnar; Donnelly, Seamas C; Egan, Jim; Henry, Michael T.; Keane, Michael P.; Kennedy, Marcus P.; McCarthy, Cormac; McElroy, Aoife; Olaniyi, Joshua A; O’Reilly, Katherine Ma; Richeldi, Luca; Leone, Paolo Maria; Poletti, Venerino; Puppo, Francesco; Tomassetti, Sara; Luzzi, Valentina; Köktürk, Nurdan; Moğulkoç, Nesrin; Fiddler, Christine; Hirani, Nikhil; Jenkins, Gisli; Maher, Toby M.; Molyneaux, Philip L.; Parfrey, Helen; Braybrooke, Rebecca; Blackwell, Timothy S.; Jackson, Peter; Nathan, Steven D.; Porteous, Mary K.; Brown, Kevin K.; Christie, Jason D.; Collard, Harold R.; Eickelberg, Oliver; Foster, Elena; Gibson, Kevin F.; Glassberg, Marilyn K.; Kass, Daniel J.; Kropski, Jonathan A.; Lederer, David J.; Linderholm, A.; Loyd, JE; Mathai, Susan K.; Montesi, Sydney B.; Noth, Imre; Oldham, Justin M.; Palmisciano, Amy; Reichner, Cristina; Rojas, Mauricio; Roman, Jesse; Schluger, Neil W.; Shea, Barry S.; Swigris, Jeffrey J.; Wolters, Paul J.; Zhang, Yingze; Prêle, Cecilia M.; Enghelmayer, Juan Ignacio; Otaola, María; Ryerson, Christopher J.; Salinas, Mauricio; Šterclová, Martina; Gebremariam, Tewodros Haile; Myllärniemi, Marjukka; Carbone, Roberto; Furusawa, Haruhiko; Hirose, Masaki; Inoue, Yoshikazu; Miyazaki, Yasunari; Ohta, Ken; Ohta, Shin; Okamoto, Tsukasa; Kim, Dong Soon; Pardo, Annie; Selman, Moisés; Aranda, Alvaro U; Park, Moo Suk; Park, Jong Sun; Song, Jin Woo; Molina-Molina, María; Planas-Cerezales, Lurdes; Westergren‐Thorsson, Gunilla; Smith, Albert V.; Manichaikul, Ani; Kim, John S.; Rich, Stephen S.; Oelsner, Elizabeth C.; Barr, R. Graham; Rotter, Jerome I.; Dupuis, Josée; O’Connor, George T.; Vasan, Ramachandran S.; Cho, Michael H.; Silverman, Edwin K.; Schwarz, Marvin I.; Steele, Mark P.; Lee, Joyce; Yang, Ivana V.; Fingerlin, Tasha E.; Schwartz, David A.

doi:10.1164/rccm.202207-1331oc

Cited by 28 publications

(11 citation statements)

References 44 publications

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“…IPF and other ILDs with pulmonary fibrosis are associated with disease-related complications including pulmonary hypertension and lung cancer. Approximately one-third of patients newly diagnosed with fibrotic ILD have evidence of obstructive sleep apnea on polysomnography . There is no evidence to date that treating the obstructive sleep apnea alters prognosis .…”

Section: Epidemiologymentioning

confidence: 99%

Interstitial Lung Disease

Maher

2024

JAMA

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ImportanceInterstitial lung disease (ILD) consists of a group of pulmonary disorders characterized by inflammation and/or fibrosis of the lung parenchyma associated with progressive dyspnea that frequently results in end-stage respiratory failure. In the US, ILD affects approximately 650 000 people and causes approximately 25 000 to 30 000 deaths per year.ObservationsThe most common forms of ILD are idiopathic pulmonary fibrosis (IPF), which accounts for approximately one-third of all cases of ILD, hypersensitivity pneumonitis, accounting for 15% of ILD cases, and connective tissue disease (CTD), accounting for 25% of ILD cases. ILD typically presents with dyspnea on exertion. Approximately 30% of patients with ILD report cough. Thoracic computed tomography is approximately 91% sensitive and 71% specific for diagnosing subtypes of ILDs such as IPF. Physiologic assessment provides important prognostic information. A 5% decline in forced vital capacity (FVC) over 12 months is associated with an approximately 2-fold increase in mortality compared with no change in FVC. Antifibrotic therapy with nintedanib or pirfenidone slows annual FVC decline by approximately 44% to 57% in individuals with IPF, scleroderma associated ILD, and in those with progressive pulmonary fibrosis of any cause. For connective tissue disease–associated ILD, immunomodulatory therapy, such as tocilizumab, rituximab, and mycophenolate mofetil, may slow decline or even improve FVC at 12-month follow-up. Structured exercise therapy reduces symptoms and improves 6-minute walk test distance in individuals with dyspnea. Oxygen reduces symptoms and improves quality of life in individuals with ILD who desaturate below 88% on a 6-minute walk test. Lung transplant may improve symptoms and resolve respiratory failure in patients with end-stage ILD. After lung transplant, patients with ILD have a median survival of 5.2 to 6.7 years compared with a median survival of less than 2 years in patients with advanced ILD who do not undergo lung transplant. Up to 85% of individuals with end-stage fibrotic ILD develop pulmonary hypertension. In these patients, treatment with inhaled treprostinil improves walking distance and respiratory symptoms.Conclusions and RelevanceInterstitial lung disease typically presents with dyspnea on exertion and can progress to respiratory failure. First-line therapy includes nintedanib or pirfenidone for IPF and mycophenolate mofetil for ILD due to connective tissue disease. Lung transplant should be considered for patients with advanced ILD. In patients with ILD, exercise training improves 6-minute walk test distance and quality of life.

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Section: Epidemiologymentioning

confidence: 99%

Interstitial Lung Disease

Maher

2024

JAMA

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“…The advent of biobanks and evolution of methods for molecular analysis, including targeted next-generation sequencing and whole genome sequencing in the early 2000s revolutionized the concept of genetic testing in ILD (40)(41)(42). Single nucleotide polymorphisms (SNPs) in genes encoding for proteins expressed by airway epithelial cells, such as MUC5B, have been identified to have both diagnostic and prognostic significance in IPF and other fibrotic ILDs such as rheumatoid arthritis-associated ILD and chronic hypersensitivity SNP-heritability in IPF was estimated to be 32% (43). Importantly, mutations in telomere-related genes such as TERT and PARN confer substantial risk of familial pulmonary fibrosis and are associated with more rapidly progressive disease, as well as poorer outcomes with immunosuppressive therapy and with lung transplantation (40,44).…”

Section: Genetic Testingmentioning

confidence: 99%

Novel diagnostic techniques in interstitial lung disease

Glenn¹,

Troy²,

Corte³

2023

Front. Med.

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Research into novel diagnostic techniques and targeted therapeutics in interstitial lung disease (ILD) is moving the field toward increased precision and improved patient outcomes. An array of molecular techniques, machine learning approaches and other innovative methods including electronic nose technology and endobronchial optical coherence tomography are promising tools with potential to increase diagnostic accuracy. This review provides a comprehensive overview of the current evidence regarding evolving diagnostic methods in ILD and to consider their future role in routine clinical care.

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“…Genetic factors play a significant role in the development of IPF. The known genetic variants associated with IPF are classified into two broad categories: common SNPs that are broadly found in the general population (allele frequency > 1%), and rare damaging variants in the spectrum of allele frequency below <1% which are typically not recurrent in the general population ( 19 ). Next-generation sequencing (NGS) technologies, where the order of nucleotides of the entire genome or of regions of interest are determined, are commonly applied to assess the contribution of rare variants to human phenotypes and have led to the identification of genes that are causal or associated with the risk of the disease.…”

Section: Genetics Of Ipfmentioning

confidence: 99%

Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine

et al. 2023

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Idiopathic pulmonary fibrosis (IPF) is a chronic, rare progressive lung disease, characterized by lung scarring and the irreversible loss of lung function. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been demonstrated to slow down disease progression, although IPF mortality remains a challenge and the patients die after a few years from diagnosis. Rare pathogenic variants in genes that are involved in the surfactant metabolism and telomere maintenance, among others, have a high penetrance and tend to co-segregate with the disease in families. Common recurrent variants in the population with modest effect sizes have been also associated with the disease risk and progression. Genome-wide association studies (GWAS) support at least 23 genetic risk loci, linking the disease pathogenesis with unexpected molecular pathways including cellular adhesion and signaling, wound healing, barrier function, airway clearance, and innate immunity and host defense, besides the surfactant metabolism and telomere biology. As the cost of high-throughput genomic technologies continuously decreases and new technologies and approaches arise, their widespread use by clinicians and researchers is efficiently contributing to a better understanding of the pathogenesis of progressive pulmonary fibrosis. Here we provide an overview of the genetic factors known to be involved in IPF pathogenesis and discuss how they will continue to further advance in this field. We also discuss how genomic technologies could help to further improve IPF diagnosis and prognosis as well as for assessing genetic risk in unaffected relatives. The development and validation of evidence-based guidelines for genetic-based screening of IPF will allow redefining and classifying this disease relying on molecular characteristics and contribute to the implementation of precision medicine approaches.

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Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants

Abstract: Cover sheet Cover sheetTitle Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants

Cited by 28 publications

References 44 publications

Interstitial Lung Disease

Interstitial Lung Disease

Novel diagnostic techniques in interstitial lung disease

Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine

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