Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis

A subset of patients with hypersensitivity pneumonitis (HP) develop lung fibrosis that is clinically similar to idiopathic pulmonary fibrosis (IPF). To address the aetiological determinants of fibrotic HP, we investigated whether the common IPF genetic risk variants were also relevant in study subjects with fibrotic HP. Our findings indicate that common genetic variants in TERC, DSP, MUC5B and IVD were significantly associated with fibrotic HP. These findings provide support for a shared etiology and pathogenesis between fibrotic HP and IPF.

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The genetic basis of idiopathic pulmonary fibrosis

European Respiratory Journal ◽

10.1183/09031936.00163814 ◽

2015 ◽

Vol 45 (6) ◽

pp. 1717-1727 ◽

Cited By ~ 79

Author(s):

Jonathan A. Kropski ◽

Timothy S. Blackwell ◽

James E. Loyd

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Genetic Variants ◽

Molecular Mechanisms ◽

Integrated Approach ◽

Current Evidence ◽

Great Promise ◽

Common Genetic Variants ◽

Rare Genetic Variants ◽

Telomere Biology

Throughout the past decade, there have been substantial advances in understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recently, several large genome-wide association and linkage studies have identified common genetic variants in more than a dozen loci that appear to contribute to IPF risk. In addition, family-based studies have led to the identification of rare genetic variants in genes related to surfactant function and telomere biology, and mechanistic studies suggest pathophysiological derangements associated with these rare genetic variants are also found in sporadic cases of IPF. Current evidence suggests that rather than existing as distinct syndromes, sporadic and familial cases of IPF (familial interstitial pneumonia) probably reflect a continuum of genetic risk. Rapidly evolving bioinformatic and molecular biology techniques, combined with next-generation sequencing technologies, hold great promise for developing a comprehensive, integrated approach to defining the fundamental molecular mechanisms that underlie IPF pathogenesis.

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Association of common genetic variants in the CPSF7 and SDHAF2 genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier

10.1101/2020.04.14.030486 ◽

2020 ◽

Author(s):

Ignazio S. Piras ◽

Christiane Bleul ◽

Ashley Siniard ◽

Amanda J. Wolfe ◽

Matthew D. De Both ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Nucleotide Polymorphisms ◽

The West ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome ◽

Fibrotic Lung Disease

AbstractCanine Idiopathic Pulmonary Fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a Genome-Wide Association Study (GWAS) in the WHWT using Whole Genome Sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide™ DNA library prep kit. After quality controls, 28 affected, 44 unaffected and 1,843,695 informative Single Nucleotide Polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the CPSF7 and SDHAF2 genes (adjusted p = 0.016 and p = 0.025, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389, however it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma further highlighting the potential relevance of our results since IPF and lung cancer share several pathological mechanisms.

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Common Idiopathic Pulmonary Fibrosis (IPF) Genetic Variants Are Associated with Chronic Hypersensitivity Pneumonitis (CHP)

10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a3143 ◽

2021 ◽

Author(s):

H. Furusawa ◽

J.H. Cardwell ◽

A.L. Peljto ◽

A.D. Walts ◽

T.J. Bang ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Genetic Variants ◽

Hypersensitivity Pneumonitis ◽

Chronic Hypersensitivity Pneumonitis

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Association of Common Genetic Variants in the CPSF7 and SDHAF2 Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier

Genes ◽

10.3390/genes11060609 ◽

2020 ◽

Vol 11 (6) ◽

pp. 609

Author(s):

Ignazio S. Piras ◽

Christiane Bleul ◽

Ashley Siniard ◽

Amanda J. Wolfe ◽

Matthew D. De Both ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Specific Factor ◽

Nucleotide Polymorphisms ◽

The West ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome

Canine idiopathic pulmonary fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a genome-wide association study (GWAS) in the WHWT using whole genome sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality controls, 28 affected, 44 unaffected, and 1,843,695 informative single nucleotide polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the cleavage and polyadenylation specific factor 7 (CPSF7) and succinate dehydrogenase complex assembly factor 2 (SDHAF2) genes (adjusted p = 0.016 and 0.024, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389; however, it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma, further highlighting the potential relevance of our results because IPF and lung cancer share several pathological mechanisms.

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Genes, other than Muc5b, Play a Role in Bleomycin-Induced Lung Fibrosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00615.2020 ◽

2021 ◽

Author(s):

Evgenia Dobrinskikh ◽

Alani M. Estrela ◽

Corinne E. Hennessy ◽

Naoko Hara ◽

Marvin I. Schwarz ◽

...

Keyword(s):

Risk Factor ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Hierarchical Clustering ◽

Recombinant Inbred ◽

Genetic Disease ◽

Genetic Risk ◽

Lung Fibrosis ◽

Diversity Outbred

Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function MUC5B promoter variant rs35705950 is the dominant genetic risk factor for IPF yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of MUC5B. Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is Muc5b dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for Muc5b expression and lung fibrosis three weeks after intratracheal bleomycin administration. While we identified strains with low Muc5b expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high Muc5b expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between Muc5b expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with Muc5b and cause lung fibrosis.

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