Gene Set Analysis of Lung Samples Provides Insight into Pathogenesis of Progressive, Fibrotic Pulmonary Sarcoidosis

Lockstone, Helen; Sanderson, Sharon; Кулакова, Н. В.; Baban, Dilair; Leonard, Angela; Kok, Wai Ling; McGowan, Simon J.; McMichael, A; Ho, Ling‐Pei

doi:10.1164/rccm.200912-1855oc

Cited by 79 publications

(83 citation statements)

References 29 publications

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“…The enzyme activates vitamin D3, which has a well-established general immunoregulatory function [57,58] and also plays a role in lung immunity and in sarcoidosis [59,60]. Moreover, this gene has very recently been reported to be differentially expressed in sarcoidosis patients with a progressive-fibrotic, compared to a self-limiting, course of the disease [61]. Since the entire 12q13.3-q14.1 locus showed a subphenotype-specific genetic association pattern in our study, it is conceivable that specific genetic variants in the associated region may influence the regulation of CYP27B1 expression restricted to certain stages or subtypes of the disease.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

Hofmann

Fischer

Nothnagel³

et al. 2012

Eur Respir J

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Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability.To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages.After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p50.0215) in the validation panel and yielded a p-value of 9.22610 -8 (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p50.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

Hofmann

Fischer

Nothnagel³

et al. 2012

Eur Respir J

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“…We found that CD87/UPAR protein levels were elevated in serum, suggesting that this molecule could serve as a possible biomarker in IPF patients. A recent study has reported an increased expression of CD11b and CD18 in transbronchial biopsies of granulomatous areas in lungs of patients with progressive, fibrotic pulmonary sarcoidosis compared to patients with nodular self limiting disease [39]. Although the IPF patients in this study have not been classified according to severity of disease, our further validation studies will include investigating lung biopsy tissues in addition to whole-blood specimens for possible correlation with severity and clinical course of disease.…”

Section: The Elevated Level Of Il-17rb+/cd14+ Cells Observed In Our Smentioning

confidence: 94%

Differential expression of monocyte/macrophage- selective markers in human idiopathic pulmonary fibrosis

Desai¹,

Mattson²,

Paintal

et al. 2011

Experimental Lung Research

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Idiopathic interstitial pneumonias are a group of idiopathic interstitial lung diseases of which idiopathic pulmonary fibrosis (IPF) is the lesion of usual interstitial pneumonia. Although the pathogenic mechanisms remain incompletely understood, disease-specific changes in blood, a readily accessible biospecimen, have not been fully characterized. To identify biomarkers from blood and sera, the immune status of IPF patients and control subjects without structural lung disease was quantified by measuring cell surface markers, mRNA levels, and serum proteins. Statistically significant differences in cellular and molecular markers were observed between the 2 groups. The cytokine receptor IL-17RB was significantly higher in CD14+ peripheral blood mononuclear cells (PBMCs) from IPF patients, whereas expression of the chemokine receptor CXCR4 was lower. Gene expression analyses identified 18 differentially expressed genes out of 195 selected. Of these, EMR1, CCR3, UPAR, FCGR2A, OPN, CEACAM3, CD16a, CD18, CD11b, LTF, and LCN2 were up-regulated, whereas IL-17RB, IL-10, PDGFA, CD301/Clec10a, CD25/IL-2RA, IL-23p19, and IL-15 were down-regulated in IPF. Differentially regulated genes were in the functional areas of inflammation and cell signaling. Serum levels of UPAR and OPN were higher in IPF. These observations reveal significant differences in cell and molecular markers involved in monocyte/macrophage activation and migration, and suggest a role for IL-17RB in IPF.

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“…The natural course of sarcoidosis is heterogeneous; the majority of patients have a self-limiting course, but one-third of patients develop progressive disease [1,2]. Our prior study revealed a robust peripheral blood gene expression signature in sarcoidosis with an over-representation of genes related to interferon (IFN) Type I and II signaling pathways [3].…”

Section: Introductionmentioning

confidence: 99%

Interferon-inducible chemokines reflect severity and progression in sarcoidosis

Nguyen

Agarwal

et al. 2013

Respir Res

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BackgroundIdentification of serum proteins that track with disease course in sarcoidosis may have clinical and pathologic importance. We previously identified up-regulated transcripts for interferon-inducible chemokines CXCL9, and CXCL10, in blood of sarcoidosis patients compared to controls. The objective of this study was to determine whether proteins encoded by these transcripts were elevated in serum and identified patients with remitting vs. chronic progressive sarcoidosis longitudinally.MethodsSerum levels of CXCL9, CXCL10, and proteins associated with inflammation and/or disease activity (sIL2R, ACE, ESR and CRP) were measured in a prospective cohort of sarcoidosis subjects and controls. Comparisons were made between groups and clinical course using pulmonary function measures and a severity score developed by Wasfi et al.ResultsIn a cross-sectional analysis of 36 non-immunosuppressed sarcoidosis subjects, serum CXCL9, CXCL10, and sIL2R were significantly elevated compared to 46 controls (p < 0.0001). CXCL9 and CXCL10 were strongly inter-correlated (p = 0.0009). CXCL10 and CXCL9 were inversely correlated with FVC% predicted and DLCO% predicted, respectively. CXCL10 and CXCL9 significantly correlated with sarcoidosis severity score. sIL2R, ESR, CRP, and ACE serum levels did not correlate with pulmonary function measures or severity score. In the longitudinal analysis of 26 subjects, changes in serum CXCL10 level over time corresponded with progression versus remission of disease.ConclusionsInterferon-γ–inducible chemokines, CXCL9 and CXCL10, are elevated in sarcoidosis and inter-correlated with each other. Chemokine levels correlated with measures of disease severity. Serial measurements of CXCL10 corresponded to clinical course.

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Gene Set Analysis of Lung Samples Provides Insight into Pathogenesis of Progressive, Fibrotic Pulmonary Sarcoidosis

Cited by 79 publications

References 29 publications

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

Differential expression of monocyte/macrophage- selective markers in human idiopathic pulmonary fibrosis

Interferon-inducible chemokines reflect severity and progression in sarcoidosis

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