Additional file 2: Table S2. of N-acetylcysteine exposure is associated with improved survival in anti-nuclear antibody seropositive patients with usual interstitial pneumonia

Multivariable-adjusted NAC-associated mortality risk stratified by ANA seropositivity after exclusion of patients receiving an anti-fibrotic. (DOCX 61 kb

Additional file 5: Table S5. of N-acetylcysteine exposure is associated with improved survival in anti-nuclear antibody seropositive patients with usual interstitial pneumonia

rs3750920 (TOLLIP) genotypes stratified by NAC Exposure and ANA Status. (DOCX 42 kb

Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis

Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ,20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis

Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk genome-wide association studies. We used the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR (mammalian target of rapamycin) signalling, telomere maintenance and spindle assembly genes in IPF risk

Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing

Background: Specific common and rare single nucleotide variants (SNVs) increase the likelihood of developing sporadic idiopathic pulmonary fibrosis (IPF). We performed target enriched sequencing on three loci previously identified by a genome-wide association study to gain a deeper understanding of the full spectrum of IPF genetic risk and performed a two-stage case-control association study. Methods: A total of 1.7 Mb of DNA from 181 IPF patients was deep sequenced (100X) across 11p15.5, 14q21.3, and 17q21.31 loci. Comparisons were performed against 501 unrelated controls and replication studies were assessed in 3,968 subjects. Results: Thirty-six SNVs were associated with IPF susceptibility in the discovery stage (p<5.0x10-8). After meta-analysis, the strongest association corresponded to rs35705950 (p=9.27x10-57) located upstream from the mucin 5B (MUC5B) gene. Additionally, a novel association was found for two co-inherited low-frequency SNVs (<5%) in MUC5AC gene, predicting a missense amino acid change in mucin 5AC (lowest p=2.27x10-22). Conditional and haplotype analyses in 11p15.5 supported the existence of additional contribution of MUC5AC variants to IPF risk. Conclusions: This study reinforces the significant IPF associations of these loci and implicates MUC5AC as another key player in IPF susceptibility

Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis

<div><p>Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ∼20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - <em>CX3CR1</em>, <em>FKBP1A</em>, <em>NOG</em>, <em>RBM12B</em>, <em>SENS3</em>, <em>TSHZ2</em>; T cell/JAK-STAT pathway genes such as <em>AKT3</em>, <em>CBLB</em>, <em>DLG1</em>, <em>IFNG</em>, <em>IL2RA</em>, <em>IL7R</em>, <em>ITK</em>, <em>JUN</em>, <em>MALT1</em>, <em>NFATC2</em>, <em>PLCG1</em>, <em>SPRED1</em>). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.</p> </div

Validation in independent datasets.

<p>The upper panels show the comparison between the 20-gene signature and the TCR/JS/CCR signaling pathway gene signature. The distribution of prediction accuracy is based on 1,000 times of five-fold cross-validation. The dashed lines indicate the average classification accuracy for the 20-gene signature or the TCR/JS/CCR signaling pathway gene signature. The lower panels show the results of principal component analysis on expression values of the 20-gene signature. X-axis: principal component 1 with eigenvalue; Y-axis: principal component 2 with eigenvalue.</p

The 31 differentially-expressed TCR/JS/CRR signaling pathway genes in sarcoidosis.

<p>EA: Caucasian Americans; AA: African Americans; FDR: false discovery rate.</p

Patient characteristics and concomitant medications.

<p>Patient characteristics and concomitant medications.</p

The unbiased 20-gene signature for complicated sarcoidosis.

<p>Here, the weight of each gene represents the frequency of the gene being selected during the last round of RFE procedure.</p