scholarly journals Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol

2015 ◽  
Vol 12 (10) ◽  
pp. 1561-1571 ◽  
Author(s):  
David R. Moller ◽  
Laura L. Koth ◽  
Lisa A. Maier ◽  
Alison Morris ◽  
Wonder Drake ◽  
...  
Keyword(s):  
Genomic Research ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

scholarly journals Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol

2015 ◽  
Vol 12 (10) ◽  
pp. 1551-1560 ◽  
Author(s):  
Charlie Strange ◽  
Robert M. Senior ◽  
Frank Sciurba ◽  
Scott O’Neal ◽  
Alison Morris ◽  
...  
Keyword(s):  
Genomic Research ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Gene coexpression networks reveal novel molecular endotypes in alpha-1 antitrypsin deficiency

Thorax ◽  
2020 ◽  
pp. thoraxjnl-2019-214301
Author(s):  
Jen-hwa Chu ◽  
Wenlan Zang ◽  
Milica Vukmirovic ◽  
Xiting Yan ◽  
Taylor Adams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Severity ◽  
T Lymphocyte ◽  
Genomic Research ◽  
Gene Module ◽  
Augmentation Therapy ◽  
Clinical Variables ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

BackgroundAlpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals.MethodsWe performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects’ clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay.ResultWe observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns.ConclusionsWe successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals’ genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.

scholarly journals Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis

2019 ◽  
Vol 54 (2) ◽  
pp. 1801762
Author(s):  
Changwan Ryu ◽  
Caitlin Brandsdorfer ◽  
Taylor Adams ◽  
Buqu Hu ◽  
Dylan W. Kelleher ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
African Americans ◽  
Clinical Findings ◽  
Genomic Research ◽  
Healthy Controls ◽  
Tissue Remodelling ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Mechanistic Basis ◽  
Alpha 1 Antitrypsin

Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the human MT-ATP6 gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between MT-ATP6 concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls, MT-ATP6 concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive MT-ATP6 concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.

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