An observational study in Chronic Beryllium Disease, sponsored by National Jewish Health. Completed at 1 site in United States. Open to participants aged 18 Years to 80 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-04-29.
Sponsored by National Jewish Health · Observational
This study will provide important results for each aim, while also providing an integrative transcriptional and epigenomic profile of CBD.
In Aim 1 the Investigator will define genome-wide epigenetic alterations of CBD, by determining genes that are DM in pivotal immune cells, in the target organ (CD4+ BAL cells) in CBD compared to BeS and healthy controls. In addition, the Investigator will determine the impact of Be exposure on the methylation profile of CBD and BeS cells compared to each other and normal controls. This information will be used to define DM regions, genes and their networks.
Using the cases and controls from Aim 1, we will evaluate the gene-expression from these same subjects in Aim 2 to define functional epigenetic loci based on DE in CD4+ BAL cells with and without Be exposure. The Investigator will also integrate ENCODE/RE methylation, histone modification, and chromatin accessibility data as well as our genome-wide association study (GWAS) data to prioritize epigenetic marks and networks for confirmation and validation in Aim 3. In Aim 3, the Investigator will test the generalizability of their findings, explore the potential of methylation marks as biomarkers of disease in PBMCs and determine if change in methylation of these targets with AZA or folic acid affects key immune and regulatory pathways in a second set of CBD and BeS subjects. Throughout the Aims, the Investigator will use both fresh CD4+ T cells to directly assess disease relevance and Be-stimulated cultured CD4+ T cells (compared to unstimulated cultured T cells) to assess the impact of environmental exposure .
National Jewish Health is the lead sponsor of 108 studies on the registry; 14 are open to participants now.
Counted across the registry records on this site, refreshed daily.
We will enroll subjects using standard case and control definitions. We will enroll up to 150 subjects. Controls will be frequency matched on age, gender, race and smoking status to limit methylation changes related to these factors.
Chronic Beryllium Disease (CBD):
Beryllium Sensitization:
Normal Controls:
Exclusion Criteria:
Chronic Beryllium Disease:
Beryllium Sensitization:
Normal Controls:
Those that have been diagnosed with the disease. No interventions will be administered.
Other: Nothing
Those that have been diagnosed with beryllium sensitization and do not have chronic beryllium disease. No interventions will be administered.
Other: Nothing
Those that do not have chronic beryllium disease or beryllium sensitization. No interventions will be administered
Other: Nothing
No interventions will be administered.
Determine the critical immune and environmentally-induced epigenetic alterations in the CD4+ T cells at the site of disease involvement from CBD compared to BeS and control subjects.
The Investigators goal is to define an epigenomic profile for BeS and CBD and for Be exposure in the lung. Most studies using similar methods have demonstrated significant hypo- and hyper-methylation, in disease states, which we also expect to find. In addition, we expect to confirm an association between CBD and Th1 epigenetic regulation, finding DM in regions such as FOXP3, Th1 differentiation pathways and TNFalpha, likely with modulation of these and other regions with Be exposure. There is no information regarding methylation alterations induced by an immune mediated exposure such as Be. The investigator expects to define new and unique genes with DM, some involved in the immune response and others in pathways and networks not known to be associated with granulomatous inflammation, shedding light on the pathogenesis of this and similar diseases.
Time frame: Year 1 through year 2
Define the functional impact of critical immune and environmentally-induced epigenetic alterations in gene expression from BAL CD4+ T cells from CBD compared to BeS and control subjects used in Aim 1
At the end of Aim 2, the Investigator will have 20 genes with validated methylation and expression changes. These methylation changes are likely to be regulatory in CD4+ T cells not only based on relationship with expression but also network analysis of methylation changes (Aim 1), relationship with immune cell phenotypes, cell specific chromatin/histone marks from ENCODE and RE datasets, and our CBD GWAS SNPs (Aim 2). The Investigator has a pipeline of data analysis currently in place as evidenced by our preliminary data; as new approaches such as these become available, we will use them to analyze our data.
Time frame: year 1 through year 4
Test the generalizability of our findings and validity of identified methylation and gene expression changes as potential biomarkers and therapeutic targets.
This Aim will result in a set of key data, including potential new biomarkers of disease and exposure in CBD. The Investigator expects to be able to validate the 20 loci identified in Aim 2 in BAL as well as PBMCs. Even with a sample size of n=10 in their gene-expression studies, the Investigator was able to define significant DE in PBMCs in CBD that they are currently exploring as biomarkers in a larger population; the Investigator expects that with changes found evaluating the relationship between DM and DE that they will be able to use the PBMCs as a biomarker of disease and exposure.
Time frame: Year 3 through year 5
This study is completed, as verified in Apr 2021. You cannot join it, but the record below documents what was studied.
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Berylliosis
National Jewish Health