Using Functional Genomic Data in Monocytes/Macrophages and Genotyping to Nominate Disease-Driving Single Nucleotide Polymorphisms and Target Genes in Juvenile Idiopathic Arthritis.

Introduction: GWAS have identified multiple regions that confer risk for juvenile idiopathic arthritis (JIA). However, identifying the single nucleotide polymorphisms (SNPs) that drive disease risk is impeded by the SNPs' that identify risk loci being in linkage disequilibrium (LD) with hundreds of other SNPs. Since the causal SNPs remain unknown, it is difficult to identify target genes and use genetic information to inform patient care.

A systematic strategy for identifying causal single nucleotide polymorphisms and their target genes on Juvenile arthritis risk haplotypes.

Background: Although genome-wide association studies (GWAS) have identified multiple regions conferring genetic risk for juvenile idiopathic arthritis (JIA), we are still faced with the task of identifying the single nucleotide polymorphisms (SNPs) on the disease haplotypes that exert the biological effects that confer risk. Until we identify the risk-driving variants, identifying the genes influenced by these variants, and therefore translating genetic information to improved clinical care, will remain an insurmountable task. We used a function-based approach for identifying causal variant candidates and the target genes on JIA risk haplotypes.

Comparison of the three-dimensional chromatin structures of adolescent and adult peripheral blood B cells: implications for the study of pediatric autoimmune diseases.

Background/purpose: Knowledge of the 3D genome is essential to elucidate genetic mechanisms driving autoimmune diseases. The 3D genome is distinct for each cell type, and it is uncertain whether cell lines faithfully recapitulate the 3D architecture of primary human cells or whether developmental aspects of the pediatric immune system require use of pediatric samples. We undertook a systematic analysis of B cells and B cell lines to compare 3D genomic features encompassing risk loci for juvenile idiopathic arthritis (JIA), systemic lupus (SLE), and type 1 diabetes (T1D).

Systemic lupus erythematosus in American Indian/Alaska natives: Incorporating our new understanding of the biology of trauma.

Objective: To review the literature regarding systemic lupus erythematosus (SLE) in American Indian/Alaska Native (AI/AN) people and relate prevalence and/or disease severity to our emerging understanding of the biology of trauma and toxic stress.

Methods: We conducted a search and review of the literature using search terms "lupus and American Indians" "ACEs and disease outcome" "Biology of Adversity" "lupus and ACE scores," " lupus and childhood abuse." These search criteria were entered into Google Scholar and articles retrieved from PubMed, NBCI.

Association of anti-TPM4 autoantibodies with vasculopathic cutaneous manifestations in juvenile dermatomyositis.

Objectives: AECAs are detected in multiple forms of vasculitis or vasculopathy, including JDM. High levels of tropomyosin alpha-4 chain (TPM4) gene expression in cutaneous lesions and TPM4 protein expression in some endothelial cells (ECs) have been proven. Furthermore, the presence of autoantibodies to tropomyosin proteins have been discovered in DM.

Analysis of chromatin data supports a role for CD14+ monocytes/macrophages in mediating genetic risk for juvenile idiopathic arthritis.

Introduction: Genome wide association studies (GWAS) have identified multiple regions that confer genetic risk for the polyarticular/oligoarticular forms of juvenile idiopathic arthritis (JIA). However, genome-wide scans do not identify the cells impacted by genetic polymorphisms on the risk haplotypes or the genes impacted by those variants. We have shown that genetic variants driving JIA risk are likely to affect both innate and adaptive immune functions.

Health inequities in the rheumatic diseases of childhood.

Purpose Of Review: To describe differences in disease manifestations and outcomes in pediatric rheumatic diseases as they occur in non-European-descended populations in North America.

Recent Findings: Differences in disease prevalence, clinical phenotypes, disease course, and outcomes have been described across the spectrum of pediatric-onset rheumatic diseases. Although these differences are commonly explained by differences in genetic risk or access to tertiary healthcare facilities, our emerging understanding of the immunobiology of historical/ongoing trauma suggest a more complex explanation for these observed differences.

Chromatin architecture around stroke haplotypes provides evidence that genetic risk is conferred through vascular cells.

Genome-wide association studies (GWAS) have identified numerous stroke-associated SNPs. To understand how SNPs affect gene expression related to increased stroke risk, we studied epigenetic landscapes surrounding 26 common, validated stroke-associated loci. We mapped the SNPs to linkage disequilibrium (LD) blocks and examined H3K27ac, H3K4me1, H3K9ac, and H3K4me3 histone marks and transcription-factor binding-sites in pathologically relevant cell types (hematopoietic and vascular cells).

Association of anti-HSC70 autoantibodies with cutaneous ulceration and severe disease in juvenile dermatomyositis.

Objectives: JDM is an inflammatory myopathy characterized by prominent vasculopathy. AECAs are frequently detected in inflammatory and autoimmune diseases. We sought to determine whether AECAs correlate with clinical features of JDM, and thus serve as biomarkers to guide therapy or predict outcome.

Identification of Circulating Gene Expression Signatures of Intracranial Aneurysm in Peripheral Blood Mononuclear Cells.

Peripheral blood mononuclear cells (PBMCs) play an important role in the inflammation that accompanies intracranial aneurysm (IA) pathophysiology. We hypothesized that PBMCs have different transcriptional profiles in patients harboring IAs as compared to IA-free controls, which could be the basis for potential blood-based biomarkers for the disease. To test this, we isolated PBMC RNA from whole blood of 52 subjects (24 with IA, 28 without) and performed next-generation RNA sequencing to obtain their transcriptomes.

Epigenetic landscapes of intracranial aneurysm risk haplotypes implicate enhancer function of endothelial cells and fibroblasts in dysregulated gene expression.

Background: Genome-wide association studies have identified many single nucleotide polymorphisms (SNPs) associated with increased risk for intracranial aneurysm (IA). However, how such variants affect gene expression within IA is poorly understood. We used publicly-available ChIP-Seq data to study chromatin landscapes surrounding risk loci to determine whether IA-associated SNPs affect functional elements that regulate gene expression in cell types comprising IA tissue.

Broadening our understanding of genetic risk for scleroderma/systemic sclerosis by querying the chromatin architecture surrounding the risk haplotypes.

Background: Genetic variants in the human leukocyte antigen (HLA) locus contribute to the risk for developing scleroderma/systemic sclerosis (SSc). However, there are other replicated loci that also contribute to genetic risk for SSc, and it is unknown whether genetic risk in these non-HLA loci acts primarily on the vasculature, immune system, fibroblasts, or other relevant cell types. We used the Cistrome database to investigate the epigenetic landscapes surrounding 11 replicated SSc associated loci to determine whether SNPs in these loci may affect regulatory elements and whether they are likely to impact a specific cell type.

CD4+ T cells from children with active juvenile idiopathic arthritis show altered chromatin features associated with transcriptional abnormalities.

Juvenile idiopathic arthritis (JIA) is one of the most common chronic diseases in children. While clinical outcomes for patients with juvenile JIA have improved, the underlying biology of the disease and mechanisms underlying therapeutic response/non-response are poorly understood. We have shown that active JIA is associated with distinct transcriptional abnormalities, and that the attainment of remission is associated with reorganization of transcriptional networks.

Whole blood transcriptome biomarkers of unruptured intracranial aneurysm.

Background: The rupture of an intracranial aneurysm (IA) causes devastating subarachnoid hemorrhages, yet most IAs remain undiscovered until they rupture. Recently, we found an IA RNA expression signature of circulating neutrophils, and used transcriptome data to build predictive models for unruptured IAs. In this study, we evaluate the feasibility of using whole blood transcriptomes to predict the presence of unruptured IAs.

Classification models using circulating neutrophil transcripts can detect unruptured intracranial aneurysm.

Background: Intracranial aneurysms (IAs) are dangerous because of their potential to rupture. We previously found significant RNA expression differences in circulating neutrophils between patients with and without unruptured IAs and trained machine learning models to predict presence of IA using 40 neutrophil transcriptomes. Here, we aim to develop a predictive model for unruptured IA using neutrophil transcriptomes from a larger population and more robust machine learning methods.

Characterization of Long Non-coding RNA Signatures of Intracranial Aneurysm in Circulating Whole Blood.

Background And Objective: Long non-coding RNAs (lncRNAs) may serve as biomarkers for complex disease states, such as intracranial aneurysms. In this study, we investigated lncRNA expression differences in the whole blood of patients with unruptured aneurysms.

Methods: Whole blood RNA from 67 subjects (34 with aneurysm, 33 without) was used for next-generation RNA sequencing.

Broadening our understanding of the genetics of Juvenile Idiopathic Arthritis (JIA): Interrogation of three dimensional chromatin structures and genetic regulatory elements within JIA-associated risk loci.

Objective: The risk loci for juvenile idiopathic arthritis (JIA) consist of extended haplotypes that include functional elements in addition to canonical coding genes. As with most autoimmune diseases, the risk haplotypes for JIA are highly enriched for H3K4me1/H3K27ac histone marks, epigenetic signatures that typically identify poised or active enhancers. In this study, we test the hypothesis that genetic risk for JIA is exerted through altered enhancer-mediated gene regulation.

Double negative T cells, a potential biomarker for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that is a challenge to diagnose and treat. There is an urgent need for biomarkers to help define organ involvement, and more effective therapies. A unique population of T cells, the CD3CD4CD8 (DNeg) cells, is significantly increased in lupus patients.

The feasibility of developing biomarkers from peripheral blood mononuclear cell RNAseq data in children with juvenile idiopathic arthritis using machine learning approaches.

Background: The response to treatment for juvenile idiopathic arthritis (JIA) can be staged using clinical features. However, objective laboratory biomarkers of remission are still lacking. In this study, we used machine learning to predict JIA activity from transcriptomes from peripheral blood mononuclear cells (PBMCs).

Epigenetic landscapes suggest that genetic risk for intracranial aneurysm operates on the endothelium.

Background: Genetics play an important role in intracranial aneurysm (IA) pathophysiology. Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are linked to IA but how they affect disease pathobiology remains poorly understood. We used Encyclopedia of DNA Elements (ENCODE) data to investigate the epigenetic landscapes surrounding genetic risk loci to determine if IA-associated SNPs affect functional elements that regulate gene expression and if those SNPs are most likely to impact a specific type of cells.

Using the tools of proteomics to understand the pathogenesis of idiopathic inflammatory myopathies.

Purpose Of Review: One of the most important advances in medical research over the past 20 years has been the emergence of technologies to assess complex biological processes on a global scale. Although a great deal of attention has been given to genome-scale genetics and genomics technologies, the utility of studying the proteome in a comprehensive way is sometimes under-appreciated. In this review, we discuss recent advances in proteomics as applied to dermatomyositis/polymyositis as well as findings from other inflammatory diseases that may enlighten our understanding of dermatomyositis/polymyositis.

Plasma exosomes from children with juvenile dermatomyositis are taken up by human aortic endothelial cells and are associated with altered gene expression in those cells.

Background: The pathology of juvenile dermatomyositis (JDM) is characterized by prominent vessel wall and perivascular inflammation. This feature of the disease has remained unexplained and under-investigated. We have hypothesized that plasma exosomes, which play an important role in inter-cellular communication, may play a role in the vascular injury associated with JDM.