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Genomic Studies of Autoimmune Rheumatic Disease

自身免疫性风湿病的基因组研究

基本信息

批准号：
10922455
负责人：
Lindsey Criswell
金额：
$ 176.81万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10922455
关键词：
15 year old African American Age Antibodies Antimalarials Asian ancestry Autoantibodies Autoimmune Diseases Award B-Lymphocytes Binding Biological Biopsy Biopsy Specimen Blood Blood Cells CD14 gene CD19 gene California Candidate Disease Gene Cell Separation Cells Chemical Exposure Chemicals Clinical Clinical Data Cohort Studies Collaborations Coupled DNA DNA Methylation DNA Repair DNA Transposable Elements Data Data Set Development Diagnosis Disease Disease remission Drops East Asian Elements Endogenous Retroviruses Enrollment Environmental Exposure Environmental Risk Factor Epigenetic Process Epithelial Cells Estrogen deficiency Eugenol European Exclusion Family Family member Fibroblasts Flare Funding Gene Expression Regulation Gene set enrichment analysis Generations Genes Genetic Genetic Research Genetic study Genomics Gland Goals Health Heterogeneity Hypermethylation Immune Individual Inflammation Interferons International Ions Labial Salivary Gland Laboratories Lacrimal gland structure Leadership Link Lipid Peroxidation Liquid Chromatography Longitudinal Studies Lupus Manuscripts Mass Spectrum Analysis Measures Methods Methylation Modeling Modification NF-kappa B National Human Genome Research Institute National Institute of Dental and Craniofacial Research National Institute of Environmental Health Sciences Not Hispanic or Latino Nuclear Nucleotides Oxidative Stress Participant Pathogenesis Pathway Analysis Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Physicians Plasma Population Positioning Attribute Production RNA Race Rattus Registries Reporting Research Research Project Grants Rheumatoid Arthritis Risk Saliva Salivary Glands Sample Size Sampling San Francisco Serum Signal Pathway Signal Transduction Site Sjogren&apos s Syndrome Smoke Statistical Methods Systemic Lupus Erythematosus Testing Time Tissues United States National Institutes of Health Universities Up-Regulation Variant Viral Proteins Whole Blood Wildfire Work anti-dsDNA antibodies apoAI regulatory protein-1 autoencoder autoimmune rheumatologic disease bead chip biobank burden of illness cell type climate change climate-related health clinical care clinical phenotype cohort design differential expression disorder risk environmental chemical epidemiology study epigenetic profiling epigenome exome sequencing experience genetic epidemiology genome wide association study genome-wide gut microbiota illness length improved metabolome metabolomics mouse model multi-ethnic multi-racial multiple omics neutrophil patient subsets phthalates programs rare variant recruit repository rheumatologist sample collection sex small molecule sociodemographic factors transcriptome sequencing working group

项目摘要

Local ancestry in SLE: During the current reporting period, a manuscript examining the local ancestry in the MHC region in SLE patients from a multi-ethnic cohort is under review. This set of patients was pulled from the CLUES cohort. SLE patients of African American, Mestizo and Asian descent tend to have more severe manifestations than populations of European descent. Differences in global and local ancestry may shed light on underlying mechanisms that lead to the differences in disease burden. However, results indicated that small effect sizes were not statistically significant. Local genetic ancestry within the MHC region was not a major contributor to SLE manifestations among SLE patients from admixed populations. Exposome in SLE: Another manuscript under review examined environmental exposures in 332 SLE patients from the CLUES cohort and 100 controls matched by age, sex and race. Plasma samples from SLE patients were profiled using liquid chromatography coupled with Q-TOF mass spectrometry (LC/Q-TOF MS) methods for measuring environmental chemicals. Mass spectrometry features present in more than 25% of the samples were selected for further analysis and matched to potential chemicals. Associations with SLE and SLE manifestations were performed adjusting for age and sex. We observed seven features that matched to phthalate metabolites, a formetanate metabolite, and eugenol and were associated with SLE, and 11 features were significantly correlated with use of antimalarials. This hypothesis-free study of blood chemicals in SLE identified differences in chemical exposures associated with SLE, SLE manifestations and sociodemographic factors. SLE FLARE study: We profiled 51 SLE patients undergoing a disease flare on the Illumina EPIC chip which consists of 850,000 CpGs genome-wide. These SLE flaring patients were undergoing routine clinical care at the time of recruitment. A flare was characterized by the treating rheumatologist and with the SLEDAI score, which is a validated measure of disease activity in lupus. Standard QC pipelines for the EPIC methylation chip were applied. Using the R package limma, differentially methylated positions (DMPs) associated with SLEDAI score were identified. Models identifying the DMPs accounted for the paired design and adjusted for blood cell proportions, batch, age, sex, medications and genetic principal components. Hierarchical clustering was performed on the 5,000 most significant DMPs to identify patient subtypes. Analyses were performed to exclude pairs that showed no change in SLEDAI score. Hierarchical clustering then revealed three distinct lupus patient clusters from changes in methylation. We found that patients in cluster 3 are approximately 15 years older and experienced a remission after flare. Patients in cluster 2 had a younger age at SLE diagnosis, shorter disease duration and experienced a 17% drop in neutrophils in less active disease states. Patients in cluster 1 tended to have a younger age at SLE diagnosis and longer disease duration. Clusters 1 and 3 showed association with interferon pathways. Next steps for this project include adding additional pairs to the analysis integrating multi-omics approaches using metabolomics and single cell RNA approaches. Human Endogenous Retrovirus Expression and SLE: The expression of transposable elements (TEs) such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs) may contribute to production of type I IFN and generation of autoantibodies. Cell-sorted RNA-seq data were profiled from PBMCs of 119 SLE patients from the CLUES cohort. TEs in these 4 cell-types were quantified with Telescope resulting in expression of 27,135 TEs. Differential expression of locus specific TEs was performed across 11 SLE phenotypes including anti-smith antibody, disease activity, and anti-dsDNA antibody status adjusting for sex, age, genetic principal components 1-10, and medication use. Differentially expressed locus-specific TEs per cell type were used to perform family and viral protein enrichment analysis. There was an upregulation of the IFN signaling pathway in CD4, CD19 and CD14 cells and an upregulation of genes in pathways related to BCR signaling, NF-kB activation, and DNA repair in CD19. These findings suggest that expression of TEs might be contributing to activation of SLE-related mechanisms in a cell-specific manner. Metabolomics in SLE: The study to characterize the metabolome in flaring SLE patients is in progress. In addition to capturing hazardous exposures, LC-QTOF/MS can also capture small molecules produced endogenously by inflammation, oxidative stress, lipid peroxidation, and the gut flora, referred to as the metabolome. Data has been generated by the Metabolomics Core at NIEHS and preliminary analysis completed at NIEHS suggests some modest differences between pre-flare and post-flare samples. We aim to characterize the metabolome at different stages of disease activity in SLE patients as well as comparing the metabolome in SLE patients to healthy controls. Sjogrens Disease (SjD) Projects: During the current reporting period, we are preparing a manuscript for submission on DNA methylation from 1095 labial salivary glands (LSG) from the SICCA cohort. Glands from 592 SjD cases and 467 symptomatic non-cases were profiled on the on the Illumina Infinium MethylationEPIC BeadChip array which consisted of 865,859 CpG sites. The participants in this analysis are from either non-Hispanic White or East Asian ancestry. Previous work from this group demonstrated that DNA methylation analyses on LSG can distinguish between severe and mild SjD cases. However, previous work did not adjust for cellular heterogeneity and was performed on a sample size of 131 glands. Standard QC pipelines were applied which led to a final dataset of 739,650 CpG sites for analysis and a total of 9 cell-type proportions were estimated that included epithelial cells, fibroblasts and 7 types of immune cells. Statistical methods applied included variational autoencoder (VAE), hierarchical clustering, and the identification of differentially methylated regions. Gene set enrichment analysis and differential methylation analyses within cell types were also performed. The largest number of differences occurred in B cells and epithelial cells. These observed differences correspond with pathways with biological relevance to disease pathogenesis. In B cells, the gene NR2F2, which was shown to be differentially expressed in lacrimal glands in mouse models was hypomethylated, and NDRG2, which is associated with increased saliva production in estrogen-deficient rats, was hypermethylated. The clustering of methylation data from LSG resulted in distinct groups of severe and mild SjD cases. These clusters also showed differing cell proportions and differential methylation within predicted cell-types, thus highlighting the need to perform cell-specific analysis in SjD. WES in Sjgrens Disease: We have also generated Whole Exome Sequencing (WES) data at NISC on approximately 400 samples of European descent from the SICCA cohort. These 400 samples were chosen for their extreme phenotypes of severe Sjogrens disease case vs non-case. Gene based analysis was performed to test for association using the rare variants in each gene region. This analysis showed there were no genes significantly associated with severe Sjogrens Disease and rare or deleterious variants were more common in the non-cases. Pathway analysis suggested that genes with rare variants are enriched in ion and nucleotide binding pathways. Next steps involve generating additional WES data in an additional 384 samples of extreme phenotypes (East Asian descent) at NISC and acquiring publicly available healthy control data to increase the power of this study.