Primary Sjogren's syndrome (pSS) is a common, progressive autoimmune disorder distinguished by immunological targeting of salivary and lacrimal glands. Systemic manifestations are variable and may include vasculitis, neurologic disease, interstitial nephritis, thyroid dysfunction, fatigue, arthritis, and lymphoma. A concurrent second autoimmune disease, such as systemic lupus erythematosus or rheumatoid arthritis, occurs in half of all SS patients. Heterogeneity of clinical and laboratory findings are influenced by underlying genetic variation that remains largely unexplored. Diagnosis is often delayed and problematic and therapies are primarily directed at symptoms. Our overall goal is to understand the etiology and pathogenesis of SS through genetics. We will evaluate selected interferon (INF) pathway candidate genes and apply unbiased genome scan approaches to a carefully defined sub-phenotype of SS in large patient cohorts to define genetic variation that leads to the INF dependence of SS. Our preliminary studies have shown interferon (IFN) mediated pathways are dysregulated in SS and appear to be predominant in the subset of patients with anti-Ro/SSA. We propose to apply state-of-the art genetic and genomic approaches to identify and characterize molecular disease mechanisms in this subset of SS patients. We will first generate global gene expression data in our cohort of SS patients to identify those with dysregulation of IFN pathways. We will also measure serum IFNa activity through cellular functional assays. Homogeneous subsets of patients with these two IFN-related traits, plus anti-Ro/SSA will then be selected for genome wide association studies tailored to identify and characterize important variants involved in dysregulation of IFN pathways in SS. Replication, fine mapping and characterization of genetic effects will be pursued. These studies should reveal novel, fundamental knowledge about SS that will lead to the development of more precise diagnostic tests and therapeutic intervention targeted at causal molecular events.
The goal of this large scale project is to identify genes that promote dysregulation of interferon related pathways in Sjogren's Syndrome using a comprehensive genome wide approach. The resulting knowledge should generate novel opportunities for the development of improved diagnostic tools, biomarkers for monitoring disease, and innovative therapies for this complex disorder and other related autoimmune diseases.
|Wang, Chih-Chuan; Ortiz-González, Xilma R; Yum, Sabrina W et al. (2018) ?IV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy. Am J Hum Genet 102:1158-1168|
|Scofield, R Hal; Sharma, Rohan; Harris, Valerie M (2018) Reply. Arthritis Rheumatol 70:626-627|
|Glauzy, Salomé; Boccitto, Marco; Bannock, Jason M et al. (2018) Accumulation of Antigen-Driven Lymphoproliferations in Complement Receptor 2/CD21-/low B Cells From Patients With Sjögren's Syndrome. Arthritis Rheumatol 70:298-307|
|St Clair, E William; Baer, Alan N; Wei, Chungwen et al. (2018) Clinical Efficacy and Safety of Baminercept, a Lymphotoxin ? Receptor Fusion Protein, in Primary Sjögren's Syndrome: Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol 70:1470-1480|
|Koelsch, Kristi A; Cavett, Joshua; Smith, Kenneth et al. (2018) Evidence of Alternative Modes of B Cell Activation Involving Acquired Fab Regions of N-Glycosylation in Antibody-Secreting Cells Infiltrating the Labial Salivary Glands of Patients With Sjögren's Syndrome. Arthritis Rheumatol 70:1102-1113|
|Hinks, Anne; Marion, Miranda C; Cobb, Joanna et al. (2018) Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis. Arthritis Rheumatol 70:957-962|
|Pelikan, Richard C; Kelly, Jennifer A; Fu, Yao et al. (2018) Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks. Nat Commun 9:2905|
|Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :|
|Kheir, Joseph M; Guthridge, Carla J; Johnston, Jonathon R et al. (2018) Unique clinical characteristics, autoantibodies and medication use in Native American patients with systemic lupus erythematosus. Lupus Sci Med 5:e000247|
|Young, K A; Munroe, M E; Harley, J B et al. (2018) Less than 7 hours of sleep per night is associated with transitioning to systemic lupus erythematosus. Lupus 27:1524-1531|
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