Sjogren's syndrome (SS) is a common, complex autoimmune disorder characterized by lymphocytic infiltration into exocrine glands causing dry mouth and eyes, fatigue, malaise, and polyarthritis. Diagnosis of SS remains challenging and limited therapeutic options often culminate in irreversible destruction of the exocrine glands. SS shares many clinical and immunological similarities with other autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, Though large-scale genetic and genomic studies performed in these other diseases have proven enormously successful in identifying novel target pathways and loci associated with disease, the genetics of SS are woefully unexplored, giving us an opportunity to make an important contribution toward conquering this enigmatic disease. With the guidance, assistance and resources provided by the Oklahoma Sjogren's Syndrome Centers for Research Translation (OSSCORT), we will use state-of-the-art genetic and analytical tools to integrate extensive laboratory, clinical and genetic data to identify and characterize the molecular basis of etiology and pathogenesis of human SS. Specifically, we propose to 1) test for association of SS with genetic variants previously shown to be association with SLE and other autoimmune diseases using the ImmunoChip;2) perform genome-wide association studies to identify novel candidate loci associated with SS susceptibility and disease subphenotypes through integrative analyses of genetic, genomic, laboratory and clinical data, and 3) establish novel robust genetic associations with SS through replication in independent cohorts. We will exploit our substantial infrastructure and network of multidisciplinary experts to achieve these goals. No other group in the world has the sample sizes, volume of clinical data, or concentration of expertise to conduct these studies. At the completion of Project 1, we will provide new genes with fundamental insights into the mechanisms regarding etiology of SS. At the same time, the infrastructure developed through this OSSCORT will provide the basis for and have profound effects on future investigations in SS and potentially related autoimmune disease.

Public Health Relevance

We are witnesses to the genetic revolution coming to fruition for the basic understanding of human disease and hope to include in this march of progress. SS is clearly a disabling disorder affecting a significant proportion of the US population. The identification of genes associated with SS has significant potential for rapidly advancing our understanding of disease mechanism and ultimately, in its etiology and pathogenesis.

Agency
National Institute of Health (NIH)
Type
Specialized Center (P50)
Project #
5P50AR060804-04
Application #
8712118
Study Section
Special Emphasis Panel (ZAR1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
City
Oklahoma City
State
OK
Country
United States
Zip Code
Vivino, Frederick B; Carsons, Steven E; Foulks, Gary et al. (2016) New Treatment Guidelines for Sjögren's Disease. Rheum Dis Clin North Am 42:531-51
Fayyaz, Anum; Kurien, Biji T; Scofield, R Hal (2016) Autoantibodies in Sjögren's Syndrome. Rheum Dis Clin North Am 42:419-34
Szczerba, Barbara M; Kaplonek, Paulina; Wolska, Nina et al. (2016) Interaction between innate immunity and Ro52-induced antibody causes Sjögren's syndrome-like disorder in mice. Ann Rheum Dis 75:617-22
Pan, Z-J; Horton, C G; Lawrence, C et al. (2016) Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3(+) regulatory T cells specific for the ubiquitous RNA-binding nuclear antigen La/Sjögren's syndrome (SS)-B. Clin Exp Immunol 186:18-29
Sandhya, Pulukool; Kurien, Biji Theyilamannil; Danda, Debashish et al. (2016) Update on Pathogenesis of Sjögren's syndrome. Curr Rheumatol Rev :
Joachims, Michelle L; Leehan, Kerry M; Lawrence, Christina et al. (2016) Single-cell analysis of glandular T cell receptors in Sjögren's syndrome. JCI Insight 1:
Harris, Valerie M; Sharma, Rohan; Cavett, Joshua et al. (2016) Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome. Clin Immunol 168:25-9
Rasmussen, Astrid; Radfar, Lida; Lewis, David et al. (2016) Previous diagnosis of Sjögren's Syndrome as rheumatoid arthritis or systemic lupus erythematosus. Rheumatology (Oxford) 55:1195-201
Wolska, Nina; Rybakowska, Paulina; Rasmussen, Astrid et al. (2016) Brief Report: Patients With Primary Sjögren's Syndrome Who Are Positive for Autoantibodies to Tripartite Motif-Containing Protein 38 Show Greater Disease Severity. Arthritis Rheumatol 68:724-9
Nocturne, Gaetane; Tarn, Jessica; Boudaoud, Saida et al. (2016) Germline variation of TNFAIP3 in primary Sjögren's syndrome-associated lymphoma. Ann Rheum Dis 75:780-3

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