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)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
1P50AR060804-01
Application #
8102491
Study Section
Special Emphasis Panel (ZAR1-MLB (M1))
Project Start
2011-07-21
Project End
2016-06-30
Budget Start
2011-07-21
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$421,829
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Leehan, Kerry M; Pezant, Nathan P; Rasmussen, Astrid et al. (2017) Minor salivary gland fibrosis in Sjögren's syndrome is elevated, associated with focus score and not solely a consequence of aging. Clin Exp Rheumatol :
Sandhya, Pulukool; Kurien, Biji Theyilamannil; Danda, Debashish et al. (2017) Update on Pathogenesis of Sjogren's Syndrome. Curr Rheumatol Rev 13:5-22
Zhao, Jian; Ma, Jianyang; Deng, Yun et al. (2017) A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet 49:433-437
Shiboski, Caroline H; Shiboski, Stephen C; Seror, Raphaèle et al. (2017) 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren's Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts. Arthritis Rheumatol 69:35-45
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Carapito, Raphael; Gottenberg, Jacques-Eric; Kotova, Irina et al. (2017) A new MHC-linked susceptibility locus for primary Sjögren's syndrome: MICA. Hum Mol Genet 26:2565-2576
Leehan, Kerry M; Pezant, Nathan P; Rasmussen, Astrid et al. (2017) Fatty infiltration of the minor salivary glands is a selective feature of aging but not Sjögren's syndrome. Autoimmunity 50:451-457
Talsania, Mitali; Scofield, Robert Hal (2017) Menopause and Rheumatic Disease. Rheum Dis Clin North Am 43:287-302
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

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