Sarcoidosis is a multisystem granulomatous disorder of unknown etiology. Sarcoidosis frequently affects the lungs and may cause significant morbidity. Environmental factors are considered as potential triggers for the disease, but no single trigger for the development of sarcoidosis has been identified. The critical role for geneti factors contributing to sarcoidosis etiology is strongly supported by twin studies, disease clustering in families, and racial differences in incidence rates. Multiple genes may be involved in sarcoidosis, but no gene has been functionally demonstrated to influence sarcoidosis. Clinically, the elevated immunoglobulins and immune complexes in the circulation and the altered expressions of IgG Fc receptors (Fc?Rs) on the immune cells are observed in sarcoidosis patients, suggesting that IgG immune complexes and their receptors may be involved in the pathogenesis of sarcoidosis. However, up to now, biomarkers for sarcoidosis have not been identified. Recent data from our group demonstrated that the functional variants of IgG Fc receptor (Fc?R) influence granulomatosis with polyangiitis, suggesting that Fc?R genes may play a role in the granulomatous inflammation of sarcoidosis. Fc?Rs serve as the essential link between the humoral and cellular immunities and play a central role in human immune responses. Technically, homologous human Fc?R genes are not suitable for genome-wide association study (GWAS) assays and therefore, the genetic markers within the human Fc?R gene cluster are not included in any GWAS assays. Additionally, Fc?R genes have copy number variations (CNVs, gene deletions or duplications on the chromosome), which lead to Fc?R gene deficiency or gain-of-function. In the preliminary studies, we observed that Fc?RIIIA CNVs are significantly associated with systemic lupus erythematosus, suggesting that structural variations of Fc?R genes may have a significant impact on chronic inflammatory diseases. The candidate gene approach has been successfully used in our previous genetic studies in demonstrating the role of Fc?R SNPs (single nucleotide polymorphisms) in autoimmune diseases. However, the role of Fc?Rs in sarcoidosis is unknown thus far. Therefore, in the current proposal, we hypothesize that genetic variations (CNVs and SNPs) of Fc?R genes play a critical role in the pathogenesis of sarcoidosis. Taking advantage of specimens and data collected by NHLBI Biologic Specimen Repository in the ACCESS (A Case Control Etiologic Study of Sarcoidosis) program, we will vigorously test our hypothesis through the following specific aims: 1) To determine whether Fc?R CNVs are risk factors for sarcoidosis;and 2) to investigate whether functional Fc?R SNPs are associated with sarcoidosis. The delineation of the role of Fc?R variants in the development of sarcoidosis will provide significant insights into the genetics of sarcoidosis and the immunological mechanisms underlying sarcoidosis. In addition, our study may lead to the development of new strategies for the prediction and treatment of other immunoglobulin-mediated inflammatory diseases.

Public Health Relevance

Sarcoidosis is a granulomatous disease affecting multiple human organs. In people with sarcoidosis, abnormal masses or nodules (called granulomas) consisting of inflamed tissues may disrupt the normal structures and functions of the affected organs. The cause of sarcoidosis is unknown. Genetic factors are assumed to contribute to the development of sarcoidosis. The present study is intended to determine whether genetic variations in the genes coding for immunoglobulin Fc receptors play an important role in the pathogenesis of sarcoidosis. The delineation of the role of immunoglobulin Fc receptors in sarcoidosis will provide novel insights into the genetics of sarcoidosis and the immunological mechanisms underlying sarcoidosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZHL1-CSR-P (F1))
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Wagner, Elizabeth
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University of Minnesota Twin Cities
Schools of Veterinary Medicine
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