PROJECT SUMMARY Sarcoidosis is a multisystem granulomatous disorder of unknown etiology. Sarcoidosis frequently affects the lungs and may cause significant morbidity and mortality. 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 genetic 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. Up to now, biomarkers for sarcoidosis have not been identified. Clinically, the elevated IgG and IgG immune complexes in the circulation and the changed expressions of low affinity IgG Fc receptors (Fc?Rs) on immune cells were found in sarcoidosis patients, suggesting that IgG production and Fc?Rs may be involved in the pathogenesis of sarcoidosis. As the sole high affinity Fc?R capable of binding monomeric IgG, Fc?RIA contributes substantially to inflammatory and immune responses. Fc?RIA has eluded the genetic analysis thus far due to the existence of other highly homologous genes in human genome. In the preliminary studies, we have developed genotyping assays and identified two novel single nucleotide polymorphisms (SNPs) within Fc?RIA gene. Our preliminary data also show that the expressions of Fc?RIA on monocytes and neutrophils were significantly increased in sarcoidosis patients compared to healthy controls and that Fc?RIA SNPs were associated with sarcoidosis susceptibility and severity. Our data indicate that Fc?RIA genetic variations may have a significant impact on the development of sarcoidosis. The genetic effects of Fc?RIA on sarcoidosis and other inflammatory diseases are unknown to date. Therefore, we hypothesize that Fc?RIA genetic variations affect receptor functions and influence the pathogenesis of sarcoidosis. We will vigorously test our hypothesis through the following specific aims: 1) to identify novel SNPs in Fc?RIA gene and to determine whether Fc?RIA SNPs are risk factors for sarcoidosis and disease severity; and 2) to determine to determine whether Fc?RIA variants affect receptor functions. The delineation of the role of Fc?RIA variants in the development of sarcoidosis will provide significant insights into the genetics of sarcoidosis and the immunological mechanism of sarcoidosis. Our study may also lead to new strategies for diagnosis and prognosis of sarcoidosis and other inflammatory diseases, significantly contributing to the goal of precision (or personalized) medicine.