PROJECT SUMMARY/ABSTRACT Sarcoidosis is a chronic multi-organ granulomatous disease of unknown etiology, typically characterized by lung involvement, which disproportionately affects African-American women. Sarcoidosis is thought to be caused by environmental factors in the setting of a genetically susceptible host. Although sarcoidosis has a significant genetic basis, the genetic architecture of sarcoidosis risk is poorly defined. In preliminary studies, the PI's team has performed a phenome-wide association study (PheWAS) using the Vanderbilt University's genetic biobank (BioVU) to investigate the phenotypic consequences of an African ancestry-specific loss-of- function frameshift variant in the PLA2R1 gene. PLA2R1 encodes the phospholipase A2 receptor (PLA2R), a transmembrane protein from the mannose receptor family, whose biological function is not clearly understood. We have unexpectedly discovered that African-Americans homozygous for the PLA2R1 frameshift variant have about 5-fold higher risk of sarcoidosis and 10-fold higher risk of tuberculosis. The objective of this research is to corroborate and expand upon these preliminary findings by analyzing biospecimens from “A Case Controlled Etiologic Study of Sarcoidosis (ACCESS)” as an independent validation cohort. Our central hypothesis is that PLA2R1 deficiency increases the risk of sarcoidosis among African-Americans in the ACCESS study, in part by increasing susceptibility to latent infection with Mycobacterium tuberculosis. Studies proposed in Aim 1A seek to validate genetic PLA2R1 deficiency as a monogenic cause of sarcoidosis among African-Americans in the ACCESS study. Aim 1B will establish whether genetic PLA2R1 deficiency increases sarcoidosis risk specifically among African-Americans with latent tuberculosis infection. Aim 2 will determine whether sarcoidosis may be triggered by an acquired PLA2R loss-of-function triggered by the development of inhibitory anti-PLA2R auto-antibodies. The rationale for these studies is that a detailed understanding of the phenotypic consequences of the complete PLA2R1 deficiency is a powerful tool to unveil the actual biological roles of human PLA2R using human genetics. This collaborative research project is highly responsive to RFA-HL-23- 018 because it will leverage unique resources from the NHLBI BioLINCC biorepository (DNA and plasma specimens from the ACCESS study) to investigate a novel genetic cause of sarcoidosis in African-Americans. The proposed research is innovative because it would represent the first example of a monogenic cause of sarcoidosis, while providing insights into novel unexpected biological functions of human PLA2R1. This research is significant because genetic PLA2R deficiency could explain as many as 4% of all cases of sarcoidosis in African-Americans, which is highly relevant to understanding health disparities in this disease.