PLA2R1 Loss-of-Function: A Monogenic Cause of Sarcoidosis in African-Americans in the ACCESS Cohort

项目总结/摘要 结节病是一种病因不明的慢性多器官肉芽肿性疾病， 肺部受累，这不成比例地影响非洲裔美国妇女。结节病被认为是 由遗传易感宿主环境中的环境因素引起。虽然结节病有一个 虽然结节病的遗传基础很重要，但结节病风险的遗传结构定义不清。在初步研究中， PI的研究小组利用范德比尔特大学的 基因生物库（BioVU），以调查非洲祖先特异性缺失的表型后果， PLA 2 R1基因中的功能移码变体。PLA 2 R1编码磷脂酶A2受体（PLA 2 R）， 来自甘露糖受体家族的跨膜蛋白，其生物学功能尚不清楚。 我们意外地发现，非裔美国人的PLA 2 R1移码变异纯合子， 患结节病的风险约高5倍，患结核病的风险高10倍。本研究的目的是 通过分析来自“病例控制”的生物标本， 结节病病因学研究（ACCESS）”作为独立验证队列。我们的核心假设是， 在ACCESS研究中，PLA 2 R1缺乏增加了非裔美国人患结节病的风险，部分原因是 通过增加对结核分枝杆菌潜伏感染的易感性。目标1A中提议的研究 试图验证遗传性PLA 2 R1缺陷是非洲裔美国人结节病的单基因原因， Access研究。目的1B将确定遗传性PLA 2 R1缺陷是否增加结节病风险 特别是在潜伏性结核病感染的非洲裔美国人中。目标2将决定是否 结节病可能是由获得性PLA 2 R功能丧失触发的，该功能丧失是由抑制性PLA 2 R的发展触发的。 抗PLA 2 R自身抗体。这些研究的基本原理是， 完全PLA 2 R1缺陷的后果是揭示PLA 2 R1的实际生物学作用的有力工具。 使用人类遗传学的人类PLA 2 R。该合作研究项目高度响应RFA-HL-23- 018，因为它将利用来自NHLBI BioLINCC生物储存库的独特资源（DNA和血浆 来自ACCESS研究的标本），以调查非洲裔美国人结节病的新遗传原因。 这项研究是创新的，因为它代表了第一个单基因原因的例子。 结节病，同时提供对人PLA 2 R1的新的意想不到的生物学功能的见解。这 这项研究意义重大，因为遗传性PLA 2 R缺陷可以解释多达4%的所有病例， 非裔美国人的结节病，这是高度相关的了解这种疾病的健康差距。

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.