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

PLA2R1 功能丧失：ACCESS 队列中非裔美国人结节病的单基因原因

• 批准号: 10651396
• 负责人: DORIN-BOGDAN BORZA
• 金额: $ 10.91万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651396
• 关键词: Affect; African American; African American population; African ancestry; American; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune; Biological; Biological Process; Candidate Disease Gene; Chronic; DNA; Development; Disease; Environmental Risk Factor; Epithelial Cells; Etiology; Family; Genes; Genetic; Goals; Granulomatous disease; Human; Human Genetics; Immune; Integral Membrane Protein; Kidney; Kidney Diseases; Lung; Mediating; Membranous Glomerulonephritis; Mycobacterium tuberculosis; National Heart, Lung, and Blood Institute; Natural Immunity; Organ; Pathway interactions; Phenotype; Phospholipase A2; Plasma; Predisposition; Proxy; Pulmonary Fibrosis; Research; Research Project Grants; Resources; Risk; Role; Sarcoidosis; Serology; Specimen; Testing; Tuberculosis; Universities; Validation; Variant; Woman; biobank; case control; cohort; genetic architecture; genetic association; genetic variant; health disparity; high risk; innovation; insight; latent infection; loss of function; mannose receptor; mycobacterial; novel; pathogenic autoantibodies; phenome; receptor; tool

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.

项目摘要/摘要 结节病是一种病因不明的慢性多器官肉芽肿性疾病，其典型特征是 由于肺部受累，这对非裔美国女性的影响不成比例。结节病被认为是 在遗传易感宿主的环境中由环境因素引起的。虽然结节病有一种 尽管存在显著的遗传基础，但结节病风险的遗传结构并不明确。在初步研究中， PI的团队使用范德比尔特大学的 基因生物库(BioVU)调查非洲血统特有的-1基因缺失的表型后果 PLA2R1基因功能移码变异体。PLA2R1编码磷脂酶A2受体(PLA2R)，a 来自甘露糖受体家族的跨膜蛋白，其生物学功能尚不清楚。 我们出人意料地发现，PLA2R1移码变体纯合子的非裔美国人 患结节病的风险增加约5倍，患结核病的风险增加约10倍。这项研究的目的是 通过分析《病例对照》中的生物标本来证实和扩展这些初步发现 结节病的病因学研究(ACCESS)“作为一个独立的验证队列。我们的中心假设是 在ACCESS研究中，PLA2R1缺乏在一定程度上增加了非裔美国人患结节病的风险 通过增加对结核分枝杆菌潜伏感染的易感性。目标1A中建议的研究 寻求证实PLA2R1基因缺失是非洲裔美国人结节病的单基因原因 访问研究。目标1B将确定PLA2R1基因缺陷是否会增加结节病的风险 特别是在有潜在结核病感染的非裔美国人中。目标2将决定是否 结节病可能由获得性PLA2R功能丧失触发，该功能丧失是由抑制性疾病的发展引起的 抗PLA2R自身抗体。这些研究的基本原理是，对表型的详细理解 PLA2R1完全缺乏的后果是揭示PLA2R1实际生物学作用的有力工具 利用人类遗传学研究人类PLA2R。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生物存储库(DNA和血浆)的独特资源 来自ACCESS研究的样本)，以调查非裔美国人结节病的一种新的遗传原因。 这项拟议的研究具有创新性，因为它将代表第一个单基因致病原因的例子 结节病，同时提供了对人类PLA2R1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PLA2R缺陷可以解释多达4%的 非裔美国人的结节病，这与了解这种疾病的健康差异高度相关。