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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要结节病是一种病因不明的慢性多器官肉芽肿性疾病，其典型特征是肺部受累，这对非裔美国女性影响尤为严重。结节病被认为是由遗传易感宿主环境中的环境因素引起。虽然结节病有尽管存在重要的遗传基础，但结节病风险的遗传结构尚不清楚。在初步研究中， PI 团队利用范德比尔特大学的遗传生物库（BioVU）研究非洲血统特异性缺失的表型后果 PLA2R1 基因中的功能移码变体。 PLA2R1 编码磷脂酶 A2 受体 (PLA2R)，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 PLA2R1 移码变体纯合的非洲裔美国人患结节病的风险约高 5 倍，患结核病的风险约高 10 倍。这项研究的目的是通过分析“病例对照”中的生物样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 ACCESS 研究中，PLA2R1 缺陷在一定程度上增加了非洲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 中提出的研究试图验证遗传性 PLA2R1 缺陷是非洲裔美国人结节病的单基因原因访问研究。目标 1B 将确定遗传性 PLA2R1 缺陷是否会增加结节病风险特别是在患有潜伏性结核感染的非裔美国人中。目标 2 将确定是否结节病可能是由获得性 PLA2R 功能丧失引发的，而这种功能丧失是由抑制性的发展引发的抗 PLA2R 自身抗体。这些研究的基本原理是对表型的详细了解 PLA2R1 完全缺乏的后果是揭示其实际生物学作用的有力工具使用人类遗传学的人类 PLA2R。该合作研究项目对 RFA-HL-23- 高度响应 018 因为它将利用 NHLBI BioLINCC 生物样本库的独特资源（DNA 和血浆）来自 ACCESS 研究的标本）来调查非裔美国人结节病的新遗传原因。拟议的研究具有创新性，因为它将代表单基因原因的第一个例子结节病，同时提供对人类 PLA2R1 的新的意想不到的生物学功能的见解。这研究意义重大，因为遗传性 PLA2R 缺陷可以解释多达 4% 的病例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。