PLA2R1 Gene as a Novel SLE Susceptibility Locus: Mechanistic Insights from African-Specific, Common Loss-of-Function Variant
Abstract
Systemic lupus erythematosus (SLE) is a devastating disease in which a malfunctioning of immune system attacks organs such as the kidneys, with life threatening consequences. The disease affects up to 1.5 million Americans, mostly women of child-bearing age. Lupus is more common and severe in African-Americans, who are three times more likely to develop lupus than Caucasians. Genetic predisposition is a major lupus risk factor. Genetic association studies have identified about 40 gene variants that affect lupus susceptibility, mainly in people of European ancestry, but no variants are yet known that modify lupus risk specifically in African-Americans. We have discovered a PLA2R1 gene variant uniquely found in people of African ancestry, which is present in about 18% of African-Americans and is associated with two-fold lower risk of lupus. The PLA2R1 gene encodes the phospholipase A2 receptor (PLA2R), a cell membrane-bound protein that acts as a clearance receptor for its sPLA2 ligands (enzymes that generate inflammatory lipid mediators) and promotes cell death. PLA2R1 expressed in kidney cells is the major target autoantigen in membranous nephropathy, an autoimmune kidney disease. Although PLA2R protein belongs to a family of pattern recognition receptors that are involved in immune regulation, the roles of human PLA2R in the immune system function are completely unknown. The objectives of this research proposal are to establish that the PLA2R1 gene is a novel genetic risk factor for lupus and to understand how the African PLA2R1 variant protects against lupus. The rationale for the proposed research is that current therapies for lupus are non-specific, have toxic side effects, and too often fail to improve disease. Thus, more effective drugs for lupus are urgently needed. Our aims will address three key questions, helping to build the foundation for future drug development: (1) Precisely how much does the African PLA2R1 variant protect against lupus? (2) Does the variant increases or decreases the risk of other diseases, and if so which ones? (3) How does the African PLA2R1 variant protect against lupus in African-Americans? Relationship to specific Fiscal Year 2019 (FY19) Focus Areas of Lupus Research Program. This proposal addresses how lupus heterogeneity (i.e., PLA2R1 gene variants) impacts the risk of disease (FY19 LRP Focus Area #1), how the underlying genetic components relate to clinical disease characteristics (Focus Area #4), and disease mechanisms (Focus Area #2). The ultimate applicability of the research. The role of PLA2R in lupus and the effect of PLA2R1 variants on lupus risk have been hitherto unknown. Therefore, our proposed research will advance basic lupus research by identifying new molecules and pathways that contribute to lupus. Moreover, our research will also advance translational lupus research by identifying new targets for drugs to prevent or treat lupus in African-Americans. What types of patients will it help and, how? Only about 18% of African-Americans carry the lupus-protective PLA2R1 variant, a low-risk genotype. For the remaining 82% of African-Americans who have the high-risk genotype (as many as 32 million people within the United States), novel therapies that can reproduce the protective effects of the African PLA2R1 variant would decrease the risk of lupus by about half. What are the potential clinical applications, benefits, and risks? The African-specific PLA2R1 gene variant prevents the expression of a functional membrane-bound PLA2R protein. This is a rare experiment of nature that can provide unique insights into the biological roles of PLA2R. This variant has revealed an unexpected role of PLA2R in lupus. Once we learn how the African-specific PLA2R1 variant protects against lupus, we can start designing new lupus drugs that target PLA2R in a manner that mimics the effects of the lupus-protective PLA2R1 variant. The risks of PLA2R-targeting therapies are lik
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010698
Entities
People
- Dorin-Bogdan Borza
Organizations
- Meharry Medical College
- United States Army