Identification of potential therapeutic targets for complement-associated glomerular diseases using Mendelian...

Area of Science:

• Immunology
• Nephrology
• Genetics

Background:

• The complement system is integral to innate immunity and implicated in glomerular diseases.
• Uncontrolled complement activation contributes to IgA nephropathy (IgAN), membranous nephropathy (MN), and diabetic nephropathy (DN).

Purpose of the Study:

• To investigate the causal role of complement components in IgAN, MN, and DN using Mendelian randomization.
• To identify potential therapeutic targets within complement pathways for these kidney diseases.

Main Methods:

• Mendelian randomization analysis utilizing protein Quantitative Trait Loci data.
• Gene expression analysis, protein-protein interaction networks, and enrichment analysis were performed.
• Investigated causal associations between complement proteins and IgAN, MN, and DN.

Main Results:

• Genetically elevated complement factor H-related protein 1 (CFHR1) showed a causal link to increased IgAN risk (OR 1.239).
• CFHR1 expression was found in renal T cells and plasma cells, with its network enriched in immune pathways.
• Genetically elevated complement factor D (CFD) was causally associated with increased DN risk (OR 1.264).
• CFD expression was observed in renal macrophages, and its network involved inflammatory processes.
• No significant causal associations were found for complement proteins with MN after FDR correction.

Conclusions:

• Elevated CFHR1 is causally associated with IgA nephropathy risk.
• Elevated CFD is causally associated with diabetic nephropathy risk.
• Targeting complement regulators CFHR1 and CFD presents potential therapeutic strategies for IgAN and DN.