A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults.
• MN is characterized by autoantibodies against glomerular antigens, primarily phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A).
• Genetic variations in loci including PLA2R1, HLA-DRB1, HLA-DQA1, IRF4, and NFKB1 influence MN risk in Europeans.

Purpose of the Study:

• To investigate genetic risk differences in membranous nephropathy (MN) based on autoantibody status.
• To determine if genetic risk scores (GRS) differentiate between PLA2R1-positive, THSD7A-positive, and antibody-negative MN.

Main Methods:

• Genome-wide genotyping of 1,409 MN individuals using a dense SNV array.
• Calculation of a genetic risk score (GRS) based on established European MN loci.
• Comparison of GRS in MN patients with known antibody status against healthy controls and individuals with steroid-sensitive nephrotic syndrome.

Main Results:

• The GRS was significantly elevated in anti-PLA2R1 antibody-positive MN patients compared to controls and anti-THSD7A-positive patients.
• A higher GRS was inversely correlated with younger age of disease onset in PLA2R1-positive MN.
• Individuals with antibody-negative MN exhibited an intermediate GRS, suggesting potential underlying PLA2R1 autoimmunity in some cases.

Conclusions:

• Genetic risk factors for PLA2R1- and THSD7A-associated MN are distinct.
• Elevated GRS in a subset of antibody-negative MN cases indicates possible PLA2R1 autoimmunity.
• Genetic risk profiling may aid in understanding MN pathogenesis and patient stratification.