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

Abstract

=Introduction: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults and is characterized by detectable autoantibodies against glomerular antigens, most commonly phospholipase A2 receptor-1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A). In Europeans genetic variation in at least five loci, PLA2R1, HLA-DRB1, HLA-DQA1, IRF4 and NFKB1 affect the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states. Methods: 1409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilising the previously identified European MN loci and results were compared with 4929 healthy controls and 422 individuals with steroid sensitive nephrotic syndrome. Results: GRS was calculated in the 759 MN individuals in whom antibody status was known. The GRS for MN was elevated in the anti-PLA2R1 antibody positive (N=372) compared with both the unaffected control (N=4929) and anti-THSD7A positive (N=31) groups (p<0.0001 for both comparisons), suggesting that this GRS reflects anti-PLA2R1 MN. Among PLA2R1 positive patients, GRS was inversely correlated with age of disease onset (p=0.009). Further, the GRS in the dual antibody negative group (N=355) was intermediate between controls and the PLA2R1 positive group (p<0.0001). Conclusion: We demonstrate that the genetic risk factors for PLA2R1- and THSD7A-antibody associated MN are different. A higher GRS is associated with younger age of onset of disease. Further, a proportion of antibody negative MN cases have an elevated GRS similar to PLA2R1-positive disease. This suggests that in some individuals with negative serology the disease is driven by autoimmunity against PLA2R1.