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. 2023 Mar 13;3(1):116-125.
doi: 10.1159/000529959. eCollection 2023 Jan-Dec.

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

Sanjana Gupta  1 , Mallory Lorraine Downie  1 , Chris Cheshire  1 , Stephanie Dufek-Kamperis  1 , Adam Paul Levine  1   2 , Paul Brenchley  3 , Elion Hoxha  4 , Rolf Stahl  4 , Neil Ashman  5 , Ruth Jennifer Pepper  1 , Sean Mason  6 , Jill Norman  1 , Detlef Bockenhauer  1 , Horia Constantin Stanescu  1 , Robert Kleta  1 , Daniel Philip Gale  1
Affiliations

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

Sanjana Gupta et al. Glomerular Dis. .

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, affects the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states.

Methods: 1,409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilizing the previously identified European MN loci, and results were compared with 4,929 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 = 4,929) 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.

Keywords: Autoantibody; Genetic risk score; Membranous nephropathy; Phospholipase A2 receptor 1; Thrombospondin type-1 domain containing 7A.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1.
Fig. 1.
The genetic risk score (GRS) is associated with a diagnosis of MN and distinguishes between the different antibody types. The number of individuals in each group is shown. The black dot represents the median. Statistically significant differences (using a Kruskal-Wallis test) from Controls are highlighted by blue braces (p < 0.0001). Statistically significant differences from PLA2RPos are highlighted by red braces (p < 0.0001). SSNS, steroid-sensitive nephrotic syndrome; PLA2RPos, anti-PLA2R1 antibody-positive MN; THSD7APos, anti-THSD7A antibody-positive MN; DualNeg, PLA2R1 and THSD7A antibody-negative MN.
Fig. 2.
Fig. 2.
The genetic risk score is associated with age of onset in anti-PLA2R1 antibody membranous nephropathy. Linear regression of genetic risk score and the age of onset of anti-PLA2R1 antibody membranous nephropathy in a German European cohort, n = 224, p = 0.009. The red line demonstrates the line of best fit for the model; Y = −0.002 × +0.41, and the shaded grey area demonstrates the standard error of the estimate (+/− 0.03).
See this image and copyright information in PMC

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