Supplementary Material for: A genetic risk score distinguishes different types of autoantibody mediated membranous nephropathy

=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.

引言：膜性肾病（Membranous nephropathy, MN）是成人肾病综合征的首要病因，其特征为可检测到针对肾小球抗原的自身抗体，最常见的靶抗原为磷脂酶A2受体1（phospholipase A2 receptor-1, PLA2R1）与1型血小板反应蛋白结构域包含7A（thrombospondin type-1 domain containing 7A, THSD7A）。在欧洲人群中，PLA2R1、HLA-DRB1、HLA-DQA1、IRF4及NFKB1至少5个位点的遗传变异会影响疾病发病风险。本研究旨在探究不同自身抗体状态下的遗传风险差异。
研究方法：本研究对1409例MN患者开展高密度单核苷酸变异（SNV）芯片全基因组基因分型。利用此前已鉴定的欧洲人群MN相关位点计算遗传风险评分（genetic risk score, GRS），并将结果与4929名健康对照及422例激素敏感型肾病综合征（steroid sensitive nephrotic syndrome）患者进行对比分析。
研究结果：本研究对759例已知自身抗体状态的MN患者计算了GRS。抗PLA2R1抗体阳性组（N=372）的MN遗传风险评分显著高于健康对照组（N=4929）与抗THSD7A抗体阳性组（N=31），两组比较均p<0.0001，提示该GRS可特异性反映抗PLA2R1相关MN。在PLA2R1阳性患者中，GRS与疾病发病年龄呈负相关（p=0.009）。此外，双抗体阴性组（N=355）的GRS介于对照组与PLA2R1阳性组之间（p<0.0001）。
研究结论：本研究证实，与PLA2R1和THSD7A抗体相关的膜性肾病，其遗传危险因素存在显著差异。更高的GRS与更早的疾病发病年龄相关。此外，部分自身抗体阴性的MN患者具有与PLA2R1阳性患者相似的升高的GRS，这提示在部分血清学检测阴性的个体中，该病的发病机制由针对PLA2R1的自身免疫所驱动。