The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 1...

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Hauptverfasser: Liu, Lili, Mladkova, Nikol, Li, Yifu, Ren, Hong, Wang, Weiming, Cui, Zhao, Lin, Li, Yu, Xialian, Xu, Jing, Sidore, Carlo, Balderes, Olivia, Rosen, Raphael J, Zanoni, Francesca, Zhang, Jun Y, Marasa, Maddalena, Khan, Atlas, Ozay, Fatih, Canetta, Pietro A, Bomback, Andrew S, Appel, Gerald B, Sanna-Cherchi, Simone, Mariani, Laura H, Perkowska-Ptasinska, Agnieszka, Durlik, Magdalena, Mucha, Krzysztof, Moszczuk, Barbara, Foroncewicz, Bartosz, Pączek, Leszek, Habura, Ireneusz, Ars, Elisabet, Ballarín Castan, José Aurelio, Mani, Laila-Yasmin, Vogt, Bruno, Yildiz, Abdülmecit, Arikan, Hakki, Basturk, Taner, Karahan, Gonca, Akgul, Sebahat Usta, Sever, Mehmet Sukru, Zhang, Dan, Santoro, Domenico, Bonomini, Mario, Londrino, Francesco, Gesualdo, Loreto, Reiterova, Jana, Tesar, Vladimir, Izzi, Claudia, Savoldi, Silvana, Spotti, Donatella, Messa, Piergiorgio, Galliani, Marco, Roccatello, Dario, Zaza, Gianluigi, Lugani, Francesca, Ghiggeri, GianMarco, Pisani, Isabella, Allegri, Landino, Sprangers, Ben, Park, Jin-Ho, Cho, BeLong, Kim, Yon Su, Kim, Dong Ki, Suzuki, Hitoshi, Amoroso, Antonio, Cattran, Daniel C, Fervenza, Fernando C, Pani, Antonello, Hamilton, Patrick, Harris, Shelly, Gupta, Sanjana, Cheshire, Chris, Dufek, Stephanie, Issler, Naomi, Connolly, John, Stanescu, Horia C, Kenny, Eimear E, Wuttke, Matthias, Eckardt, Kai-Uwe, Köttgen, Anna, Hofstra, Julia M, Coenen, Marieke J. H, Kiemeney, Lambertus A, Kretzler, Matthias, Beck, Lawrence H, Debiec, Hanna, Ronco, Pierre, Wetzels, Jack F. M, Zoledziewska, Magdalena, Cucca, Francesco, Ionita-Laza, Iuliana, Lee, Hajeong, Hoxha, Elion, Stahl, Rolf A. K, Scolari, Francesco, Zhao, Ming-hui, Gharavi, Ali, Kleta, Robert, Chen, Nan, Kiryluk, Krzysztof, Universitat Autònoma de Barcelona
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Zusammenfassung:Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10 −12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10 −14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10 −103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10 −49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10 −93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10 −23 and OR = 3.39, P = 5.2 × 10 −82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk. Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.