The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
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Xie, Jingyuan | Liu, Lili | Mladkova, Nikol | Li, Yifu | Ren, Hong | Wang, Weiming | Cui, Zhao | Lin, Li | Hu, Xiaofan | Yu, Xialian | Xu, Jing | Liu, Gang | Caliskan, Yasar | Sidore, Carlo | Balderes, Olivia | Rosen, Raphael | Bodria, Monica | Zanoni, Francesca | Zhang, Jun | Krithivasan, Priya | Mehl, Karla | Marasa, Maddalena | Khan, Atlas | Ozay, Fatih | Canetta, Pietro | Bomback, Andrew | Appel, Gerald | Sanna-Cherchi, Simone | Sampson, Matthew | Mariani, Laura | Perkowska-Ptasinska, Agnieszka | Durlik, Magdalena | Mucha, Krzysztof | Moszczuk, Barbara | Foroncewicz, Bartosz | Pączek, Leszek | Habura, Ireneusz | Ars, Elisabet | Ballarin, Jose | Mani, Laila-Yasmin | Vogt, Bruno | Ozturk, Savas | Yildiz, Abdülmecit | Seyahi, Nurhan | Arikan, Hakki | Koc, Mehmet | 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 | Marcantoni, Carmelita | Messa, Piergiorgio | Galliani, Marco | Roccatello, Dario | Granata, Simona | 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 | Fervenza, Fernando | Pani, Antonello | Hamilton, Patrick | Harris, Shelly | Gupta, Sanjana | Cheshire, Chris | Dufek, Stephanie | Issler, Naomi | Pepper, Ruth | Connolly, John | Powis, Stephen | Bockenhauer, Detlef | Stanescu, Horia | Ashman, Neil | Loos, Ruth | Kenny, Eimear | Wuttke, Matthias | Eckardt, Kai-Uwe | Köttgen, Anna | Hofstra, Julia | Coenen, Marieke | Kiemeney, Lambertus | Akilesh, Shreeram | Kretzler, Matthias | Beck, Lawrence | Stengel, Benedicte | Debiec, Hanna | Ronco, Pierre | Wetzels, Jack | Zoledziewska, Magdalena | Cucca, Francesco | Ionita-Laza, Iuliana | Lee, Hajeong | Hoxha, Elion | Stahl, Rolf | Brenchley, Paul | Scolari, Francesco | Zhao, Ming-Hui | Gharavi, Ali | Kleta, Robert | Chen, Nan | Kiryluk, Krzysztof
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Abstract 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.
