The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
Tarih
2020Yazar
Sidore, Carlo
Cattran, Daniel C.
Fervenza, Fernando C.
Pani, Antonello
Hamilton, Patrick
Akilesh, Shreeram
Kretzler, Matthias
Beck, Lawrence H.
Stengel, Benedicte
Debiec, Hanna
Ronco, Pierre
Wetzels, Jack F. M.
Zoledziewska, Magdalena
Cucca, Francesco
Ionita-Laza, Iuliana
Lee, Hajeong
Hoxha, Elion
Stahl, Rolf A. K.
Brenchley, Paul
Scolari, Francesco
Zhao, Ming-hui
Gharavi, Ali G.
Kleta, Robert
Chen, Nan
Kiryluk, Krzysztof
Liu, Lili
Xie, Jingyuan
Gupta, Sanjana
Cheshire, Chris
Dufek, Stephanie
Issler, Naomi
Pepper, Ruth J.
Connolly, John
Powis, Stephen
Bockenhauer, Detlef
Stanescu, Horia C.
Ashman, Neil
Loos, Ruth J. F.
Kenny, Eimear E.
Wuttke, Matthias
Eckardt, Kai-Uwe
Koettgen, Anna
Hofstra, Julia M.
Coenen, Marieke J. H.
Kiemeney, Lambertus A.
Mladkova, Nikol
Li, Yifu
Ren, Hong
Wang, Weiming
Cui, Zhao
Lin, Li
Hu, Xiaofan
Yu, Xialian
Xu, Jing
Liu, Gang
Caliskan, Yasar
Balderes, Olivia
Rosen, Raphael J.
Bodria, Monica
Zanoni, Francesca
Zhang, Jun Y.
Krithivasan, Priya
Mehl, Karla
Marasa, Maddalena
Khan, Atlas
Ozay, Fatih
Canetta, Pietro A.
Bomback, Andrew S.
Appel, Gerald B.
Sanna-Cherchi, Simone
Sampson, Matthew G.
Mariani, Laura H.
Perkowska-Ptasinska, Agnieszka
Durlik, Magdalena
Mucha, Krzysztof
Moszczuk, Barbara
Foroncewicz, Bartosz
Paczek, Leszek
Habura, Ireneusz
Ars, Elisabet
Ballarin, Jose
Mani, Laila-Yasmin
Vogt, Bruno
Ozturk, Savas
Harris, Shelly
YILDIZ, ABDULMECİT
SEYAHİ, Nurhan
Arikan, Hakki
KOÇ, 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
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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 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 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.
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