1. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
- Author
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Xie, J, Liu, L., Mladkova, N., Li, Yifu, Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X, Xu, J, Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R.J., Bodria, M., Zanoni, F., Zhang, J.Y., Krithivasan, P., Mehl, K., Marasa, M., Khan, A., Ozay, F., Canetta, P.A., Bomback, A.S., Appel, G.B., Sanna-Cherchi, S., Sampson, M.G., Mariani, L.H., Perkowska-Ptasinska, A., Durlik, M., Mucha, K., Moszczuk, B., Foroncewicz, B., Paczek, L., Habura, I., Ars, E., Ballarin, J., Mani, L.Y., Vogt, B., Ozturk, S., Yildiz, A., Seyahi, N., Arikan, H., Koc, M., Basturk, T., Karahan, G., Akgul, S.U., Sever, M.S., Zhang, D., Santoro, D., Bonomini, M., Londrino, F., Gesualdo, L., Reiterova, J., Tesar, V., Izzi, C., Savoldi, S., Spotti, D., Marcantoni, C., Messa, P., Galliani, M., Roccatello, D., Granata, S., Zaza, G., Lugani, F., Ghiggeri, G., Pisani, I., Allegri, L., Sprangers, B., Park, J.H., Cho, B., Kim, Y.S., Kim, D.K., Suzuki, H, Amoroso, A., Cattran, D.C., Fervenza, F.C., Pani, A., Hamilton, P., Harris, S., Gupta, S., Cheshire, C., Dufek, S., Issler, N., Pepper, R.J., Connolly, J., Powis, S., Bockenhauer, D., Stanescu, H.C., Ashman, N., Loos, R.J., Kenny, E.E., Wuttke, M., Eckardt, K.U., Kottgen, A., Hofstra, J.M., Coenen, M.J.H., Kiemeney, L.A.L.M., Wetzels, J., Chen, N., Kiryluk, K., Xie, J, Liu, L., Mladkova, N., Li, Yifu, Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X, Xu, J, Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R.J., Bodria, M., Zanoni, F., Zhang, J.Y., Krithivasan, P., Mehl, K., Marasa, M., Khan, A., Ozay, F., Canetta, P.A., Bomback, A.S., Appel, G.B., Sanna-Cherchi, S., Sampson, M.G., Mariani, L.H., Perkowska-Ptasinska, A., Durlik, M., Mucha, K., Moszczuk, B., Foroncewicz, B., Paczek, L., Habura, I., Ars, E., Ballarin, J., Mani, L.Y., Vogt, B., Ozturk, S., Yildiz, A., Seyahi, N., Arikan, H., Koc, M., Basturk, T., Karahan, G., Akgul, S.U., Sever, M.S., Zhang, D., Santoro, D., Bonomini, M., Londrino, F., Gesualdo, L., Reiterova, J., Tesar, V., Izzi, C., Savoldi, S., Spotti, D., Marcantoni, C., Messa, P., Galliani, M., Roccatello, D., Granata, S., Zaza, G., Lugani, F., Ghiggeri, G., Pisani, I., Allegri, L., Sprangers, B., Park, J.H., Cho, B., Kim, Y.S., Kim, D.K., Suzuki, H, Amoroso, A., Cattran, D.C., Fervenza, F.C., Pani, A., Hamilton, P., Harris, S., Gupta, S., Cheshire, C., Dufek, S., Issler, N., Pepper, R.J., Connolly, J., Powis, S., Bockenhauer, D., Stanescu, H.C., Ashman, N., Loos, R.J., Kenny, E.E., Wuttke, M., Eckardt, K.U., Kottgen, A., Hofstra, J.M., Coenen, M.J.H., Kiemeney, L.A.L.M., Wetzels, J., Chen, N., and Kiryluk, K.
- Abstract
Contains fulltext : 220480.pdf (publisher's version ) (Open Access), 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.
- Published
- 2020