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

Xie, J.; Liu, L.; Mladkova, N.; Li, Y.; 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.-.; 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.M.; Pisani, I.; Allegri, L.; Sprangers, B.; Park, J.-.; Cho, B.L.; 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.F.; Kenny, E.E.; Wuttke, M.; Eckardt, K.-.; Kottgen, A.; Hofstra, J.M.; Coenen, M.J.H.; Kiemeney, L.A.; Akilesh, S.; Kretzler, M.; Beck, L.H.; Stengel, B.; Debiec, H.; Ronco, P.; Wetzels, J.F.M.; Zoledziewska, M.; Cucca, F.; Ionita-Laza, I.; Lee, H.; Hoxha, E.; Stahl, R.A.K.; Brenchley, P.; Scolari, F.; Zhao, M.-.; Gharavi, A.G.; Kleta, R.; Chen, N.; Kiryluk, K.

doi:10.1038/s41467-020-15383-w

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.

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis / J. Xie, L. Liu, N. Mladkova, Y. Li, H. Ren, W. Wang, Z. Cui, L. Lin, X. Hu, X. Yu, J. Xu, G. Liu, Y. Caliskan, C. Sidore, O. Balderes, R.J. Rosen, M. Bodria, F. Zanoni, J.Y. Zhang, P. Krithivasan, K. Mehl, M. Marasa, A. Khan, F. Ozay, P.A. Canetta, A.S. Bomback, G.B. Appel, S. Sanna-Cherchi, M.G. Sampson, L.H. Mariani, A. Perkowska-Ptasinska, M. Durlik, K. Mucha, B. Moszczuk, B. Foroncewicz, L. Paczek, I. Habura, E. Ars, J. Ballarin, L.-. Mani, B. Vogt, S. Ozturk, A. Yildiz, N. Seyahi, H. Arikan, M. Koc, T. Basturk, G. Karahan, S.U. Akgul, M.S. Sever, D. Zhang, D. Santoro, M. Bonomini, F. Londrino, L. Gesualdo, J. Reiterova, V. Tesar, C. Izzi, S. Savoldi, D. Spotti, C. Marcantoni, P. Messa, M. Galliani, D. Roccatello, S. Granata, G. Zaza, F. Lugani, G.M. Ghiggeri, I. Pisani, L. Allegri, B. Sprangers, J.-. Park, B.L. Cho, Y.S. Kim, D.K. Kim, H. Suzuki, A. Amoroso, D.C. Cattran, F.C. Fervenza, A. Pani, P. Hamilton, S. Harris, S. Gupta, C. Cheshire, S. Dufek, N. Issler, R.J. Pepper, J. Connolly, S. Powis, D. Bockenhauer, H.C. Stanescu, N. Ashman, R.J.F. Loos, E.E. Kenny, M. Wuttke, K.-. Eckardt, A. Kottgen, J.M. Hofstra, M.J.H. Coenen, L.A. Kiemeney, S. Akilesh, M. Kretzler, L.H. Beck, B. Stengel, H. Debiec, P. Ronco, J.F.M. Wetzels, M. Zoledziewska, F. Cucca, I. Ionita-Laza, H. Lee, E. Hoxha, R.A.K. Stahl, P. Brenchley, F. Scolari, M.-. Zhao, A.G. Gharavi, R. Kleta, N. Chen, K. Kiryluk. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020 Mar 30), pp. 1600.1-1600.18.

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

Xie J.;Liu L.;Mladkova N.;Li Y.;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.;P. Messa;Galliani M.;Roccatello D.;Granata S.;Zaza G.;Lugani F.;Ghiggeri G. M.;Pisani I.;Allegri L.;Sprangers B.;Park J. -H.;Cho B. L.;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. F.;Kenny E. E.;Wuttke M.;Eckardt K. -U.;Kottgen A.;Hofstra J. M.;Coenen M. J. H.;Kiemeney L. A.;Akilesh S.;Kretzler M.;Beck L. H.;Stengel B.;Debiec H.;Ronco P.;Wetzels J. F. M.;Zoledziewska M.;Cucca F.;Ionita-Laza I.;Lee H.;Hoxha E.;Stahl R. A. K.;Brenchley P.;Scolari F.;Zhao M. -H.;Gharavi A. G.;Kleta R.;Chen N.;Kiryluk K.

2020

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.

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				Settore MED/14 - Nefrologia
			
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				30-mar-2020
			
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				NATURE COMMUNICATIONS
			
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				https://dx.doi.org/10.1038/s41467-020-15383-w
			
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