Nature Communications ( IF 16.6 ) Pub Date : 2020-03-30 , DOI: 10.1038/s41467-020-15383-w Jingyuan Xie 1 , Lili Liu 2 , Nikol Mladkova 2 , Yifu Li 2 , Hong Ren 1 , Weiming Wang 1 , Zhao Cui 3, 4, 5 , Li Lin 1 , Xiaofan Hu 1 , Xialian Yu 1 , Jing Xu 1 , Gang Liu 3, 4, 5 , Yasar Caliskan 6 , Carlo Sidore 7 , Olivia Balderes 2 , Raphael J Rosen 2 , Monica Bodria 2, 8 , Francesca Zanoni 2, 9 , Jun Y Zhang 2 , Priya Krithivasan 2 , Karla Mehl 2 , Maddalena Marasa 2 , Atlas Khan 2 , Fatih Ozay 2 , Pietro A Canetta 2 , Andrew S Bomback 2 , Gerald B Appel 2 , Simone Sanna-Cherchi 2 , Matthew G Sampson 10 , Laura H Mariani 11, 12 , Agnieszka Perkowska-Ptasinska 13 , Magdalena Durlik 13 , Krzysztof Mucha 14, 15 , Barbara Moszczuk 14 , Bartosz Foroncewicz 14 , Leszek Pączek 14, 15 , Ireneusz Habura 16 , Elisabet Ars 17 , Jose Ballarin 17 , Laila-Yasmin Mani 18 , Bruno Vogt 18 , Savas Ozturk 19 , Abdülmecit Yildiz 20 , Nurhan Seyahi 21 , Hakki Arikan 22 , Mehmet Koc 22 , Taner Basturk 23 , Gonca Karahan 24 , Sebahat Usta Akgul 24 , Mehmet Sukru Sever 6 , Dan Zhang 25 , Domenico Santoro 26 , Mario Bonomini 27 , Francesco Londrino 28 , Loreto Gesualdo 29 , Jana Reiterova 30 , Vladimir Tesar 30 , Claudia Izzi 31, 32 , Silvana Savoldi 33 , Donatella Spotti 34 , Carmelita Marcantoni 35 , Piergiorgio Messa 9 , Marco Galliani 36 , Dario Roccatello 37 , Simona Granata 38 , Gianluigi Zaza 38 , Francesca Lugani 39 , GianMarco Ghiggeri 39 , Isabella Pisani 8 , Landino Allegri 8 , Ben Sprangers 40, 41 , Jin-Ho Park 42 , BeLong Cho 42, 43 , Yon Su Kim 44, 45 , Dong Ki Kim 45, 46 , Hitoshi Suzuki 47 , Antonio Amoroso 48 , Daniel C Cattran 49 , Fernando C Fervenza 50 , Antonello Pani 51 , Patrick Hamilton 52 , Shelly Harris 52 , Sanjana Gupta 53 , Chris Cheshire 53 , Stephanie Dufek 53 , Naomi Issler 53 , Ruth J Pepper 53 , John Connolly 53 , Stephen Powis 53 , Detlef Bockenhauer 53 , Horia C Stanescu 53 , Neil Ashman 54 , Ruth J F Loos 55, 56, 57 , Eimear E Kenny 55, 58, 59 , Matthias Wuttke 60 , Kai-Uwe Eckardt 61, 62 , Anna Köttgen 60 , Julia M Hofstra 63 , Marieke J H Coenen 64 , Lambertus A Kiemeney 65 , Shreeram Akilesh 66 , Matthias Kretzler 11 , Lawrence H Beck 67 , Benedicte Stengel 68, 69 , Hanna Debiec 70 , Pierre Ronco 70, 71 , Jack F M Wetzels 63 , Magdalena Zoledziewska 7 , Francesco Cucca 7 , Iuliana Ionita-Laza 72 , Hajeong Lee 45, 46 , Elion Hoxha 73 , Rolf A K Stahl 73 , Paul Brenchley 74 , Francesco Scolari 31, 75 , Ming-Hui Zhao 3, 4, 5, 76 , Ali G Gharavi 2 , Robert Kleta 53 , Nan Chen 1 , Krzysztof Kiryluk 2
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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 × 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.
中文翻译：
膜性肾病的遗传结构及其改进无创诊断的潜力。
膜性肾病 (MN) 是一种罕见的自身免疫性肾衰竭病因。在这里，我们报告了 3,782 例原发性 MN 的全基因组关联研究 (GWAS) 和 9,038 例东亚和欧洲血统的对照。我们发现了两个以前未报告的位点，NFKB1（ rs230540，OR = 1.25，P = 3.4 × 10 -12）和IRF4（ rs9405192，OR = 1.29，P = 1.4 × 10 -14），精细定位PLA2R1位点( rs17831251, OR = 2.25, P = 4.7 × 10 −103 ) 并报告三个经典 HLA 等位基因的祖先特异性效应：东亚人中的DRB1*1501 (OR = 3.81, P = 2.0 × 10 −49 ),欧洲人中的DQA1*0501 （OR = 2.88， P = 5.7 × 10 -93），两个种族中的DRB1*0301 （OR = 3.50， P = 9.2 × 10 -23和 OR = 3.39，P = 5.2 × 10 -82， 分别）。GWAS 位点解释了东亚人 32% 的疾病风险和欧洲人 25% 的疾病风险，并正确地重新分类了验证队列中 20-37% 的病例，这些病例在血清抗 PLA2R ELISA 诊断测试中呈抗体阴性。我们的研究结果突出了 MN 的一个不寻常的遗传结构，四个位点及其相互作用占疾病风险的近三分之一。
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