The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
复制标题
膜性肾病的遗传结构及其改善非侵入性诊断的潜力
DOI：
10.1038/s41467-020-15383-w
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发表时间：
2020-03-30
影响因子：
16.6
通讯作者：
Kiryluk, Krzysztof
中科院分区：
文献类型：
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作者：
Xie, Jingyuan;Liu, Lili;Kiryluk, Krzysztof
膜性肾病（MN）是一种罕见的由自身免疫导致肾衰竭的病因。在此，我们报告一项针对原发性膜性肾病的全基因组关联研究（GWAS），研究对象包括3782例东亚和欧洲血统的患者以及9038例对照。我们发现了两个此前未报道过的基因座，即NFKB1（rs230540，优势比 = 1.25，P = 3.4×10⁻¹²）和IRF4（rs9405192，优势比 = 1.29，P = 1.4×10⁻¹⁴），对PLA2R1基因座进行了精细定位（rs17831251，优势比 = 2.25，P = 4.7×10⁻¹⁰³），并报告了三个经典HLA等位基因的种族特异性效应：东亚人中的DRB1*1501（优势比 = 3.81，P = 2.0×10⁻⁴⁹）、欧洲人中的DQA1*0501（优势比 = 2.88，P = 5.7×10⁻⁹³），以及两个种族中的DRB1*0301（优势比分别为3.50，P = 9.2×10⁻²³和优势比 = 3.39，P = 5.2×10⁻⁸²）。GWAS基因座可解释东亚人32%的疾病风险和欧洲人25%的疾病风险，并且在验证队列中，对于血清抗PLA2R ELISA诊断测试抗体呈阴性的病例，能够正确重新分类20% - 37%。我们的研究结果凸显了膜性肾病不同寻常的遗传结构，四个基因座及其相互作用几乎占了疾病风险的三分之一。
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.