Risk HLA-DQA1 and PLA(sub 2)R1 Alleles in Idiopathic Membranous Nephropathy.
Risk HLA-DQA1 and PLA(sub 2)R1 Alleles in Idiopathic Membranous Nephropathy.
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DOI：
10.1056/nejmoa1009742
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发表时间：
2011-02-17
影响因子：
158.5
通讯作者：
Kleta, Robert
中科院分区：
文献类型：
--
作者：
Stanescu, Horia C.;Arcos-Burgos, Mauricio;Kleta, Robert
背景：特发性膜性肾病是成人肾病综合征的主要病因，但其病因学基础尚不完全清楚。我们调查的遗传基础的活检证实的特发性膜性肾病的情况下，白人人群。方法：我们对特发性膜性肾病患者的单核苷酸多态性（snp）进行了独立的全基因组关联研究，这些患者来自三个白人血统人群（75名法国人，146名荷兰人和335名英国人）。将患者与种族匹配的对照组进行比较；按标准进行人口分层和质量控制。通过卡方基本等位基因检验计算关联；对显著性阈值进行多次比较调整（使用Bonferroni方法）。结果：在对556名患者（398名男性）的数据进行的联合分析中，我们在两个与特发性膜性肾病相关的基因组位点上发现了显著的等位基因。染色体2q24包含编码m型磷脂酶A（亚2）受体（PLA（亚2）R1）的基因（SNP rs4664308， P=8.6 x 10(sup -29)），先前被证明是自身免疫反应的靶标。6p21染色体含有编码HLA复合体II类HLA- dq α链1 （HLA- dqa1）的基因（SNP rs2187668， P=8.0 × 10(sup -93)）。与HLA-DQA1的关联在所有三个人群中都是显著的（分别在法国、荷兰和英国人群中P=1.8 x 10（sup -9）、P=5.6 x 10（sup -27）和P=5.2 x 10(sup -36)）。特发性膜性肾病两种风险等位基因纯合子的优势比为78.5（95%可信区间为34.6 - 178.2）。结论：6p21染色体上的HLA-DQA1等位基因与白人血统的特发性膜性肾病最密切相关。该等位基因可能促进针对目标（如PLA2R1变体）的自身免疫反应。我们的发现为理解这种疾病提供了基础，并阐明了HLA如何调节适应性免疫。中华医学杂志（英文版）；2011;31(4):616- 626。
Background: Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population.Methods: We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method).Results: In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(sub 2) receptor (PLA(sub 2)R1) (SNP rs4664308, P=8.6 x 10(sup -29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0 x 10(sup -93)). The association with HLA-DQA1 was significant in all three populations (P=1.8 x 10(sup -9), P=5.6 x 10(sup -27), and P=5.2 x 10(sup -36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2).Conclusions: An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA.N Engl J Med 2011;364:616-26.