BACKGROUND Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. METHODS We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants. RESULTS Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10-8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10-8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure. CONCLUSIONS We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.

中文翻译：

---

大规模的全基因组测序揭示了原发性膜增生性GN和C3肾小球病的遗传结构。

背景技术原发性膜增生性GN，包括补体3（C3）肾小球病，是一种罕见的，无法治愈的肾脏疾病，其特征是肾小球补体沉积。补体基因突变可引起家族性C3肾小球病，并且研究报告了非家族性原发性膜增生性GN患者补体基因的罕见变异。方法作为美国国立卫生研究院生物资源稀有疾病研究的一部分，我们分析了165例原发性膜增生性GN病例和10,250例无此病（对照）的个体的全基因组序列数据。我们检查了拷贝数，稀有和常见变体。结果我们的分析包括146例原发性膜性增生性GN病例和6442例与欧洲血统无关的对照组。我们没有观察到候选基因（编码补体替代途径成分的基因以及与相关疾病非典型溶血性尿毒症综合征相关的其他基因；病例为6.8％，对照组为5.9％）或整个基因组范围内的稀有变体没有大量富集。但是，在6p21.32（rs35406322）（P = 3.29×10-8;比值比[OR]，1.93； 95％置信区间[95％CI]，1.53至2.44）中发现了一个重要的常见变异位点。 HLA基因座。HLA类型的插补将该信号映射为包含DQA1 * 05：01，DQB1 * 02：01和DRB1 * 03：01的单倍型（P = 1.21×10-8; OR，2.19; 95％CI，1.66至2.89） 。通过分析338名具有膜增生性GN的个体和15,614名非免疫性肾衰竭的个体的HLA血清型，重复了这一发现。结论我们发现HLA类型，但并非罕见的补体基因变异与原发性膜增生性GN有关。这些发现挑战了通常导致原发性膜增生性GN的补体基因突变的范式，并在大多数情况下暗示了潜在的自身免疫机制。