Abstract：
Some patients diagnosed with benign IgA nephropathy (IgAN) develop a progressive clinical course, not predictable by known clinical or histopathological parameters. To assess if gene expression can differentiate between progressors and non-progressors with assumed benign IgAN, we tested microdissected glomeruli from archival kidney biopsy sections from adult patients with stable clinical remission (21 non-progressors) or from 15 patients that had undergone clinical progression within a 25-year time frame. Based on 1 240 differentially expressed genes from patients with suitable sequencing results, we identified eight IgAN progressor and nine non-progressor genes using a two-component classifier. These genes, including APOL5 and ZXDC, predicted disease progression with 88% accuracy, 75% sensitivity and 100% specificity on average 21.6 years before progressive disease was clinically documented. APOL lipoproteins are associated with inflammation, autophagy and kidney disease while ZXDC is a zinc-finger transcription factor modulating adaptive immunity. Ten genes from our transcriptomics data overlapped with an external genome wide association study dataset, although the gene set enrichment test was not statistically significant. We also identified 45 drug targets in the DrugBank database, including angiotensinogen, a target of sparsentan (dual antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor) currently investigated for IgAN treatment. Two validation cohorts were used for substantiating key results, one by immunohistochemistry and the other by nCounter technology. Thus, glomerular mRNA sequencing from diagnostic kidney biopsies from patients with assumed benign IgAN can differentiate between future progressors and non-progressors at the time of diagnosis.
摘要：
一些诊断为良性IgA肾病（IgAN）的患者发展为进行性临床病程，已知的临床或组织病理学参数无法预测。为了评估基因表达是否可以区分假定的良性IgAN的进展者和非进展者，我们检测了临床缓解期稳定的成年患者(21例非进展者)或在25年时间范围内发生临床进展的15例患者的存档肾活检切片的显微解剖肾小球.基于1240个来自患者的差异表达基因，具有合适的测序结果，我们使用两组分分类器鉴定了8个IgAN进展基因和9个非进展基因.这些基因,包括APOL5和ZXDC，预测疾病进展的准确率为88%，在临床记录进行性疾病之前平均21.6年，灵敏度为75％，特异性为100％。APOL脂蛋白与炎症有关，自噬和肾脏疾病，而ZXDC是调节适应性免疫的锌指转录因子。我们转录组学数据中的十个基因与外部全基因组关联研究数据集重叠，尽管基因集富集试验没有统计学意义。我们还在DrugBank数据库中确定了45个药物靶标，包括血管紧张素原,目前研究用于IgAN治疗的sparsentan（内皮素A型受体和血管紧张素II1型受体的双重拮抗剂）的靶标。两个验证队列用于证实关键结果，一个是免疫组织化学，另一个是nCounter技术。因此，来自假定为良性IgAN的患者的诊断性肾脏活检的肾小球mRNA测序可以在诊断时区分未来的进展者和非进展者。
