Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome.
Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome.
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DOI：
10.1007/s00467-022-05789-7
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发表时间：
2023-06
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儿童特发性肾病综合征（INS）根据对初始皮质类固醇治疗的反应分为类固醇敏感型（SSNS）和类固醇抵抗性肾病综合征（SRNS），成人根据组织学分为微小病变（MCD）和局灶节段性肾小球硬化（FSGS）。然而，这些实体之间存在公认的表型重叠。全基因组关联研究 (GWAS) 表明 SSNS 与 HLA 变异之间存在很强的关联，这表明存在潜在的免疫学基础。我们试图确定由与 SSNS 相关的遗传变异产生的风险评分是否可用于深入了解以其他方式呈现的 INS 病理生理学。我们根据之前欧洲 GWAS 中与儿童 SSNS 独立相关的五个变异，开发了 SSNS 遗传风险评分 (SSNS-GRS)。我们对患有儿童 SSNS、非单基因 SRNS、MCD 和 FSGS 的欧洲个体独立队列中的 SSNS-GRS 进行了量化，并将其与单基因 SRNS、膜性肾病（一种不同的免疫介导的致病性肾病综合征）和健康对照个体中量化的 SSNS-GRS 进行了对比。与健康参与者和膜性肾病患者相比，SSNS、非单基因 SRNS、MCD 和 FSGS 队列中的 SSNS-GRS 显着升高。与单基因 SRNS 相比，所有非单基因 INS 队列中的 SSNS-GRS 也显着升高。不同 INS 表现的患者之间共有的遗传危险因素强烈表明，当排除单基因原因时，存在共同的自身免疫发病机制。除了检测单基因原因之外，使用 SSNS-GRS 可能有助于对 INS 患者进行分类。图形摘要的更高分辨率版本可作为补充信息提供。在线版本包含可在 10.1007/s00467-022-05789-7 获取的补充材料。
Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways. We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls. The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS. The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information The online version contains supplementary material available at 10.1007/s00467-022-05789-7.
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