Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK.
Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Pediatr Nephrol. 2023 Jun;38(6):1793-1800. doi: 10.1007/s00467-022-05789-7. Epub 2022 Nov 10.
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.
特发性肾病综合征（INS）在儿童中根据初始皮质类固醇治疗的反应分为激素敏感型（SSNS）和激素抵抗型肾病综合征（SRNS），在成人中根据组织学分为微小病变病（MCD）和局灶节段性肾小球硬化症（FSGS）。然而，这些实体之间存在明显的表型重叠。全基因组关联研究（GWAS）表明 SSNS 与 HLA 变异之间存在强烈关联，提示存在潜在的免疫基础。我们试图确定是否可以使用与 SSNS 相关的遗传变异生成的风险评分来深入了解以其他方式表现的 INS 的病理生理学。
我们从以前的欧洲 GWAS 中与儿童 SSNS 独立相关的五个变体中开发了 SSNS 遗传风险评分（SSNS-GRS）。我们在独立的欧洲儿童 SSNS、非单基因 SRNS、MCD 和 FSGS 队列中量化了 SSNS-GRS，并将其与单基因 SRNS、膜性肾病（另一种免疫介导的肾病综合征）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。非单基因 INS 所有队列的 SSNS-GRS 也明显高于单基因 SRNS 队列。
当排除单基因原因时，不同表现形式的 INS 患者之间存在共同的遗传风险因素强烈提示存在共同的自身免疫发病机制。除了检测单基因原因外，使用 SSNS-GRS 可能有助于对 INS 患者进行分类。可提供图形摘要的更高分辨率版本作为补充信息。
