Tu Tiffany, Ochoa Alejandro, Sood Amika, Drabik Ashley, Chryst-Stangl Megan, Lane Brandon, Wu Guanghong, Donovan Frank, Harper Ursula, Chandrasekharappa Settara, Esezobor Christopher, Solarin Adaobi, Hooper David, Sethna Christine, Amaral Sandra, Kallash Mahmoud, Rheault Michelle, Verghese Priya, Dharnidharka Vikas, Salmon Eloise, Weng Patricia, Srivastava Tarak, Seifert Michael E, Pruette Cozumel, Selewski David, Gibson Keisha, Hunley Tracy, Abeyagunawardena Asiri, Thalgahagoda Shenal, Bagga Arvind, Sinha Aditi, Webb Nicholas, Greenbaum Larry, Gharavi Ali, Kiryluk Krzysztof, Kretzler Mathias, Guay-Woodford Lisa, Sanna-Cherchi Simone, Bierzynska Agnieszka, Koziell Ania, Welsh Gavin, Saleem Moin, Rotimi Charles, Chambers Eileen, Chan Cliburn, Jackson Annette, Adeyemo Adebowale, Gbadegesin Rasheed
medRxiv. 2025 Aug 7:2025.08.01.25332825. doi: 10.1101/2025.08.01.25332825.
Nephrotic syndrome (NS), a common glomerular disease in children, is classified based on response to corticosteroid therapy as either steroid-sensitive nephrotic syndrome (SSNS), or steroid-resistant nephrotic syndrome (SRNS). However, there are currently no reliable predictors of therapy response at initial clinical presentation.
We conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched controls.
A significant association with HLA loci defined by variants in , and were found for SSNS (but not SRNS), along with a second immune-related SSNS locus: . A PRS that discriminates between SSNS and SRNS was validated in two independent cohorts. The HLA haplotype was associated with ∼4 times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at onset of the disease was the best predictor of steroid responsiveness with an AUC of 0.68-0.70 and an overall classification accuracy of SSNS versus SRNS of 67-71%.
Our findings confirm that SSNS (unlike SRNS) is an immune-mediated HLA-associated disorder. The PRS for therapy response and HLA haplotype can serve as biomarkers and provide a foundation for more accurate diagnoses and tailored and individualized treatment.
To identify biomarkers of pattern of steroid responsiveness in childhood-onset nephrotic syndrome, we carried out a case-control study that included over 4,000 samples, including 994 patients with NS in the discovery phase and an additional 1,003 cases from two independent replication cohorts. We identified significant risk of steroid-sensitive NS (SSNS) at HLA class II genes and (a gene important in the regulation of T and B lymphocytes). The HLA haplotype was associated with four-fold increased odds of SSNS. A model incorporating HLA haplotype, polygenic risk score, and age at onset of the disease was the best predictor of steroid responsiveness providing useful delineation of steroid sensitivity from steroid resistance. In conclusion, age at onset of disease, HLA class II variants and polygenic risk scores are useful biomarkers of corticosteroid response in childhood NS and may serve as useful clinical decision support tools to guide treatment.
肾病综合征（NS）是儿童常见的肾小球疾病，根据对皮质类固醇治疗的反应可分为类固醇敏感型肾病综合征（SSNS）或类固醇抵抗型肾病综合征（SRNS）。然而，目前在初始临床表现时没有可靠的治疗反应预测指标。
我们进行了全基因组关联研究，开发了治疗反应的多基因风险评分（PRS），并分析了1997名（994名发现队列和1003名重复/验证队列）此前未研究过的NS患儿及3558名血统匹配对照的经典HLA等位基因。
发现SSNS（而非SRNS）与由 、 和 中的变体定义的HLA基因座存在显著关联，同时还发现了第二个与免疫相关的SSNS基因座： 。在两个独立队列中验证了区分SSNS和SRNS的PRS。HLA单倍型 与发生SSNS的风险增加约4倍相关。一个纳入HLA单倍型、PRS评分和疾病发病年龄的模型是类固醇反应性的最佳预测指标，曲线下面积为0.68 - 0.70，SSNS与SRNS的总体分类准确率为67 - 71%。
我们的研究结果证实，SSNS（与SRNS不同）是一种免疫介导的HLA相关疾病。治疗反应的PRS和HLA单倍型可作为生物标志物，为更准确的诊断以及量身定制的个体化治疗提供基础。
为了确定儿童期肾病综合征中类固醇反应模式的生物标志物，我们开展了一项病例对照研究，纳入了4000多个样本，包括发现阶段的994名NS患者以及来自两个独立重复队列的另外1003例病例。我们在HLA II类基因和 （在T和B淋巴细胞调节中起重要作用的基因）中发现了类固醇敏感型NS（SSNS）的显著风险。HLA单倍型 与SSNS的几率增加四倍相关。一个纳入HLA单倍型、多基因风险评分和疾病发病年龄的模型是类固醇反应性的最佳预测指标，有助于有效区分类固醇敏感性和类固醇抵抗性。总之，疾病发病年龄、HLA II类变体和多基因风险评分是儿童NS中皮质类固醇反应的有用生物标志物，可作为指导治疗的有用临床决策支持工具。
