Introduction 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.

Methods 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.

Results A significant association with HLA loci defined by variants in HLA-DQB1, HLA-DRB1, and HLA-DQA1 were found for SSNS (but not SRNS), along with a second immune-related SSNS locus: CLEC16A. A PRS that discriminates between SSNS and SRNS was validated in two independent cohorts. The HLA haplotype HLA-DRB1*07:01∼DQA1*02:01∼DQB1*02:02 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%.

Conclusions 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.

Translational statement 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 CLEC16A (a gene important in the regulation of T and B lymphocytes). The HLA haplotype DRB1*07:01∼DQA1*02:01∼DQB1*02:02 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.

The authors have declared no competing interest.

This study is supported by grant U01 AI152585-01 from the National Institutes of Allergy and Infectious Disease (NIAID). Funding for the CureGN consortium is provided by U24DK100845, U01DK100846, U01DK100876 U01DK100866, and U01DK100867 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional support was received from the Intramural Research Program of the National Institutes of Health in the Center for Research on Genomics and Global Health (1ZIAHG200362; CRGGH). The CRGGH is supported by the National Human Genome Research Institute (NHGRI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Center for Information Technology, and the Office of the Director at the National Institutes of Health. The 1000 Genomes Project data was generated at the New York Genome Center with funds provided by NHGRI Grant 3UM1HG008901-03S1.

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Institutional Review Board from Duke University Medical Center (Durham, NC, USA) and all collaborating institutions gave ethical approval for this work. The participants in the Bristol cohort were recruited into the epidemiology and clinical studies of nephrotic syndrome at the University of Bristol, UK, and the study was approved by the NHS Health Research Authority of the South West - Central Bristol Research Ethics Committee. The CUREGN study protocol was approved by the study single institutional review board (IRB) for domestic sites in the United States, and at the local IRB at each international site.

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