Background Few studies have addressed the effects of human leukocyte antigen (HLA) alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome (SSNS),including SSNS without recurrence (SSNSWR) and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome (SDNS/FRNS).In this study,we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS.Methods A total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit,and four-digit resolution HLA alleles were imputed from available Genome Wide Association data.The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated.Additionally,logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system.Results Compared with SSNSWR,significantly decreased serum levels of complement 3 (C3) and complement 4 (C4) at onset were detected in SDNS/FRNS (C3,P ＜ 0.001;C4,P =0.018).The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR (P =0.0001).Low level of C4 was further identified as an independent risk factor for SDNS/FRNS (P =0.008,odds ratio =0.174,95％ confidence interval 0.048-0.630).The HLA-A *11:01 allele was independently associated with S SNSWR and SDNS/FRNS (P =0.0012 and P =0.0006,respec-tively).No significant HLA alleles were detected between SSNSWR and SDNS/FRNS.In addition,a mediating effect among HLA-I alleles (HLA-B*15:11,HLA-B*44:03 and HLA-C*07:06),C4 level and SDNS/FRNS was identified.Conclusions HLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS.HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.