Association between HLA alleles and sub-phenotype of childhood steroid-sensitive nephrotic syndrome

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.

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.

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 SSNSWR and SDNS/FRNS (P = 0.0012 and P = 0.0006, respectively). 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.

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.