# Amino acid variants in the HLA-DQA1 and HLA-DQB1 molecules explain the major association of variants with relapse status in pediatric patients with steroid-sensitive nephrotic syndrome

## TL;DR

The study identifies specific amino acid variants in HLA-DQA1 and HLA-DQB1 that are linked to relapse patterns in children with steroid-sensitive nephrotic syndrome.

## Contribution

The study identifies novel amino acid variants in HLA-DQA1 and HLA-DQB1 that are specifically associated with relapse status in pediatric steroid-sensitive nephrotic syndrome patients.

## Key findings

- Variants rs1047989 and HLA-DQB1*06:02 are significantly associated with SDNS/FRNS in pediatric SSNS patients.
- HLA-DQA1 and HLA-DQB1 mRNA levels are higher during relapse compared to remission.
- The rs1047989 variant is linked to increased infection-related relapses in SDNS/FRNS patients.

## Abstract

Management of patients with steroid-sensitive nephrotic syndrome (SSNS) is challenging because of frequent relapses. Causal variants in the human leukocyte antigen (HLA) class II region that are associated with relapse remain undetermined.

We collected a cohort of East Asian individuals comprising 206 pediatric patients with SSNS and 435 healthy controls from Southwest China. Ninety children with steroid-sensitive nephrotic syndrome without relapse (SSNSWR) and 116 children with steroid-dependent and/or frequent relapse nephrotic syndrome (SDNS/FRNS) were genotyped using Sanger sequencing. We then measured the transcriptional level, allele expression imbalance (AEI) and functional proteins of HLA-DQA1 and HLA-DQB1 in different stages of SDNS/FRNS.

rs1464545187 in ANKRD36 was associated with an approximately 1.69-fold greater risk for SSNSWR (P = 0.04; 95% confidence interval [CI], 1.05–2.72). Clustered risk variants in HLA-DQA1 and HLA-DQB1 were significantly associated with SDNS/FRNS (rs1047989: P = 2.26E-07, odds ratio [OR] = 2.25, 1.65–3.05; rs9273471: P = 5.45E-05, OR = 1.84, 1.37–2.46; HLA-DQB1*06:02: P = 0.017, OR = 0.19, 0.04–0.77). The genotype distributions of rs1047989, 2:171713702, rs1049123, rs9273471, and HLA-DQB1*06:02 in patients with SSNS were significantly different from those in healthy controls. rs1047989 (HLA-DQA1) was significantly associated with a greater number of infections at relapse in SDNS/FRNS patients (P = 0.045, OR = 6.79, 95% CI: 1.29-168.52). Flow cytometry showed that the proportion of cells expressing HLA-DQA1+/DQB1+ (HLA-DQA1+, P = 0.0046; HLA-DQB1+, P = 0.0045) was lowest in the relapse stage. In addition, the mRNA levels of HLA-DQA1 and HLA-DQB1 were significantly greater in the relapse group than in the remission group (HLA-DQA1, P = 0.03; HLA-DQB1, P = 0.002). No significant AEIs were detected in the different stages of SDNS/FRNS. The rs1047989 variant is likely to affect the structure and stability of HLA-DQA1.

rs1464545187 is a risk locus for SSNSWR but not SDNS/FRNS in Chinese children. Functional variations in HLA-DQA1 and HLA-DQB1 are implicated in regulating the immune response of SSNS patients, which may explain the typical triggering of SDNS/FRNS onset by infections.

The online version contains supplementary material available at 10.1186/s13052-025-01913-z.