Dataset Information

Comprehensive Review of Steroid-Sensitive Nephrotic Syndrome Genetic Risk Loci and Transcriptional Regulation as a Possible Mechanistic Link to Disease Risk

ABSTRACT:

Introduction

The etiology of steroid-sensitive nephrotic syndrome (SSNS) is not well understood. Genetic studies have established common single nucleotide polymorphisms (SNPs) that are associated with increased SSNS disease risk. We review previous genetic association studies of SSNS and nominate particular transcriptional regulators and immune cells as potential key players in the etiology of this disease.

Methods

A list of SNPs associated with SSNS was compiled from published genome wide association and candidate gene studies. The Regulatory Element Locus Intersection (RELI) tool was used to calculate the enrichment of the overlap between disease risk SNPs and the genomic coordinates of data from a collection of >10,000 chromatin immunoprecipitation sequencing experiments.

Results

After linkage disequilibrium expansion of the previously reported tag associated SNPs, we identified 192 genetic variants at 8 independent risk loci. Using the Regulatory Element Locus Intersection algorithm, we identified transcriptional regulators with enriched binding at SSNS risk loci (10-05 < Pcorrected < 10-124), including ZNF530, CIITA, CD74, RFX5, and ZNF425. Many of these regulators have well-described roles in the immune response. RNA polymerase II binding in B cells also demonstrated enriched binding at SSNS risk loci (10-37Conclusion SSNS is a complex disease, and immune dysregulation has been previously implicated as a potential underlying cause. This assessment of established SSNS risk loci and analysis of possible function implicates transcriptional dysregulation, and specifically particular transcriptional regulators with known roles in the immune response, as important in the genetic etiology of SSNS. Graphical abstract

SUBMITTER: Stone H

PROVIDER: S-EPMC7783560 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association. STUDY DESIGN:Case-control study. SETTING & PARTICIPANTS:African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium. FACTOR:Genetic variants in HLA-DQA1 (C34Y [rs1129740]; F41S [rs1071630]) and APOL1 high-risk alleles. OUTCOMES:SSNS and SRNS. MEASUREMENTS:Direct sequencing for the HLA-DQA1 and APOL1 variants in 115 African American children (65 with SSNS and 50 with SRNS). Imputation of classic HLA alleles and amino acids was done in 363 South Asian children. RESULTS:The 2 HLA-DQA1 variants were significantly associated with SSNS in African American children (C34Y: P=5.7 × 10-11; OR, 3.53; 95% CI, 2.33-5.42; F41S: P=1.2 × 10-13; OR, 4.08; 95% CI, 2.70-6.28), but not with SRNS (C34Y: P=0.6; F41S: P=0.2). APOL1 high-risk variants were not associated with SSNS (P=0.5) but showed significant associations with SRNS (P=1.04 × 10-7; OR, 4.17; 95% CI, 2.23-7.64). HLA-DQA1*0201, HLA-DQB1*0201, and HLA-DRB1*0701 were the classic HLA alleles with the most significant associations with SSNS risk. The most significantly associated amino acid positions were HLA-DQ?1 56 and 76 (both P=2.8 × 10-7). Conditional analysis revealed that these variants most likely account for the observed association. LIMITATIONS:Modest sample size and limited statistical power to detect small to moderate effect sizes. Children studied may not be representative of all African American children in the United States. CONCLUSIONS:HLA-DQA1 is a risk locus for SSNS, but not SRNS, in African American children, consistent with its role in SSNS risk in children of European, Asian, and African ancestries. There is little evidence of a significant role for the APOL1 high-risk alleles in childhood SSNS in African American children. Refinement of the HLA-DQA1 association identified the critical classic HLA antigen types and amino acids of the HLA-DQ ?1 molecule.