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 (10-37<Pcorrected<10-5). Conclusion 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.