Genomically-driven discovery of pediatric steroid sensitive nephrotic syndrome. - Nephrotic syndrome (NS) is a rare form of chronic kidney disease resulting from glomerular filtration barrier failure and massive proteinuria. Morbidity and mortality from NS is related both the disease itself and the non- specific, immune-modulating medications used to try to treat it. NS has long been classified and treated according to either histologic appearance or ability of immunomodulating drugs to achieve remission (“steroid sensitive” [SSNS] or “steroid resistant” [SRNS]). These classifications are nonspecific and don't illuminate specific pathobiology. To achieve increasingly effective care for NS, a more precise understanding of its underlying molecular mechanisms is necessary. Human genetics studies in NS using family- and population- based methods have proven effective in empowering (1) patient classification by genetic subtype and (2) target identification for development of biomarkers and therapeutics. We are focusing on the genetic basis of pediatric SSNS, which is the most common pediatric subtype long known to have an immune component to its pathogenesis. Compared to children with SSNS, those with ISNS are less likely to reach end stage kidney disease (ESKD). However, because these children respond to steroids their lifetime burden of immunosuppression can be very high, with all the attendant infectious risks and side effects such as hypertension, osteoporosis, infertility, and cataracts. And for those children with initial SSNS who eventually reach ESKD, they have significantly increased odds of recurrent NS in their transplanted kidney. The genetic architecture of pSSNS is polygenic and published genome-wide association studies (GWAS) of small sample sizes (n=200-900 cases) had discovered four significant loci. Many of these signals are immune- related. We recently completed a global GWAS of pSSNS with 2440 cases, discovering seven more novel risk loci, establishing a pSSNS polygenic risk score (PRS), and colocalizing signals to specific genes across cell types. Here, we will dissect these pSSNS GWAS loci computationally and functionally, with a focus on integrative analysis using patient-derived molecular datasets and model systems. In Aim 1, we will discover the consequences of pSSNS risk alleles on the immune cell transcriptome of 310 with pSSNS through colocalization with immune-cell eQTLs and PRS-mRNA expression association studies. In Aim 2, we will discover the consequences of pSSNS risk alleles on the proteome of 364 children with NS through genetic associations with large-scale plasma proteomic datasets and targeted protein quantitation. In Aim 3, we will focus on furthering our mechanistic understanding and validation of top candidates through eQTL/pQTL integration, experimental systems, and targeted follow-up in independent human samples. Altogether, these studies will deepen our molecular knowledge and clinical impact of specific pediatric SSNS genetic subtypes.
