Defining nephrotic syndrome from an integrative genomics perspective

Abstract

Nephrotic syndrome (NS) is a clinical condition with a high degree of morbidity and mortality, caused by failure of the glomerular filtration barrier, resulting in massive proteinuria. Our current diagnostic, prognostic and therapeutic decisions in NS are largely based upon clinical or histological patterns such as “focal segmental glomerulosclerosis” or “steroid sensitive”. Yet these descriptive classifications lack the precision to explain the physiologic origins and clinical heterogeneity observed in this syndrome. A more precise definition of NS is required to identify mechanisms of disease and capture various clinical trajectories. An integrative genomics approach to NS applies bioinformatics and computational methods to comprehensive experimental, molecular and clinical data for holistic disease definition. A unique aspect is analysis of data together to discover NS-associated molecules, pathways and networks. Integrating multidimensional datasets from the outset highlights how molecular lesions impact the entire individual. Data sets integrated range from mutation to gene expression, to histologic changes, to progression of chronic kidney disease (CKD). This review will introduce the tenets of integrative genomics and suggest how it can increase our understanding of NS from molecular and pathophysiological perspectives. A diverse group of genome-scale experiments are presented that have sought to define molecular signatures of NS. Finally, the Nephrotic Syndrome Study Network (NEPTUNE) will be introduced as an international, prospective cohort study of patients with NS that utilizes an integrated systems genomics approach from the outset. A major NEPTUNE goal is to achieve comprehensive disease definition from a genomics perspective and identify shared molecular drivers of disease.

Genetics of hereditary nephrotic syndrome: a clinical review

“…Historically, genetic research in NS has studied families with SRNS in order to discover rare mutations in single podocyte genes that lead to this disease131420). The methodology of genetic testing is changing rapidly.…”

“…Genome-wide association studies (GWAS) typically focus on associations between single-nucleotide polymorphisms and traits such as major diseases. GWAS of cohorts of unrelated, affected subjects with SRNS can uncover disease-associated loci20). These and other approaches including enrichment and DNA pooling can complement rare variant discovery17202122).…”

Research Infrastructure for Collaborative Team Science: Challenges in Technology-Supported Workflows in and Across Laboratories, Institutions, and Geographies

“…Inescapably, workflows for systems-level renal disease research are idiosyncratic but certain phases, analytical purposes and practices are fairly common across cases [14]. For example, collaborating renal disease researchers often modularize their flows of analysis by structuring them into phases and by having specialists at specific biological scales conduct their parts of the analyses and then share them [24; 28]. The multiple scales that may come together are illustrated in Figure 1 [28-29].…”

Individual nephron proteomes connect morphology and function in proteinuric kidney disease

“…Since morphologies (as obtained in histology of biopsies) are frequently ambiguous, it has long been hoped that molecular patterns in native biomaterial provide a "molecular diagnosis", thereby revealing treatment options and personalized prognosis. In fact, in many of these diseases, transcriptomic patterns have been analyzed and yielded first insights into classification and mechanisms of diseases ("integrative genomics") (5)(6)(7)(8). However, transcripts can only partially explain protein abundances, which is why the attention is shifting towards proteome data, especially in its targeted form (9).…”