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As the field of nephrology moves towards personalized medicine, knowledge and understanding of the genetic basis of renal disease is becoming increasingly important to inform patient care. In addition to genetic forms of renal disease, genetic variants and epigenetic regulators have a role in determining kidney function and development, the risk of, severity and progression of kidney disease, and responses to therapy. Genetic and genomic studies provide important insights into the mechanistic basis of kidney disease and have the potential to identify novel therapeutic targets. This series of articles aims to explore all aspects of nephrogenetics, from the genetics of monogenic diseases to complex traits and the interpretation and application of genetic and genomic data to improve patient outcomes.
An increasing body of evidence suggests that genomic disorders and monogenic aetiologies contribute meaningfully to seemingly complex forms of chronic kidney disease (CKD). This Review describes rare genetic causes of CKD and the genetic and phenotypic complexity of this group of disorders, and discusses novel approaches to help to address the challenges posed by the complexity of CKD.
Sullivan and Susztak examine the process of translating data on genetic variants associated with common kidney diseases into information about the underlying disease mechanisms. The authors propose that identification of causal variants, genetic regulatory mechanisms, target-gene products and disease-associated phenotypes is crucial to this process.
Classification of kidney diseases according to their molecular mechanisms has potential to improve patient outcomes through the identification of targeted therapeutic approaches. This Review provides an overview of the ways in which omics and other data types can be integrated to enhance our understanding of the mechanisms underlying kidney function and failure.
This Review describes advances in genomic analysis that have enabled novel genetic discoveries, more than doubled the number of genetic loci associated with type 2 diabetes mellitus and uncovered several novel candidate genes for diabetes complications.
This Review describes the current understanding of the role of epigenetics and epigenomics in diabetic kidney disease (DKD) and how epigenetic mechanisms might contribute to metabolic memory. The authors also discuss how epigenetic factors and non-coding RNAs could be used as biomarkers and drug targets for DKD diagnosis, prognosis and treatment.
A growing body of evidence suggests that epigenetic regulation is involved in the process of acute kidney injury (AKI) and kidney repair. This Review provides a general overview of the main epigenetic mechanisms that have been linked to AKI and discusses the challenges and therapeutic implications of these findings.
This Review explores the mechanistic links underlying the associations between HLA and kidney diseases. The authors discuss how these links might provide insights into disease pathogenesis and describe the clinical implications of these insights.
The application of precision gene editing has great potential to accelerate basic research and advance clinical practice in nephrology. Here, the authors discuss this technology and the challenges and potential of genome editing in the kidney.
Genomic medicine approaches are increasingly used for diagnosis of kidney disease. Here, the authors discuss sequencing modalities, the interpretation and clinical application of genetic data, and the challenges that must be overcome to realize the potential of genomic medicine in nephrology.
Genetic research in nephrology is rapidly advancing. Key studies published in 2020 demonstrate that genetic findings can provide new tools for patient diagnosis and risk stratification as well as important insights into kidney physiology and disease mechanisms that could potentially lead to novel therapies.
New exposome-based approaches permit omic-scale characterization of the non-genetic contributors to kidney disease. High-resolution mass spectrometry analysis of plasma and urine samples captures a wide range of exogenous and endogenous metabolites that can be used in combination with genetic risk factors to identify new biomarkers of exposure and therapeutic approaches.
Growing genomic knowledge has provided immense insight into the aetiology and mechanisms of kidney diseases but raises ethical issues that risk the successful implementation of genomic medicine. We highlight such issues in two contexts: the return of individual genetic results from nephrology research and preimplantation genetic diagnosis for heritable kidney diseases.
The increasing availability of sequencing has accelerated the discovery of genetic causes of kidney disease, with clear benefits for patients. However, insufficient or contradictory evidence exists for numerous variants that were previously reported to be pathogenic, calling into question some proposed gene–disease associations. Rigorous re-appraisal of evidence is needed to ensure diagnostic accuracy.
A recent metabolite genome-wide association study (mGWAS) investigated the relationship between genetic factors and the urine metabolome in kidney disease. The findings demonstrate that mGWAS hold promise for identifying novel genetic factors involved in adsorption, distribution, metabolism and excretion of metabolites and pharmaceuticals, as well as biomarkers for disease progression.
A new genome-wide association study of patients with type 1 diabetes mellitus reveals novel loci that are associated with the development of diabetic kidney disease. The most significant of these loci encodes the α3 chain of type IV collagen, which is an important component of the glomerular basement membrane.
Chronic kidney disease (CKD) is often clinically silent and traditional clinical data alone cannot differentiate disease subtypes. A recent study of the genetic basis of CKD in adults that examined the prevalence of monogenic kidney disease aetiologies supports the use of genetic analysis to improve diagnostics and treatment in CKD.
Discoveries in 2018 using single-cell sequencing and gene-editing technologies have revealed their transformative potential for the investigation of kidney physiology and disease. Their promise is matched by the speed of their evolution.
A new study discovered thousands of expression quantitative trait loci (eQTLs) in the renal glomerular and tubulointerstitial compartments and integrated these data with other omics data sets to identify genes with roles in the pathogenesis of chronic kidney disease. This report reinforces the necessity of using compartment-derived eQTLs to advance kidney genomic discovery.
A new study reports that genome-wide polygenic risk scores can identify individuals at risk of common complex diseases, such as coronary artery disease or type 2 diabetes, with comparable performance to that of monogenic mutation screens. These findings support the potential clinical utility of genome-wide association study (GWAS)-based risk stratification; however, several issues need to be addressed before this approach can be applied to kidney disease.
Technical advances in genome sequencing and association studies have yielded critical insights into the genetic architecture of kidney diseases. Here, I summarize four key studies from 2017 that deciphered the genetic basis of known and novel diseases and provided insights into the mechanisms of glomerular, developmental defects and manifestations of kidney disorders.