Genetic and Epigenetic Studies in Diabetic Kidney Disease

Abstract

Chronic kidney disease is a worldwide health crisis, while diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease (ESRD). DKD is a microvascular complication and occurs in 30–40% of diabetes patients. Epidemiological investigations and clinical observations on the familial clustering and heritability in DKD have highlighted an underlying genetic susceptibility. Furthermore, DKD is a progressive and long-term diabetic complication, in which epigenetic effects and environmental factors interact with an individual’s genetic background. In recent years, researchers have undertaken genetic and epigenetic studies of DKD in order to better understand its molecular mechanisms. In this review, clinical material, research approaches and experimental designs that have been used for genetic and epigenetic studies of DKD are described. Current information from genetic and epigenetic studies of DKD and ESRD in patients with diabetes, including the approaches of genome-wide association study (GWAS) or epigenome-wide association study (EWAS) and candidate gene association analyses, are summarized. Further investigation of molecular defects in DKD with new approaches such as next generation sequencing analysis and phenome-wide association study (PheWAS) is also discussed.

DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA

“…This is particularly critical for translation in DKD given the difficulty obtaining serial renal biopsies to establish diagnosis, track progression, and monitor response ( Kim et al, 2018 ). Array-based approaches using blood-derived DNA have previously identified risk factors and biomarkers associated with complex phenotypes ( Sandholm et al, 2013 , 2017 ; Keating et al, 2018 ; Canadas-Garre et al, 2019 ; Gu, 2019 ; Park et al, 2019 ).…”

“…Current treatments are based on modification of risk factors and include the reduction in elevated blood pressure, hyperglycemia and hyperlipidemia. Epidemiological evidence confirms that heritable factors play a major role in the development and progression of DKD, but despite the identification of several genetic loci associated with DKD most of the inherited risk factors remain unknown (Sandholm et al, 2012(Sandholm et al, , 2013(Sandholm et al, , 2014(Sandholm et al, , 2017Canadas-Garre et al, 2018, 2019van Zuydam et al, 2018;Fu et al, 2019;Salem et al, 2019).…”

“…Differential DNA methylation has been associated with "metabolic memory" of glycemic control and with a higher risk of developing DKD (Swan et al, 2015;Keating et al, 2018;Aranyi and Susztak, 2019;Gluck et al, 2019;Gu, 2019;Jia et al, 2019;Park et al, 2019). As DKD is not clinically detectable until significant organ damage has developed (albuminuria and/or reduced eGFR), more effective diagnostic tools and treatments, guided by a better understanding of pathophysiology, are urgently required.…”

Genome-Wide Association Studies of CKD and Related Traits

“…In this review article, we will summarize recent GWAS of CKD and kidney function-related traits from largely population-based cohorts since 2016, with earlier articles having been reviewed previously (6). Findings from GWAS of diabetic nephropathy have recently been summarized elsewhere and are not reviewed in this article (7,8). Genetics of kidney disease with specific causes, such as IgA nephropathy, membranous nephropathy, steroid-sensitive nephrotic syndrome, and APOL1 risk variants, are covered in other review articles in this series.…”

Knock-Down of Long Non-Coding RNA ANRIL Suppresses Mouse Mesangial Cell Proliferation, Fibrosis, Inflammation via Regulating Wnt/β-Catenin and MEK/ERK Pathways in Diabetic Nephropathy

“…However, as to the pathology of DN, it is a synergy of multiple factors including accumulation of extracellular matrix (ECM) proteins, tubulointerstitial fibrosis, inflammation, myofibroblast activation etc. [3,4]. However, the current understandings of DN pathology are still insufficient.…”