The genetics of diabetic nephropathy

Abstract

Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive. Recently, genome-wide association studies have discovered several novel genetic variants associated with DN. The identification of such variants may potentially allow for early identification of at risk patients. Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes.

Figure 1

The pathophysiology of diabetic nephropathy. As a consequence of prolonged hyperglycaemia, diabetic nephropathy (DN) typically initiates as renal cellular hypertrophy and hyperfiltration, followed by progressive albuminuria and a decline in glomerular filtration rate (GFR). Microalbuminuria (urinary albumin excretion rate of 30–300 mg per day) develops 10–15 years after the onset of diabetes followed by macroalbuminuria (urinary albumin excretion rate of >300 mg per day) 15–25 years after diabetes onset. A combination of hyperglycaemia, inflammation, and hypertension drive the development and progression of DN. Presently, it is unclear why some diabetics are susceptible and others appear protected against the development of DN. Currently unknown causal and protective genetic variants have been suggested as one possible mechanism. At the cellular level, high glucose, Ang II, ROS, and profibrotic cytokines including TGF-β1, VEGF and CTGF have been identified as important modulators driving renal fibrosis. More recently, miRNA-mediated regulation and histone modifications have also been implicated in DN pathogenesis. Mutations in one or more key signaling pathways implicated in DN may act to suppress or drive DN progression.

Figure 2

Unravelling the genetic and molecular mechanisms that cause DN development and progression. The clinical course of DN is relatively well defined. Diagnosis of DN is complicated by the fact that: (a) patients with microalbuminuria may undergo spontaneous regression to normoalbuminuria; and (b) glomerular filtration rate (GFR) and albuminuria may progress independently of each other, i.e., patients may have micro- or macro-albuminuria even though their GFR is normal. Macroalbuminuria is usually associated with reduced GFR. Large scale genome-wide association (GWA) studies in DN are now feasible—future direction will require merging of patient cohorts, use of alternative phenotype definitions to the standard albumin excretion rate definition (e.g., estimated GFR, serum creatinine), analysis of extreme phenotype cohorts, and rare-variant GWA studies. To prioritize candidate genes from GWA studies in DN, these datasets will be integrated with whole-genome expression, proteomic, micro-RNA and epigenomic markers datasets using newly developed integrative tools to merge such datasets. As prioritized candidate genes are identified, functional analysis of these genes will be performed in established cell and animal models of DN.