Genetic Factors in Diabetic Nephropathy

Abstract

Several genes that predispose to type 2 diabetes have recently been identified. In addition to the recognized and powerful effects of environmental factors, there is abundant evidence in support of genetic susceptibility to the microvascular complication of nephropathy in individuals with both type 1 and type 2 diabetes. Familial aggregation of phenotypes such as end-stage renal disease, albuminuria, and chronic kidney disease have routinely been reported in populations throughout the world, and heritability estimates for albuminuria and glomerular filtration rate demonstrate strong contributions of inherited factors. Recent genome-wide linkage scans have identified several chromosomal regions that likely contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under these linkage peaks. These complimentary approaches have demonstrated that polymorphisms in the carnosinase 1 gene on chromosome 18q, the adiponectin gene on 3q, and the engulfment and cell motility gene on 7p are likely associated with susceptibility to diabetic nephropathy. Additional genes that seem to be of importance in renal phenotypes include manganese superoxide dismutase and angiotensin 1-converting enzyme, with nitric oxide synthase implicated in albuminuria. This article reviews the inherited aspects of diabetic kidney disease with particular emphasis on recently implicated genes and pathways. It seems likely that the risk for diabetes-associated kidney disease is magnified by inheriting risk alleles at several susceptibility loci, in the presence of hyperglycemia.Clin J Am Soc Nephrol 2: 1306 -1316, 2007. doi: 10.2215/CJN.02560607 I t was previously thought that individuals who had diabetes and developed progressive diabetic nephropathy (DN) and/or ESRD were simply exposed to long durations of diabetes with relatively poor glycemic control. In other words, all individuals with diabetes were assumed to be at essentially equivalent risk for developing nephropathy, allowing for differences in their ambient serum glucose concentration. In support of the concept that exposure to a hyperglycemic environment led to DN (often with coexisting obesity, metabolic syndrome, hypertension, and hyperlipidemia), clinical trials have conclusively demonstrated that improving glycemic control delays and, in some cases, may prevent the subsequent development of albuminuria, DN, and macrovascular complications such as coronary artery disease (1,2). The concept that select individuals with diabetes were at differential risk for developing nephropathy on the basis of familial aggregation of kidney disease was initially reported in 1989 but has only recently gained broad acceptance among nephrologists and diabetologists (3). Familial Aggregation of DNThe notion that genetic factors contribute to any complex disease rests on the demonstration of familial aggregation. Familial clustering of nephropathy could result from shared genes, environmental exposures, or their combination.After repeated demonstra...

Phenotype–genotype interactions on renal function in type 2 diabetes: an analysis using structural equation modelling

“…In accordance with our current understanding [29,30], we observed the important causal effects of lipid, RAS and glycaemia on renal function in the low-risk model, and of BP and NOS/MMP3 genotypes in the high-risk model. Several chromosomal regions linked to diabetic kidney disease contain candidate genes, including the CNDP1, ADIPOQ, ELMO1, SOD2, ACE and NOS3 [18]. In support of these findings, we have quantified the effects of the RAS and NOS genotypes on renal function in both models.…”

“…The strength of the relationships between the explanatory factors and outcome variable is indicated by the path coefficients (5) glucotoxicity, lipotoxicity, inflammation and haemodynamic abnormalities cause renal damage [18].…”

Adiponectin gene (ADIPOQ) polymorphisms correlate with the progression of nephropathy in Taiwanese male patients with type 2 diabetes

“…Asian and Hispanic patients have the highest prevalence of albuminuria (55%), while Caucasians have the lowest (40.6%) [3], indicating possible ethnic differences. The pathogenesis of DN is multifactorial, and thought to come about as a result of environmental and genetic factors [4]. Genetic factors play an important role in the observed ethnic disparity in the development of DN [4], and gender may predispose patients to the development of kidney disease, as both animal and human studies have reported a higher incidence and a faster progression rate of the disease among males [5][6][7].…”

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

“…19 -23 Nevertheless, the genetic component of the pathophysiologic process of DN has not yet been deciphered. 24 Because numerous genetic and environmental factors, along with their interactions, are considered to be implicated in the pathogenesis of DN, polymorphisms of individual genes are expected to confer a modest risk to susceptibility of DN.Genetic association studies that examined whether variants in eNOS gene are associated with DN or with diabetes leading to severe nephropathy (DSN) have yielded conflicting or inconclusive results. The lack of replication might be due to small sample sizes, different populations, sampling strategies, genotyping procedures, and number of loci included in the studies.…”