Towards understanding the inherited susceptibility for nephropathy in diabetes.

The burden of nephropathy is unequally shared across patients with diabetes. The majority of the variability in incident nephropathy remains unaccounted for by conventional risk factors. There appears to be an inherited predisposition for diabetic nephropathy, but this does not follow simple Mendelian rules. Any inherited predisposition for nephropathy is far more complicated. This article reviews the recent advances in understanding of the genetics and epigenetics of diabetic nephropathy. A few candidate genes have been reproducibly associated with diabetic nephropathy, and recent genome-wide linkage studies have also identified chromosomal loci for susceptibility genes, including 3q, 7q, 10p, 14q and 18q. Unbiased, genome-wide linkage studies have identified specific loci and genome-wide association studies a number of new loci. However, any roles of those genes in the molecular pathobiology remain to be established. Moreover, their individual contribution to the variability in incident nephropathy in diabetes appears to be small. New genome-wide approaches offer new opportunities to identify genes associated with diabetic nephropathy. However, such approaches have key limitations. Upto the present time, genetic testing has failed to identify a gene or combination of genes that will substantially identify those patients most at risk for diabetic nephropathy. It may be that epigenetic regulation of gene expression may represent a more important contributor to an inherited predisposition to diabetic nephropathy. Nonetheless, genetic studies may provide valuable information regarding the pathobiology of nephropathy and potential targets for its treatment.