Genetic determinants of diabetic nephropathy

Diabetic nephropathy is the most serious complication of diabetes mellitus. Progression of the condition leads to end-stage renal failure, and other c omplications of diabetes are also common in this group of patients. The ons et of overt albuminuria in a patient with diabetes heralds an increased ris k of death, particularly from cardiovascular disease. There is considerable evidence to show that nephropathy is influenced by genetic factors. Epidem iological studies show that only a minority of patients with diabetes devel op nephropathy irrespective of glycaemic control, suggesting that a subgrou p of patients are at higher risk of nephropathy. Marked ethnic variation is observed, with nephropathy being more common in certain ethnic groups. Fam ilial clustering of nephropathy is also observed. Parental history of hyper tension, diabetes or cardiovascular disease appears to predispose to nephro pathy in patients with diabetes. A number of methods are available to disse ct polygenic disease: animal models, genetic association studies (case-cont rol studies), affected sib-pair studies, discordant sib-pair studies and tr ansmission distortion analysis. Most published work has been based on assoc iation studies. Association studies have shown conflicting results often du e to small numbers of cases and controls, and poor phenotypic characterizat ion. The angiotensin-converting enzyme gene insertion (I)/deletion (D) poly morphism has been studied in detail, but does not appear to be a strong ris k marker for nephropathy. It does, however, appear to have a role in respon se to angiotensin-converting enzyme inhibition, with II homozygotes being t he most responsive and DD homozygotes the least. A number of other genetic loci have also shown positive associations with nephropathy, including apol ipoprotein E, heparan sulphate and aldose reductase. More recently, affecte d sib-pair analysis and discordant sib-pair analysis have suggested possibl e genetic loci on chromosomes 3, 7, 9, 12 and 20. These have yet to be repr oduced in larger numbers of families, and the specific gene regions on thes e chromosomes remain elusive. The evidence presented in this review strongl y supports the role of genetic factors in nephropathy. Detection of strong genetic risk markers for nephropathy will allow further insights into the p athogenesis of nephropathy, and possibly the development of novel therapeut ic agents for its treatment. It will also allow preventive therapy to be di rected at those patients with the greatest risk for development of diabetic nephropathy.