Genetic determinants of diabetic renal disease and their impact on therapeutic interventions

Approximately 30% of patients with type 1 and type 2 diabetes develop diabetic nephropathy. Apart from metabolic control, genetic predisposition plays an important role in its genesis. Analysis of intermediate phenotypic markers showed that the activity of Na/Li- and Na+/H(+)-countertransport is increased in patients with diabetic nephropathy. The renin-angiotensin system is of crucial importance as a system for therapeutic intervention and as genetic marker for susceptibility to renal disease. Consequently, the analysis of molecular genetic markers has focused on a polymorphism in the gene for the angiotensin II converting enzyme (ACE). However, the analysis of the I/D-polymorphism with respect to development of diabetic nephropathy in type 1 and type 2 diabetes has yielded conflicting results, at least in type 1 diabetes. These discrepant results may be due to differences in definition, sample size and ethnic background of the patients. In IgA glomerulonephritis it has been shown that the DD genotype (which is correlated with higher serum and tissue ACE activity compared to II genotype) is associated with a more rapid deterioration of renal function. The same adverse effect of the DD genotype could also be demonstrated in patients with diabetic nephropathy. Two studies examined the response to treatment according to the different genotypes, with contradictory results. A Japanese study showed a more pronounced reduction in proteinuria under ACE inhibitor treatment in patients with DD genotype, whereas a Danish study showed that patients with the DD genotype exhibited a steeper decline in renal function despite ACE inhibitor treatment. The data available for other candidate genes are fragmentary and negative throughout.