Renoprotective efficacy of renin-angiotensin inhibitors in IgA nephropathy is influenced by ACE A2350G polymorphism.

I mmunoglobulin A nephropathy (IgAN) is the most prevalent form of primary glomerulonephritis and one of the principal causes of end stage renal disease (ESRD) throughout the world. 2 It is a complex disease, in which familial clustering suggests an inherited genetic predisposition. The disease has a variable clinical course, and one third of patients with IgAN progress to ESRD within 10–20 years of its onset. 4 The mechanisms of interindividual differences in the rate of disease progression are unclear. That increased production or activity of angiotensin II plays a detrimental role in the glomerular response to injury has been well documented. Recently, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blocker (ARB) treatments have been shown to decrease proteinuria by improving glomerular permselectivity in IgAN, 7 although the therapeutic effect was not recognised in about half of the patients. An insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme gene has been shown to influence the concentration of ACE in the circulation and local tissues. Many studies have explored the association between the ACE I/D polymorphism and the development and progression of various cardiovascular diseases and renal diseases, including IgAN. Moreover, several studies have investigated associations between the ACE I/D polymorphism and the therapeutic efficacy of ACE inhibitors. The DD homozygote of the ACE I/D polymorphism has been reported as a risk factor for progression to ESRD in patients with IgAN, as well as a predictive marker for responsiveness to the antiproteinuric effects of ACE inhibitors. Other studies, however, reported that patients with the DD genotype were resistant to the renoprotective effects of ACE inhibitors, whether they had non-diabetic or diabetic nephropathy. Recently, an informative set of 13 single nucleotide polymorphisms (SNPs) across the entire ACE gene has been shown, and strong evidence from a large population based sample suggests that two SNPs—ACE A-240T and A2350G— are associated with plasma concentrations of ACE. A polymorphism in exon 17, ACE A2350G, had the most significant effect on the concentration of ACE, whereas, after the effect of A2350G was adjusted for, the I/D polymorphism was not associated with the circulating concentration of ACE. Taken together, it seems reasonable to hypothesise that these more functionally significant SNPs in the ACE gene may be involved in interindividual differences in the progression of glomerular injury. We investigated the possible role of these SNPs in the prognosis of renal function and on the therapeutic efficacy of ACE inhibitors and ARBs in patients with IgAN.