The Functional −374 T/A RAGE Gene Polymorphism Is Associated With Proteinuria and Cardiovascular Disease in Type 1 Diabetic Patients

Abstract

The hyperglycemic milieu in diabetes results in the formation of advanced glycation end products (AGEs) that predominantly act through specific receptors, particularly the receptor for AGEs (RAGE). Two functional polymorphisms in the promoter of the RAGE gene (؊429 T/C and ؊374 T/A) and one in the AGE binding domain in exon 3 (G82S) were studied in 996 Finnish type 1 diabetic patients. In patients with poor metabolic control (HbA 1c >9.5%), the AA genotype of the ؊374 T/A polymorphism was more common in those with a normal albumin excretion rate than in those with proteinuria (30 vs. 10%, P ‫؍‬ 0.01). We observed less coronary heart disease (6 vs. 14%, P < 0.05), acute myocardial infarction (2 vs. 14%, P ‫؍‬ 0.01), and peripheral vascular disease (2 vs. 14%, P < 0.05) in patients with the AA genotype of the ؊374 T/A polymorphism than in those with the TT ؉ TA genotype. Thus, the association between the RAGE ؊374 T/A homozygous AA genotype and cardiovascular disease as well as albumin excretion in type 1 diabetic patients with poor metabolic control suggests a gene-environment interaction in the development of diabetic nephropathy and cardiovascular complications. Diabetes 52:891-894, 2003 E levated arterial blood pressure, proteinuria, progressive decline in renal function, and high cardiovascular morbidity and mortality are clinical characteristics of nephropathy in type 1 diabetic subjects (1,2). The chronic hyperglycemia associated with this condition results in formation and accumulation of irreversible advanced glycation end products (AGEs) that cause a plethora of adverse effects, resulting in dysfunction of the vasculature (3). These include changes in lipid metabolism, platelet function, and extracellular matrix composition (4), effects shown to be mediated by specific AGE binding receptors. The candidate receptor most likely to be involved in these processes is the receptor for AGEs (RAGE). Blockade of AGE/RAGE binding prevents the underlying cellular changes associated with vascular disease and the formation of atherosclerosis in animal models of diabetes (5,6). RAGE is normally expressed at low levels in the vasculature; however, studies of human subjects and animal models of diabetes reveal major upregulation of RAGE in the presence of vascular disease (7,8). The role for RAGE in diabetic renal disease is emphasized by animal models engineered to overexpress RAGE, which develop diabetic nephropathy more rapidly than their nontransgenic counterparts (9).The role for a genetic influence on the pathogenesis is supported by studies that show familial clustering of diabetic nephropathy (10,11), although few genes have been identified as having a role in this disorder. The upregulation and pathogenic effects of RAGE in diabetic vascular disease highlight the RAGE gene as a candidate for involvement in the pathogenesis of nephropathy. The gene for RAGE is located on chromosome 6p21.3 near the HLA locus (12), and at least 30 polymorphisms have been identified (13-16). Most of the polymorphisms are rare codin...

DDOST, PRKCSH and LGALS3, which encode AGE-receptors 1, 2 and 3, respectively, are not associated with diabetic nephropathy in type 1 diabetes

“…First, the AGER gene encoding RAGE has been associated with cardiovascular disease [2], proteinuria [2][3][4] and retinopathy [4] in patients with type 1 diabetes. Second, AGE-R1, which is encoded by DDOST, enhances the clearance of AGEs from the circulation [8], while diabetic nephropathy in patients with type 1 diabetes has been associated with low levels of AGE-R1 in circulating mononuclear cells and with elevated levels of serum AGEs [9].…”

“…The AGER gene on chromosome 6p21 encodes the receptor for AGEs (RAGE). We have previously shown that the functional single nucleotide polymorphism (SNP) −374T/A (rs1800624) in the promoter region of AGER is associated with cardiovascular disease in Finnish patients with type 1 diabetes and with proteinuria in patients with poor glycaemic control [2]. Subsequent studies have shown that AGER is associated with diabetic nephropathy in white patients with type 1 diabetes [3,4] and with sight-threatening diabetic retinopathy in type 1 diabetes patients [4].…”

Rage gene promoter polymorphisms and diabetic retinopathy in a clinic-based population from South India

“…The association of these promoter polymorphisms has been studied in various populations with respect to DR and other diseases, but the results are conflicting. [19][20][21] Although Indians have the largest number of diabetic patients in the world, 22,23 there is a paucity of literature on the genetic factors contributing to DR in Indians. In this study, we have examined À429 TC and À374 TA promoter polymorphisms in relation to DR in South Indian Type 2 diabetic subjects.…”

Diabetic threesome (hyperglycaemia, renal function and nutrition) and advanced glycation end products: evidence for the multiple-hit agent?

“…haplotype analysis and multi-locus association studies) it has been shown that risk variants in the RAGE gene increase the susceptibility to diabetic nephropathy and accelerate its onset (155,159) . Other studies have also identified RAGE variants as risk factors for diabetic nephropathy (160,161) .…”