The −374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients

Abstract

Aims/hypothesis The receptor for AGE (RAGE) is considered to be mainly an intracellular signal-transducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune diseases. Our aim was to study whether the −374 T/A polymorphism in the gene encoding RAGE (AGER) is associated with diabetes type and presence of diabetic complications. Methods The AGER −374 T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patients and 205 non-diabetic control subjects of Scandinavian origin. Results AGER polymorphism was related to different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients had a higher frequency of the AGER −374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs 44.9%, p=0.002) and control subjects (51.1 vs 47.6%, p=0.0006). The RAGE −374 T/A polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs 40.3%, p<0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p=0.006) and with sightthreatening retinopathy than without (56.1 vs 47.6%, p=0.03). In type 2 diabetic patients with HbA 1c values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy than without (54.3 vs 38.2%, p=0.02). Conclusions/interpretation Our results show an association between the AGER −374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1-dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2 diabetes, in an HbA 1c -dependent manner in the latter group, and also with sight-threatening retinopathy in type 1 diabetic patients.

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].…”

“…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].…”

Involvement of advanced glycation end products in the pathogenesis of diabetic complications: the protective role of regular physical activity

“…The class of S100A12 proteins consists of pro-inflammatory cytokines, mainly expressed by granulocytes, and are involved in the transduction of intercellular signalling events of Ca2+ [16], with a possible influence in the inflammatory process and in autoimmune diseases [76]. The AGEs and the S100/Calgranulins are those which have been most studied as agents of proinflammatory signalling [43,105] and which appear to trigger intercellular signalling mechanisms that could participate in some of the pathologies associated with diabetes, such as nephropathy [91], retinopathy [14], cardiovascular diseases [68] and loss of bone mass [42].…”

Short Communication The functional polymorphisms -429T>C and -374T>A of the RAGE gene promoter are not associated with gestational diabetes in Euro-Brazilians

“…Association studies of RAGE polymorphisms with diabetes, cardiovascular disease and inflammatory diseases such as rheumatoid arthritis showed controversial results (Bucciarelli et al, 2002;Kankova et al, 2005;Lindholm et al, 2006;Bierhaus and Nawroth, 2009). …”