Lindholm E, Bakhtadze E, Sjögren M, Cilio C M, Agardh E, Groop L, Agardh C-D
Department of Clinical Sciences, University Hospital MAS, Lund University, Lund, Sweden.
Diabetologia. 2006 Nov;49(11):2745-55. doi: 10.1007/s00125-006-0412-3. Epub 2006 Sep 13.
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.
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.
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 sight-threatening 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.
目的/假设：晚期糖基化终末产物受体（RAGE）被认为主要是一种细胞内信号转导分子或促炎肽，可能在炎症和自身免疫性疾病中具有重要作用。我们的目的是研究RAGE编码基因（AGER）中的-374 T/A多态性是否与糖尿病类型及糖尿病并发症的存在相关。
对867例1型糖尿病患者、2467例2型糖尿病患者以及205例具有斯堪的纳维亚血统的非糖尿病对照者进行AGER -374 T/A多态性基因分型。
AGER多态性与不同的HLA - DQB1基因型及糖尿病并发症的存在有关。1型糖尿病患者中AGER -374 A/A或T/A基因型的频率高于2型糖尿病患者（51.1%对44.9%，p = 0.ooo2）和对照者（51.1%对47.6%，p = 0.0006）。RAGE -374 T/A多态性与HLA - DQB1基因型相关；具有HLA风险基因型的患者中A/A或T/A基因型的频率高于具有其他HLA - DQB1基因型的患者（60.3%对40.3%，p < 0.000001）。在1型糖尿病患者中，患有糖尿病肾病的患者A/A或T/A基因型的频率高于未患糖尿病肾病的患者（61.1%对46.8%，p = 0.006），患有威胁视力的视网膜病变的患者高于未患视网膜病变的患者（56.1%对47.6%，p = 0.03）。在糖化血红蛋白（HbA1c）值低于中位数的2型糖尿病患者中，患有糖尿病肾病的患者T/T基因型的频率高于未患糖尿病肾病的患者（54.3%对38.2%，p = 0.02）。
结论/解读：我们的结果显示AGER -374 T/A多态性与1型糖尿病之间存在关联。这种关联依赖于HLA - DQB1。该多态性在1型和2型糖尿病中均与糖尿病肾病相关，在后者中以HbA1c依赖的方式存在，并且在1型糖尿病患者中还与威胁视力的视网膜病变相关。
