The functional -374 T/A RAGE gene polymorphism is associated with proteinuria and cardiovascular disease in type 1 diabetic patients.
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.
Pettersson-Fernholm
Kim
K
Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland.
Forsblom
Carol
C
Hudson
Barry I
BI
Perola
Markus
M
Grant
Peter J
PJ
Groop
Per-Henrik
PH
D000328:Adult; D000419:Albuminuria / Q000235:genetics; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics; D005260:Female; D005387:Finland; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011507:Proteinuria / Q000235:genetics*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics*
D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic