The Functional −374 T/A RAGE Gene Polymorphism Is Associated With Proteinuria and Cardiovascular Disease in Type 1 Diabetic Patients
- Kim Pettersson-Fernholm12,
- Carol Forsblom12,
- Barry I. Hudson34,
- Markus Perola56,
- Peter J. Grant3,
- Per-Henrik Groop12 and
- for the FinnDiane Study Group
- 1Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland
- 2Folkhälsan Research Centre, University of Helsinki, Helsinki, Finland
- 3Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds General Infirmary, Leeds, U.K.
- 4Department of Surgery, Columbia University, New York, New York
- 5Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland
- 6Department of Genetics, University of California, Los Angeles, California
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 (HbA1c >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.
Footnotes
-
Address correspondence and reprint requests to Per-Henrik Groop, Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8 (C318b), POB 63, FIN-00014, University of Helsinki, Helsinki, Finland. E-mail: per-henrik.groop{at}folkhalsan.fi.
Received for publication 24 June 2002 and accepted in revised form 19 November 2002.
AER, albumin excretion rate; AGE, advanced glycation end product; AMI, acute myocardial infarction; CHD, coronary heart disease; CVD, cardiovascular disease; ESRD, end-stage renal disease; PVD, peripheral vascular disease; RAGE, receptor for AGEs; RIA, radioimmunoassay.
- †
† Deceased.
- DIABETES
