Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy

Citation
Bi. Hudson et al., Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy, DIABETES, 50(6), 2001, pp. 1505-1511
Citations number
25
Categorie Soggetti
Endocrynology, Metabolism & Nutrition","Endocrinology, Nutrition & Metabolism
Journal title
DIABETES
ISSN journal
00121797 → ACNP
Volume
50
Issue
6
Year of publication
2001
Pages
1505 - 1511
Database
ISI
SICI code
0012-1797(200106)50:6<1505:EONPIT>2.0.ZU;2-1
Abstract
Interactions between advanced glycation end products (AGEs) and the recepto r for AGE (RAGE) are implicated in the vascular complications in diabetes. We have identified eight novel polymorphisms, of which the -1420 (GGT)n, -1 393 G/T, -1390 G/T, and -1202 G/A were in the overlapping PBX2 3' untransla ted region (UTR), and the -429 T/C (66.5% TT, 33.5% TC/CC), -407 to -345 de letion (99% I, 1% I/D, 0% D), -374 T/A (66.4% TT, 33.6% TA/AA), and +20 TIA were in the RAGE promoter. To evaluate the effects on transcriptional acti vity, me measured chloramphenicol acetyl transferase (CAT) reporter gene ex pression, driven by variants of the -738 to +49 RAGE gene fragment containi ng the four polymorphisms identified close to the transcriptional start sit e. The -429 C, -374 A, and 63-bp deletion alleles resulted in a mean increa se of CAT expression of twofold (P < 0.0001), threefold (P < 0.001), and fo urfold (P < 0.05), respectively, with the -374 T and A alleles yielding hig hly differential binding of nuclear protein extract from both monocyte- and hepatocyte-derived cell lines. The prevalence of the functional polymorphi sms were investigated in subjects with type 2 diabetes (106 with and 109 wi thout retinopathy), with the -429 C allele showing an increase in the retin opathy group (P < 0.05). These data suggest that the polymorphisms involved in differences in RAGE gene regulation may influence the pathogenesis of d iabetic vascular complications.