title: Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus.
abstract: There is increasing evidence implicating genetic factors in the susceptibility to diabetic microvascular complications. Recent studies suggest that increased expression of the cytokine vascular endothelial growth factor (VEGF) may play a role in the pathogenesis of diabetic complications. A number of polymorphisms in the promoter region of the VEGF gene have been identified. The aim was to investigate whether an 18 base pair (bp) deletion (D)/insertion (I) polymorphism at position -2549 in the promoter region of the VEGF gene is associated with the susceptibility to diabetic microvascular complications. Two hundred and thirty-two patients with type 1 diabetes mellitus (T1DM) and 141 normal healthy controls were studied. The D/D genotype was significantly increased in those patients with nephropathy (n=102) compared to those with no complications after 20 years duration of diabetes (uncomplicated, n=66) (40.2% vs. 22.7%, respectively, chi(2)=5.5, P<.05). The combination of polymorphisms of VEGF together with the aldose reductase (ALR2) gene showed that in the nephropaths, 8 of the 83 subjects had the VEGF I allele together with the Z+2 5'ALR2 allele compared with 27 of the 62 uncomplicated patients (chi(2)=26.7, P<.00001). The functional role of the D/I polymorphism was examined by cloning the region into a luciferase reporter assay system and transient transfection into HepG2 cells. The construct containing the 18 bp deletion had a 1.95-fold increase in transcriptional activity compared with its counterpart that had the insert (P<.01). These results suggest that polymorphisms in the promoter region of the VEGF gene together with the ALR2 may be associated with the pathogenesis of diabetic nephropathy.
authors.affiliation: Molecular Medicine Research Group, Plymouth Postgraduate Medical School, University of Plymouth, ITTC Building, Tamar Science Park, Derriford Road, UK.
authors.forename: Bingmei
authors.initials: B
authors.lastname: Yang
authors.forename: Deborah F
authors.initials: DF
authors.lastname: Cross
authors.forename: Martin
authors.initials: M
authors.lastname: Ollerenshaw
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Millward
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Demaine
mesh_terms: D000328:Adult; D000449:Aldehyde Reductase / Q000235:genetics; D000483:Alleles; D020029:Base Pairing; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics; D003930:Diabetic Retinopathy / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000449:Aldehyde Reductase