A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes.

Vascular endothelial growth factor (VEGF), a major mediator of vascular permeability and angiogenesis, may play a pivotal role in mediating the development and progression of diabetic retinopathy. In the present study, we examined the genetic variations of the VEGF gene to assess its possible relation to diabetic retinopathy in type 2 diabetic patients. Among seven common polymorphisms in the promoter region, 5'-untranslated region (UTR) and 3'UTR of the VEGF gene, genotype distribution of the C(-634)G polymorphism differed significantly (P = 0.011) between patients with (n = 150) and without (n = 118) retinopathy, and the C allele was significantly increased in patients with retinopathy compared with those without retinopathy (P = 0.0037). The odds ratio (OR) for the CC genotype of C(-634)G to the GG genotype was 3.20 (95% CI 1.45-7.05, P = 0.0046). The -634C allele was significantly increased in patients with nonproliferative diabetic retinopathy (non-PDR) (P = 0.0026) and was insignificantly increased in patients with proliferative diabetic retinopathy (PDR) (P = 0.081) compared with patients without retinopathy, although frequencies of the allele did not differ significantly between the non-PDR and PDR groups. Logistic regression analysis revealed that the C(-634)G polymorphism was strongly associated with an increased risk of retinopathy (P = 0.0018). Furthermore, VEGF serum levels were significantly higher in healthy subjects with the CC genotype of the C(-634)G polymorphism than in those with the other genotypes. These data suggest that the C(-634)G polymorphism in the 5'UTR of the VEGF gene is a novel genetic risk factor for diabetic retinopathy.

[1]  D. Foreman,et al.  VEGF localisation in diabetic retinopathy , 1998, The British journal of ophthalmology.

[2]  K. Donaghue,et al.  A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. , 1998, The Journal of clinical endocrinology and metabolism.

[3]  N. Sakane,et al.  β3-Adrenoreceptor Gene Polymorphism: A Newly Identified Risk Factor for Proliferative Retinopathy in NIDDM Patients , 1997, Diabetes.

[4]  E S Gragoudas,et al.  Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. , 1996, Ophthalmology.

[5]  T. Saruta,et al.  Association between diabetic retinopathy and genetic variations in alpha2beta1 integrin, a platelet receptor for collagen. , 2000, Blood.

[6]  T. Werner,et al.  MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. , 1995, Nucleic acids research.

[7]  W. Renner,et al.  A Common 936 C/T Mutation in the Gene for Vascular Endothelial Growth Factor Is Associated with Vascular Endothelial Growth Factor Plasma Levels , 2000, Journal of Vascular Research.

[8]  D. Eliott,et al.  Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. , 1997, Investigative ophthalmology & visual science.

[9]  J. Fiddes,et al.  The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. , 1991, The Journal of biological chemistry.

[10]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[11]  K. Lam,et al.  An (A-C)n dinucleotide repeat polymorphic marker at the 5' end of the aldose reductase gene is associated with early-onset diabetic retinopathy in NIDDM patients. , 1995, Diabetes.

[12]  K. Mittal.  The HLA Polymorphism and Susceptibility to Disease 1 , 1976, Vox sanguinis.

[13]  L. Aiello,et al.  Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. , 1999, Diabetes.

[14]  Joan W. Miller,et al.  Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. , 1994, American journal of ophthalmology.

[15]  H. Joensuu,et al.  Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[16]  V. Pravica,et al.  Novel polymorphisms in the promoter and 5' UTR regions of the human vascular endothelial growth factor gene. , 1999, Human immunology.

[17]  Å. Lernmark,et al.  HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM , 1996, Diabetologia.

[18]  R. Frank.  Vascular endothelial growth factor--its role in retinal vascular proliferation. , 1994, The New England journal of medicine.

[19]  M. Bottomley,et al.  Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. , 2000, Cytokine.

[20]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[21]  D. Hwang,et al.  Clinical usefulness of serum and plasma vascular endothelial growth factor in cancer patients: which is the optimal specimen? , 2000, International journal of oncology.

[22]  L. Aiello,et al.  Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. , 1994, The New England journal of medicine.

[23]  K. Donaghue,et al.  A novel polymorphism in the aldose reductase gene promoter region is strongly associated with diabetic retinopathy in adolescents with type 1 diabetes. , 1999, Diabetes.