Diabetes duration may modify the association between genetic variation in the glycoprotein Ia subunit of the platelet collagen receptor and risk of severe diabetic retinopathy: a working hypothesis

Summary

Genetic factors appear to contribute to the severity and progression of diabetic retinopathy. We assessed the associations of the C807T and Glu505Lys variants of the glycoprotein Ia ( ₂ integrin) subunit of the platelet/endothelial collagen receptor and risk of retinopathy in a population-based survey of 288 diabetic patients in one Swedish community. Neither variant was associated with retinopathy risk overall. However, the 807T variant was associated with increased risk of severe retinopathy, and the association was modified by diabetes duration. Among patients with diabetes of longer duration ( 25 years), the 807T variant was strongly associated with risk of severe retinopathy (odds ratio 7.49, 95% confidence interval 1.75 to 32.1). There was no association between the 807T variant and risk of severe retinopathy among patients with diabetes duration <25 years. The Lys505 variant of glycoprotein Ia was associated with an odds ratio for severe retinopathy of 1.88 (95% confidence interval 0.83 to 4.24). Overall, there was a significant interaction between glycoprotein Ia genotype and duration of diabetes on the risk of retinopathy (P-value for interaction = 0.019).These results suggest the hypothesis that genetic variation of platelet glycoprotein Ia may play a particularly important role during the advanced stages of diabetic retinopathy.

Keywords

Glycoprotein Ia - diabetic retinopathy - type 2 diabetes - type 1 diabetes - platelet

• References

• 1 Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1984; 102: 520-6.
• 2 Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984; 102: 527-32.
• 3 Sobol AB, Watala C. The role of platelets in diabetes-related vascular complications. Diabetes Res Clin Pract 2000; 50: 1-16.
• 4 Santoro SA, Zutter MM. The α₂β₁ integrin: A collagen receptor on platelets and other cells. Thromb Haemost 1995; 74: 813-21.
• 5 Kunicki TJ, Kritzik M, Annis DS. et al. Hereditary variation in platelet integrin α₂β₁ density is associated with two silent polymorphisms in the α₂ gene coding sequence. Blood 1997; 89: 1939-43.
• 6 Roest M, Sixma JJ, Wu Y-P. et al. Platelet adhesion to collagen in healthy volunteers is influenced by variation of both α₂β₁ density and von Willebrand factor. Blood 2000; 96: 1433-7.
• 7 Kritzik M, Savage B, Nugent DJ. et al. Nucleotide polymorphisms in the α₂ gene define multiple alleles that are associated with differences in platelet α₂β₁ density. Blood 1998; 92: 2382-8.
• 8 Corral J, Rivera J, Gonzalez-Conejero R. et al. The number of platelet glycoprotein Ia molecules is associated with the genetically linked 807 C/T and HPA-5 polymorphisms. Transfusion 1999; 39: 372-8.
• 9 Santoso S, Kunicki TJ, Kroll H. et al. Association of the platelet glycoprotein Ia C₈₀₇T gene polymorphism with nonfatal myocardial infarction in younger patients. Blood 1999; 93: 2449-53.
• 10 Carlsson LE, Santoso S, Spitzer C. et al. The α₂ gene coding sequence T807/A873 of the platelet collagen receptor integrin α₂β₁ might be a genetic risk factor for the development of stroke in younger patients. Blood 1999; 93: 3583-6.
• 11 Reiner AP, Kumar PN, Schwartz SM. et al. Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke 2000; 31: 1628-33.
• 12 Reiner AP, Aramaki KM, Teramura G, Gaur L. Analysis of platelet glycoprotein Ia (α₂ in-tegrin) allele frequencies in three North American poplulations reveals genetic association between nucleotide 807C/T and amino acid 505 Glu/Lys (HPA-5) dimorphisms. Thromb Haemost 1998; 80: 449-56.
• 13 Matsubara Y, Murata M, Maruyama T. et al. Association between diabetic retinopathy and genetic variations in α₂β₁ integrin, a platelet receptor for collagen. Blood 2000; 95: 1560-4.
• 14 Tsai DH, Jiang YD, Wu KD, Tai TY, Chuang LM. Platelet collagen receptor alpha2beta1 integrin and glycoprotein IIIa Pl(A1/A2) polymorphisms are not associated with nephropathy in type 2 diabetes. Am J Kidney Dis 2001; 38: 1185-90.
• 15 Pavkovic M, Dimitrovski C, Laban-Guceva N. et al. The polymorphisms of platelet glycoprotein receptors IIIa and Ia and their relationship with diabetic retinopathy in patients with type 2 diabetes mellitus. Blood 2001; 98: 4024a.
• 16 The Diabetes Control and Complications Trial Research Group. Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes 1997; 46: 1829-39.
• 17 Early Treatment Diabetic Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report No 12. Ophthalmology 1991; 98: 823-33.
• 18 Karamanos B, Porta M, Songini M. et al. Different risk factors of microangiopathy in patients with type I diabetes mellitus of short versus long duration. The EURODIAB IDDM Complications Study. Diabetologia 2000; 43: 348-555.
• 19 Jacquelin B, Tarantino MD, Kritzik M. et al. Allele-dependent transcriptional regulation of the human integrin α₂ gene. Blood 2001; 97: 1721-6.
• 20 Vijan S, Hofer TP, Hayward RA. Cost-utility analysis of screening intervals for diabetic retinopathy in patients with type 2 diabetes mellitus. JAMA 2000; 283: 889-96.