Renin-Angiotensin System Gene Polymorphisms and Retinopathy in Chinese Patients With Type 2 Diabetes

Diabetic eye disease is the leading cause of new cases of blindness in many developed countries, for which macular edema and proliferative retinopathy are major causes of loss of vision (1). Genetic studies have previously suggested that diabetic retinopathy is partly determined by genetic factors (2). Angiotensin II, produced locally within the retina, has potent hemodynamic and growth-promoting effects and stimulates ocular neovascularization (3,4). The presence of retinopathy is associated with an activated renin-angiotensin system (RAS) (5), and inhibition of the RAS significantly reduced the progression of retinopathy in nonhypertensive patients with type 1 diabetes (6). The ACE gene insertion/deletion (I/D) polymorphism has been reported to be associated with retinopathy in type 1 diabetic subjects, but the findings are heterogeneous (7,8). Only limited data are available describing the angiotensinogen (AGT) M235T and the angiotensin II type 1 receptor (AT₁R) A1166C polymorphisms and retinopathy (9,10).

In this study, we examined the associations between these three polymorphisms and diabetic retinopathy in 827 Chinese type 2 diabetic patients (based on 1985 World Health Organization criteria). All subjects gave written informed consent and were of Han Chinese origin. They were examined by the physicians or ophthalmologists through dilated pupils. Retinopathy was considered to be present if there was one or more areas of hemorrhages, microaneurysms, cotton wool spots, and/or laser coagulation scars related to diabetic retinopathy or history of vitrectomy (11). The RAS genotype and allele frequencies were identified using PCR/restriction fragment-length polymorphism protocols (12) in 326 patients with retinopathy and 501 diabetic patients without retinopathy who were matched for age (59.8 ± 11.4 vs. 60.4 ± 9.3 years), sex (44.2 female vs. 39.3% male), disease duration (6.3 [range 5.6–7.0] vs. 6.0 years [5.6–6.3]), and age of onset of diabetes (53.2 ± 9.7 vs. 51.9 ± 12.4 years). Of those with retinopathy, 66.6% had nonproliferative, 8.3% preproliferative, and 8.9% proliferative disease and 16.2% had advanced eye disease. Of the patients, 30.1% with retinopathy had received laser therapy in at least one eye, with 18.7, 29.2, 53.8, and 69.4% being treated in the groups with increasing severity of retinopathy.

The allele frequencies were 32.7 and 32.1% for the ACE D allele, 16.1 and 13.8% for the AGT M allele, and 4.6 and 3.4% for the AT₁R C allele in those without and with retinopathy, respectively. The genotype distributions for these gene polymorphisms are described in Table 1. No differences were identified in the genotype or allele frequencies between the groups either for the dichotomous classification of retinopathy or when the severity of the retinopathy was graded.

The ACE D allele has been associated with increasing ACE levels (12). Subjects with the angiotensinogen M235T polymorphism TT genotype have increased serum AGT levels, while the AT₁R 1166C allele is associated with enhanced responsiveness to angiotensin II (13). The ACE DD genotype was found to be associated with the presence of proliferative retinopathy in a relatively small case-control study of type 1 diabetic subjects (7). In the current study, the analysis comparing age-, sex-, and diabetes duration-matched subjects found no evidence of associations between the distribution of genotypes or alleles of these RAS gene polymorphisms and retinopathy. Our data support the majority of the literature regarding the ACE I/D gene polymorphism, which has reported no significant association with retinopathy in diabetic patients (7,8).