['Genetic factors may be involved in the development, and particularly in the severity, of diabetic retinopathy (DR), in addition to chronic hyperglycaemia. Increased nitric oxide generation has been suggested to play a significant role in the pathogenesis of DR.', 'To examine whether the eNOS4 is involved in the risk of severe DR, 200 unrelated Caucasian Type 1 diabetic patients of long duration were randomly selected (M/F 103/97, age 44.4 +/- 12.4 years, diabetes duration 27.7 +/- 10.0 years, body mass index 24.3 +/- 3.4 kg/m2, HbA1c 8.6 +/- 1.3%). The eNOS4 polymorphism was analysed by polymerase chain reaction, and DR by retinal angiography and classified as presence (n = 101) or absence (n = 99) of severe (proliferative or pre-proliferative) DR.', 'The genotype distribution of eNOS4b/b (wild-type), eNOS4b/a (heterozygous) and eNOS4a/a (homozygous) was 72%, 24.5% and 3.5%, respectively. Frequency of eNOS4a/a was significantly lower in patients with severe DR (n = 0) when compared with controls (n = 7, odds ratio (OR) = 0 (95% confidence interval (CI) = 0.5-0.74), P = 0.02). eNOS4b/b was more frequent in patients with severe DR (n = 80) when compared with controls (n = 64, OR = 2.1 (95% CI = 1.1-4.12), P = 0.032). Frequency of eNOS4b/a was not different between the study (n = 21) and control groups (n = 28, ns). The allelic frequencies between the study and control groups were different (4b: n = 181 vs. n = 156, respectively, OR = 2.3 (95% CI = 1.27-4.25), P = 0.005; 4a: n = 21 vs. n = 42, respectively, OR = 0.4 (95% CI = 0.24-0.79), P = 0.005).'] Does eNOS4 polymorphism of the endothelial nitric oxide synthase predict risk for severe diabetic retinopathy?