HLA-DR3 and DR4 and their relation to the incidence and progression of diabetic retinopathy

Abstract

Purpose Cross-sectional data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy indicated that patients with HLA-DR4, but not DR3, were more likely to have prevalent proliferative retinopathy than those without both antigens. We describe the relation of HLA-DR3 and DR4 antigens to the 14-year incidence and progression of diabetic retinopathy and macular edema in this cohort. Design A population-based cohort study. Participants A probability sample of male and female patients receiving primary care for diabetes in 11 counties of southern Wisconsin. Methods Participants were invited for a baseline examination in 1980 to 1982, with follow-up examinations at 4, 10, and 14 years later. At the 4-year examination, a random sample of participants (n = 428) diagnosed with diabetes before the age of 30 and taking insulin were selected for HLA-DR typing. Main outcome measures Fourteen-year incidence and progression of diabetic retinopathy and macular edema based on masked stereoscopic fundus photographic grading. Results There was no relation between HLA-DR3 and DR4 status with the 14-year incidence and progression of diabetic retinopathy, progression to proliferative retinopathy, and incidence of macular edema. Patients with either HLA-DR3 or DR4 were less likely to progress to proliferative retinopathy compared with those who were negative for both, although these relations were not statistically significant. The associations did not vary after adjusting for hypertension status, baseline retinopathy, and glycosylated hemoglobin levels, or after stratifying by duration of diabetes (less than 10 years vs. 10 years or more) and age at diagnosis of diabetes (less than 15 years vs. 15 years or more). Furthermore, 10-year mortality and 14-year nephropathy rates did not differ by HLA-DR3 or DR4 status, suggesting that selective mortality did not explain the pattern of associations seen. Conclusions In contrast to the initial cross-sectional findings, these data suggest that HLA-DR3 or DR4 status is unrelated to 14-year incidence and progression of diabetic retinopathy. The discrepancy may be related to increasing homogeneity of retinopathy and diminishing power to detect small differences, but it may also reflect the uncertain and inconsistent effects of HLA-DR3 or DR4 on the development and progression of diabetic retinopathy.