Does familial clustering of risk factors for long-term diabetic complications leave any place for genes that act independently?

Long-term complications of type 1 diabetes, including nephropathy and retinopathy, share diabetes duration and hyperglycemia as major risk factors. Cross-sectional studies of sibpairs, both with type 1 diabetes, have shown familial clustering of specific complications, leading to the hypothesis that there are genetic contributors. However, because of the cross-sectional design of these studies, they were not able to account for the long-term effect of glycemia. Glycemia, measured by HbA1c, is correlated in sibs with type 1 diabetes. Recently, specific genetic loci that are associated with differences in HbA1c between people with type 1 diabetes have been convincingly identified, and they have also been shown to be associated with diabetic complications. This raises the question: how much of the familial clustering of diabetic complications is due to genes that influence risk without acting through the conventional risk factors? Implications for the design of genetic studies of diabetic complications are discussed.