Hypothesis--haptoglobin genotype and diabetic nephropathy.

Vascular complications cause serious morbidity in patients with diabetes mellitus. Three such complications are nephropathy, retinopathy and accelerated atherosclerotic cardiovascular disease. There is currently scant evidence of a genetic marker that predicts which patients will have vascular complications. Oxidative stress has an important role in the development of diabetic vascular complications. Haptoglobin (Hp) is a hemoglobin-binding protein that has a major role in protecting against heme-driven oxidative stress. There are two common alleles for Hp (1 and 2) and, therefore, three common Hp genotypes: Hp 1-1, Hp 2-1, and Hp 2-2. The antioxidant protection provided by Hp is genotype-dependent; the protein encoded by Hp 1-1 provides superior antioxidant protection compared with that encoded by Hp 2-2. We have shown that diabetic individuals with Hp 2-2 are more likely to develop nephropathy, retinopathy, and cardiovascular disease than those with the Hp 2-1 or Hp 1-1 genotypes.