Pharmacogenomic Application Of The Haptoglobin Genotype In The Prevention Of Diabetic Nephropathy

Objective. To determine if there exists a pharmacogenomic interaction between the Hp genotype and antioxidant administration on the development of Diabetic Nephropathy (DN). Introduction : A common functional allelic polymorphism in the Haptoglobin (Hp) gene has been demonstrated to be a major determinant of susceptibility to cardiovascular disease and in the progression of renal disease in individuals with Diabetes Mellitus in multiple independent longitudinal studies. In vitro studies have demonstrated that the protein product associated with the disease causing Hp 2 allele is defective in its ability to protect against oxidative stress mediated by extracorpuscular hemoglobin. We have recently demonstrated in man that vitamin E selectively provides cardiovascular protection to Hp 2–2 individuals and not to individuals without the Hp 2–2 genotype. Whether such a pharmacogenomic interaction also exists for DN is not known. Methods : Wild type C57Bl/6 mice have only an Hp 1 allele. The Hp 2 allele is found only in man. We genetically engineered a murine Hp 2 allele and inserted it in the murine Hp locus by homologous recombination. We assessed morphometric, histologic, and functional parameters involved in the development and progression of DN in DM mice with either the Hp 1–1 or Hp 2–2 genotype and the modulation of these parameters by vitamin E. Results : Morphometric analysis demonstrated that glomerular and proximal tubular hypertrophy were significantly increased in Hp 2–2 DM mice. Histological analysis demonstrated that Hp 2–2 DM mice had significantly more collagen type IV, smooth muscle actin, and increased renal iron deposition. Studies of renal function demonstrated creatinine clearance time and albuminuria were increased in Hp 2–2 DM mice. Vitamin E provided significant protection against the development of functional and histological features characteristic of DN to Hp 2–2 DM but not to Hp 1–1 DM mice. Conclusions : These studies serve to strengthen the association between the Hp 2–2 genotype and DN and suggest a pharmacogenomic interaction may exist between the Hp genotype and vitamin E on the prevention of DN.