Abstract
Research over the past 10 years in our laboratory has led to two major findings. The first is that haptoglobin (Hp) genotype can predict the risk of developing vascular complications in individuals with diabetes mellitus (DM), and the second, more far-reaching discovery, is that vitamin E treatment can significantly reduce vascular complications in individuals with DM and the Hp 2-2 genotype. The former finding has been well documented in numerous studies which included over 50,000 patients of diverse geographical and ethnic backgrounds. The latter discovery is more recent and less well accepted by the medical community due to confounding reports over the past 30 years regarding the efficacy of vitamin E treatment for vascular disease. We propose that the benefit of vitamin E treatment was not obvious in earlier studies due to the absence of any genetic basis for patient selection. Our studies dividing DM individuals into vitamin E treatment subgroups based on Hp genotype show a clear benefit for individuals of the Hp 2-2 genotype, while patients carrying the other two Hp genotypes are not affected or may be adversely affected by receiving vitamin E. These findings may explain the overall lack of benefit seen in previous vitamin E studies and emphasize the importance of carefully selecting which patients should receive vitamin E therapy. The pharmacogenomic paradigm discussed in this review potentially could result in a dramatic improvement in the health of millions of individuals worldwide using a treatment that is both accessible and affordable to all.
Highlights
Haptoglobin (Hp) was first described as a hemoglobin (Hb)-binding protein present in serum by Polonovski and Jayle in 1938 when they observed that the addition of Hb to serum resulted in an increase in the peroxidase activity of the Hb.[1]
Smithies described the separation by gel electrophoresis of Hp proteins into three distinct patterns which he attributed to a genetic polymorphism.[4]
The results showed that Hp 2-2 diabetics who received vitamin E had a 31% reduction in the composite primary end-point of myocardial infarction (MI), stroke, and cardiovascular disease (CVD) death compared to placebo controls
Summary
Haptoglobin (Hp) was first described as a hemoglobin (Hb)-binding protein present in serum by Polonovski and Jayle in 1938 when they observed that the addition of Hb to serum resulted in an increase in the peroxidase activity of the Hb.[1]. The alpha and beta chains are disulfide linked and form the Hp monomer. The most significant consequence of the duplication event which led to the formation of the Hp 2 allele is the addition of a cysteine residue in the alpha-2 chain. This cysteine participates in the formation of disulfide linkage between two Hp monomers. Each Hp 2 monomer has the ability to form two intermolecular disulfide bonds This single feature leads to a profound difference in polymeric structure. Hp 2-2 individuals have yet a different arrangement in that the Hp 2 monomers form cyclic polymers containing an average of four Hp 2 subunits (Figure 2)
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