Ph.D Thesis

Ph.D StudentFarbstein Dan
SubjectPharmacogenetic Interaction between Haptoglobin Genotype
and Vitamin E Treatment on HDL Structure and
Function in the Settings of Diabetes
DepartmentDepartment of Medicine
Supervisor PROF. Andrew Peter Levy
Full Thesis textFull thesis text - English Version


Diabetes Mellitus (DM) is a risk factor for cardiovascular morbidity and mortality.

Cardiovascular disease is the leading cause of death in DM, and both macrovascular and microvascular complications are common sequalae of the disease. Vitamin E supplementation is cardioprotective to individuals with DM and Haptoglobin (Hp) 2-2 genotype, but appears to increase cardiovascular events in individuals with DM and Haptoglobin (Hp) 2-1 genotype.

In this research we attempt to examine the hypothesis that the pharmacogenetic interaction between vitamin E and Hp genotype on cardiovascular risk is secondary to the interaction between Hp genotype and vitamin E on HDL structure and function.

Methods: 79 DM paitents with Hp 1-1, Hp 2-1 or Hp 2-2 genotypes were studied in a double-blind placebo controlled crossover study. Participants were treated with vitamin E (400IU) or placebo for 3 months, and then crossed over for an equivalent duration. Serum was collected at baseline and after completion of each treatment. HDL was purified by affinity chromatography, employing a protocol developed specifically for this study.

Results: HDL function improved in Hp2-2 after vitamin E supplementation, but deteriorated in Hp2-1. The increase in HDL function in Hp2-2 was accompanied by a decrease in HDL lipid peroxides, a change not observed in Hp2-1. Labile plasma iron decreased after vitamin E supplementation in Hp2-2, but did not change in Hp2-1 patients. Nitration of ApoA1 was decreased Hp2-2 following vitamin E supplementation, but not in Hp2-1. Vitamin E also differentially modified inflammatory markers. HDL associated complement component 3 (Complement C3) was decreased in Hp2-2 following vitamin E supplementation, while it did not change in Hp 2-1. CD163 expression on monocytes was decreased in Hp2-1 following vitamin E supplementation, while in Hp2-2 vitamin E increased CD163 expression.

Conclusions: We demonstrate a pharmacogenetic interaction between vitamin E supplementation and Hp genotype on HDL structure and function in DM. Vitamin E enhances HDL function and decreases oxidative burden in Hp 2-2 patients. Hp2-1 patients present a reverse relationship such that vitamin E supplementation reduced HDL function. This is caused by the limited ability of Hp2-2 to suppress Hb related oxidative stress and protect HDL structure and function, compared to Hp2-1. The decline in HDL function

following vitamin E supplementation in Hp 2-1 patients may be attributed to excessive levels of antioxidants. It is possible that Hp2-1 patients will benefit from lower doses of vitamin E that would decrease oxidation processes.