Pharmacogenomic interaction between the Haptoglobin genotype and vitamin E on atherosclerotic plaque progression and stability

Abstract

Structured Abstract Objective Homozygosity for a 1.7kb intragenic duplication of the Haptoglobin (Hp) gene (Hp 2-2 genotype), present in 36% of the population, has been associated with a 2–3 fold increased incidence of atherothrombosis in individuals with Diabetes (DM) in 10 longitudinal studies compared to DM individuals not homozygous for this duplication (Hp 1-1/2-1). The increased CVD risk associated with the Hp 2-2 genotype has been shown to be prevented with vitamin E supplementation in man. We sought to determine if there was an interaction between the Hp genotype and vitamin E on atherosclerotic plaque growth and stability in a transgenic model of the Hp polymorphism. Methods and Results Brachiocephalic artery atherosclerotic plaque volume was serially assessed by high resolution ultrasound in 28 Hp 1-1 and 26 Hp 2-2 mice in a C57Bl/6 ApoE−/− background. Hp 2-2 mice had more rapid plaque growth and an increased incidence of plaque hemorrhage and rupture. Vitamin E significantly reduced plaque growth in Hp 2-2 but not in Hp 1-1 mice with a significant pharmacogenomic interaction between the Hp genotype and vitamin E on plaque growth. Conclusions These results may help explain why vitamin E supplementation in man can prevent CVD in Hp 2-2 DM but not in non Hp 2-2 DM individuals.

Role of Haptoglobin in Health and Disease: A Focus on Diabetes

“…Although the risk is higher for those with Hp2-2, there are several ways to reduce this risk back to baseline cardiovascular risk for patients with diabetes. The administration of exogenous antioxidants such as vitamin C and vitamin E can mitigate the deleterious effects of an Hp2-2 genotype ( 12 , 134 , 143 , 148 , 149 ). Thus, it is crucial for the research and diagnostic community to develop new methods of identifying patient genotype and advancing therapeutics for the treatment of people with diabetes who have the Hp2 polymorphism.…”

“…A rapid test can be employed to initiate a therapy such as vitamin E or vitamin C to minimize the progression of CVD by as much as 30–40% ( 143 ). Initiation of 400 IU of vitamin E has been shown effective in reducing cardiovascular events ( 12 , 144 ).…”

Nature-Inspired Bioactive Compounds: A Promising Approach for Ferroptosis-Linked Human Diseases?

“…Early studies showed that selenium supplementation, a co-factor for GPx4 activity, can stop the development of atherosclerosis plaques and reduce lesions in animal models [ 136 , 137 , 138 ]. Furthermore, ferroptosis inhibitors, such as Fer-1, DFO, and vitamin E, can prevent atherosclerosis [ 139 , 140 ]. Indeed, Bai et al showed that Fer-1 inhibits lipid peroxidation and iron accumulation and induces GPx4 overexpression as well as GSH production in an atherosclerosis mice model [ 12 ].…”

Ferroptosis: the potential value target in atherosclerosis

“…The below aspects deserve further research. Firstly, vitamin (Vit) E inhibits ferroptosis [106], and Vit E has been shown to increase antioxidant resistance in vitro and prevent atherosclerotic plaque formation [107], but a 4.5-year follow-up found no significant difference in the risk of cardiovascular events in patients with or without Vit E supplementation [108][109][110]. However, it is worth studying whether Vit E affects AS through ferroptosis.…”