Genetics of redox systems and their relationship with cardiovascular disease

Abstract

As atherosclerosis is still one of the major causes of death in Western populations, it is important to identify those individuals who are at increased risk for the disease so that aggressive treatment may be administered as early as possible. Following the understanding that oxidative stress has a pivotal role in the development and progression of atherosclerosis, many polymorphisms in genes that are related to redox systems were examined for their association with increased risk for cardiovascular disease (CVD). Although many polymorphisms were studied, only a handful showed consistent relevance to CVD in different trials. This article focuses on six of these polymorphisms, examining their effect on the risk for CVD as well as their effect on protein expression and function. Reports regarding pharmacogenetic implications of these polymorphisms, where such exist, are discussed as well.

Fig. 1

The interaction between haptoglobin (Hp) genotype and diabetes mellitus (DM) leading to high-density lipoprotein (HDL) dysfunction. Hemoglobin (Hb) released intravascularly from red blood cells (RBC) is rapidly bound by Hp protein to form an Hp-Hb complex. In Hp 2–2 diabetic individuals, the complex is cleared more slowly than in Hp 1–1 diabetic individuals by the scavenger receptor CD163. The Hp-Hb complex can bind to apolipoprotein A1 (ApoA1) in HDL, with increased binding of Hp 2-2–Hb occurring due its increased affinity for HDL and its increased plasma concentration. The Hp 2-2–Hb complex, but not the Hp 1-1–Hb complex, when bound to HDL can produce reactive oxygen species that can oxidize protein (eg, ApoA1, glutathione peroxidase [GPx], and lecithin: cholesterol acyl transferase [LCAT]) and lipid components (cholesterol [Chol]) of HDL and render the HDL dysfunctional (because of decreased reversed cholesterol transport [RCT] and antioxidant activity), pro-atherogenic, and pro-thrombotic. Antioxid—antioxidant; Para—paraoxynase. (From Asleh et al. [73]. Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2–2 genotype. Diabetes 2008;57:2794–800)