Abstract 2646: Haptoglobin 2 Allele Associates with Symptomatic Carotid Stenosis and Major Cardiovascular Events

Abstract

Objectives: Haptoglobin (Hp) is a plasma protein which binds free hemoglobin (Hb) protecting tissues from iron-induced oxidative damage and promoting Hb clearance via macrophage CD163 receptor. There are two common alleles for Hp (Hp 1 and Hp 2), which influence it’s capacity to bind Hb and induce downstream signaling via CD163+ macrophages. We have previously shown that the CD163-heme oxygenase-1 (HO1) pathway is upregulated in symptomatic carotid stenosis (CS) and other groups have associated the Hp 2-2 genotype with cardiovascular complications in diabetics. Here, our objective was to study whether Hp polymorphism influences the risk of symptomatic CS and major cardiovascular events in the general population. Methods: We genotyped Hp polymorphism in 90 patients with a high-grade CS (≥ 70%) from Helsinki Carotid Endarterectomy Study (HeCES) and in 1426 individuals with carotid ultrasound examination data from the Health 2000 Survey, an epidemiological cross-sectional health survey carried out in Finland in the year 2000. Results: In the Health 2000 population, the Hp genotype frequencies were 0.170 (Hp 1-1), 0.445 (Hp 1-2) and 0.386 (Hp 2-2) consistent with Hardy-Weinberg equilibrium and with those reported from caucasian populations. In the CS patients, the genotype frequencies were skewed towards the Hp 2-2 genotype but not significantly. However, among the patients with symptomatic CS (ipsilateral TIA or stroke), the frequency of Hp 2-2 genotype was significantly higher than in the control population (0.528 vs 0.386, P =0.044). Hp genotypes correlated with HO1 protein expression in the plaque (r=0.46, P = 0.038) but not with iron. In the Health 2000 population, Hp 2 allele was associated with an increased risk of major cardiovascular events (major coronary heart disease event, ischemic stroke or TIA; 13.3% vs 8.3, P =0.032) and the increased risk was present regardless of diabetes. Hp 2 allele was not associated with carotid IMT or presence of plaques. Conclusions: Hp 2 allele associates with the risk of symptomatic CS and major ischemic cardiovascular events. This is likely due to the defective ability of Hp 2 to block oxidative reactions mediated by iron/heme, to clear free Hb present in intraplaque hemorrhages as well as the effects of the Hb-Hp 2 complex on intracellular signaling cascades via the CD163 receptor.