Haptoglobin 2-2 genotype is associated with presence and progression of MRI depicted atherosclerotic intraplaque hemorrhage

Background: Atherosclerotic intraplaque hemorrhage (IPH) is a source of free hemoglobin that binds the haptoglobin protein and forms a complex cleared by CD163 macrophages. Compared to the other common haptoglobin genotypes, hemoglobin-haptoglobin2-2 complex has the lowest affinity for tissue macrophages resulting in lower rate of hemoglobin uptake and increased oxidative burden. We hypothesized that haptoglobin2-2 patients' failure to clear hemoglobin results in a greater prevalence and progression of IPH. Methods: Prevalence and volume of IPH were measured in eighty patients with advanced vascular disease using MRI. Haptoglobin was genotyped using PCR. Mixed Models Repeated Measures Analyses were performed to detect any differences in prevalence and volume of IPH between the haptoglobin genotypes. Results: Haptoglobin2-2 patients had a statistically significant higher prevalence of baseline IPH (OR = 4.34, p-value: 0.01, 95% CI: 1.31–14.35). Longitudinal analysis of 48 IPH positive carotids indicated a statistically significant progression of IPH volume over time in haptoglobin2-2 patients (Type 3 test for fixed effect p-value = 0.0106; baseline vs. year 3: β = 0.11, SE = 0.05, p-value = 0.03; year 2 vs. year 3: β = 0.05, SE = 0.02, p-value = 0.03). Conclusions: Patients with the Hp2-2 genotype had a significantly higher prevalence of carotid baseline IPH, which progressed over a two year follow up period. Detection of pre-symptomatic vascular disease using haptoglobin genotyping may allow for better risk stratification of populations at risk of stroke and in need of more targeted imaging investigations. Keywords: Vascular intraplaque hemorrhage, Biomarkers, Haptoglobin genotype, Magnetic resonance imaging, Strok